Recurrence-free Survival Benefit Research Articles

MRI-based prediction of microvascular invasion/high tumor grade and adjuvant therapy benefit for solitary HCC ≤ 5 cm: a multicenter cohort study.

To develop and externally validate an MRI-based diagnostic model for microvascular invasion (MVI) or Edmondson-Steiner G3/4 (i.e., high-risk histopathology) in solitary BCLC 0/A hepatocellular carcinoma (HCC) ≤ 5 cm and to assess its performance in predicting adjuvant therapy benefits. This multicenter retrospective cohort study included 577 consecutive adult patients who underwent contrast-enhanced MRI and subsequent curative resection or ablation for solitary BCLC 0/A HCC ≤ 5 cm (December 2011 to January 2024) from four hospitals. For resection-treated patients, a diagnostic model integrating clinical and 50 semantic MRI features was developed against pathology with logistic regression analyses on the training set (center 1) and externally validated on the testing dataset (centers 2-4), with its utilities in predicting posttreatment recurrence-free survival (RFS) and adjuvant therapy benefit evaluated by Cox regression analyses. Serum α-fetoprotein > 100 ng/mL (odds ratio (OR), 1.94; p = 0.006), non-simple nodular growth subtype (OR, 1.69; p = 0.03), and the VICT2 trait (OR, 4.49; p < 0.001) were included in the MVI or high-grade (MHG) trait, with testing set AUC, sensitivity, and specificity of 0.832, 74.0%, and 82.5%, respectively. In the multivariable Cox analysis, the MHG-positive status was associated with worse RFS (resection testing set HR, 3.55, p = 0.02; ablation HR, 3.45, p < 0.001), and adjuvant therapy was associated with improved RFS only for the MHG-positive patients (resection HR, 0.39, p < 0.001; ablation HR, 0.30, p = 0.005). The MHG trait effectively predicted high-risk histopathology, RFS and adjuvant therapy benefit among patients receiving curative resection or ablation for solitary BCLC 0/A HCC ≤ 5 cm. Question Despite being associated with increased recurrence and potential benefit from adjuvancy in HCC, microvascular invasion or Edmondson-Steiner grade 3/4 are hardly assessable noninvasively. Findings We developed and externally validated an MRI-based model for predicting high-risk histopathology, post-resection/ablation recurrence-free survival, and adjuvant therapy benefit in solitary HCC ≤ 5 cm. Clinical relevance Among patients receiving curative-intent resection or ablation for solitary HCC ≤ 5 cm, noninvasive identification of high-risk histopathology (MVI or high-grade) using our proposed MRI model may help improve individualized prognostication and patient selection for adjuvant therapies.

Adjuvant camrelizumab plus apatinib in resected hepatocellular carcinoma with microvascular invasion: a multi-center real world study.

Hepatocellular carcinoma (HCC) treatment currently lacks adjuvant therapy with a high level of supporting evidence to reduce recurrence after hepatectomy. This study aimed to assess the safety and efficacy of camrelizumab plus apatinib in the adjuvant therapy of patients with HCC with microvascular invasion (MVI). Data were retrospectively collected on consecutive patients with HCC who underwent radical resection and were diagnosed with MVI-positive tumors between October 2019 and June 2022 at four centers. The association between adjuvant therapy and prognosis [recurrence-free survival (RFS), overall survival (OS)] was evaluated by propensity score matching (PSM), the log-rank test, Cox regression analysis, and subgroup analysis. Furthermore, grade 3 or 4 treatment-related adverse events (TRAEs) of adjuvant therapy were reported. Among the 111 patients in the adjuvant therapy group and 276 patients in the observation group at enrolment, there were 99 and 172 in the adjuvant therapy and observation groups after PSM, respectively. RFS was better in the adjuvant therapy group [hazard ratio (HR) 0.52; 95% confidence interval (CI): 0.39 to 0.69; P<0.001], whereas OS was not (HR 0.62; 95% CI: 0.39 to 0.99; P=0.079). These results were confirmed after PSM. Subgroup analyses were generally consistent in favour of adjuvant camrelizumab plus apatinib with better RFS. Grade 3 or 4 TRAEs accounted for 20.7% during adjuvant therapy; the most common TRAEs included hypertension and proteinuria. Postoperative adjuvant camrelizumab plus apatinib significantly improved the RFS benefits with acceptable toxicities in patients with HCC with MVI.

TP53 signature predicts pathological complete response after neoadjuvant chemotherapy for breast cancer: Observational and confirmational study using prospective study cohorts

The TP53 signature is considered a predictor of neoadjuvant chemotherapy (NAC) response and prognostic factor in breast cancer. The objective of this study was to confirm TP53 signature can predict pathological complete response (pCR) and prognosis in cohorts of breast cancer patients who received NAC in prospective studies.Development cohorts (retrospective [n = 37] and prospective [n = 216] cohorts) and validation cohorts (NAC administered prospective study cohorts [n = 407] and retrospective perioperative chemotherapy (PC)-naïve, hormone receptor (HrR)-positive cohort [PC-naïve_HrR+ cohort] [n = 322]) were used. TP53 signature diagnosis kit was developed using the development cohorts. TP53 signature predictability for pCR and the relationship between recurrence-free survival (RFS), overall survival (OS), and the TP53 signature were analyzed.The pCR rate of the mutant (mt) signature group was significantly higher than that of the wild-type (wt) signature group (odds ratio, 5.599; 95 % confidence interval = 1.876–16.705; P = 0.0008). The comparison of the RFS and OS between the HrR+ and HER2− subgroup of the NAC cohort and of the PC-naïve_HrR+ cohort indicated that the RFS and OS benefit of NAC was greater in the mt signature group than in the wt signature group. From post hoc analyses, the RFS and OS benefit from adding capecitabine to FEC+T as NAC might be observed only in the mt signature group.The TP53 signature can predict the pCR after NAC, and the RFS and OS benefit from NAC may be greater in the mt signature group than in the wt signature group.

Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab in resected melanoma: 3-year update from the mRNA-4157-P201 (KEYNOTE-942) trial.

LBA9512 Background: mRNA-4157 is a novel, mRNA-based individualized neoantigen therapy designed to increase endogenous antitumor T-cell responses by targeting unique patient (pt) tumor mutations. In the primary analysis of the Ph 2 mRNA-4157-P201 (KEYNOTE-942) trial (median planned follow-up, 23 mo), pts with completely resected high-risk stage IIIB–IV cutaneous melanoma receiving mRNA-4157 + pembrolizumab (pembro; combo) had prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) vs pembro alone (Weber JS, et al. Lancet. 2024). Methods: Pts were assigned 2:1 to mRNA-4157 (1 mg IM, max 9 doses) + pembro (200 mg IV, max 18 cycles) or pembro alone. The primary endpoint was investigator-assessed RFS; secondary endpoints were DMFS and safety. This planned supportive analysis was triggered when the last randomized pt had ≥2 y follow-up. Translational subgroup analyses were also reported. HLA genotypes were analyzed by exome sequencing of DNA from PBMC. RFS and DMFS were not formally tested; nominal 2-sided p-values are descriptive. Results: With an additional year follow-up (data cutoff, 03 Nov 2023; median [range], 34.9 [25.1–51.0] mo) after primary analysis, minimal new events occurred. RFS benefit in the combo vs pembro arm was maintained with 49% risk reduction in recurrence and/or death (HR [95% CI], 0.510 [0.288–0.906]; 2-sided nominal p-value 0.019). The 2.5-yr RFS rate of combo treatment (tx) vs pembro alone was 74.8% vs 55.6%. Combo tx also produced clinically meaningful, sustained improvement in DMFS vs pembro alone (HR [95% CI], 0.384 [0.172–0.858], 2-sided nominal p-value 0.0154). OS favored combo vs pembro alone; 2.5-y OS rate was 96.0% vs 90.2% (HR [95% CI], 0.425 [0.114–1.584]). RFS benefit of combo vs pembro was maintained in TMB high (HR [95% CI], 0.564 [0.253–1.258]), TMB non-high (0.571 [0.245–1.331]), PD-L1 positive (0.471 [0.226–0.979]), PD-L1 negative (0.147 [0.034–0.630]), and ctDNA negative (0.207 [0.091–0.470]) subgroups; ctDNA positive HR was not estimable. No significant associations between individual HLA alleles and RFS were observed in either tx arm. Maximal heterozygosity at HLA class I genotype loci (A, B, C) improved RFS vs homozygosity for ≥1 locus in the pembro arm (HR [95% CI], 0.425 [0.179–1.01]) but not combo arm (1.252 [0.498–3.146]). mRNA-4157 was well tolerated and combo tx had a safety profile consistent with previous analysis with no potentiation of immune-related AEs. Conclusions: The current analysis with ∼3 y median follow-up showed durable and meaningful long-term RFS and DMFS benefit with mRNA-4157 + pembro vs pembro alone. A trend for improved OS with combo tx was also observed. HLA and translational subgroup results suggest mRNA-4157 + pembro may benefit a broader pt population vs pembro alone. Clinical trial information: NCT03897881 .

The efficacy and safety study of thymosin α1 combined with PD-1 antibodies as adjuvant therapy in patients with hepatocellular carcinoma with high-risk recurrence factors after radical resection.

e16226 Background: Anti-PD-1 immunotherapy has revolutionized unresectable hepatocellular carcinoma (HCC) treatment. The efficacy of postoperative adjuvant therapy (PAT) using anti-PD-1 in treating HCC is currently the subject of extensive research. This study explored the efficacy and safety of anti-PD-1 antibodies combined with thymosin alpha-1 (Tα1) for patients with HCC and high-risk recurrent factors (HRRFs) post-hepatectomy. Methods: Data from 273 patients with HCC and HRRFs who underwent hepatectomy at Tongji Hospital (January 2019 to July 2022) were prospectively collected. Patients were nonrandomly divided into Tα1+ anti-PD-1 antibodies (65, 23.8%), anti-PD-1 antibodies (84, 30.8%), and control (no adjuvant therapy, 124, 45.4%) groups based on finances and willingness. After propensity score matching (PSM), recurrence-free survival (RFS) and overall survival (OS) were compared. Cox regression analysis identified the RFS- and OS-related prognostic factors, followed by subgroup analysis. Results: After PSM, 65 patients were matched. The anti-PD-1 antibodies + Tα1 group exhibited longer RFS than the anti-PD-1 antibodies (P = 0.014) and control (P &lt; 0.0001) groups. The anti-PD-1 antibodies group had longer RFS than the control group (P &lt; 0.0001). The anti-PD-1 antibodies + Tα1 (P = 0.00049) and anti-PD-1 antibodies groups (P = 0.0041) demonstrated longer OS than the control group. The 1- and 2-year RFS rates in the Tα1 + anti-PD-1 antibodies, anti-PD-1 antibodies, and control groups were 98.4%, 86.2%, and 49.2% (P &lt; 0.001), and 80.2%, 65.8%, and 24.6% (P &lt; 0.001), respectively. The corresponding 1-, 2-, and 3-year OS rates were 100.0%, 100.0%, and 84.6% (P &lt; 0.001), 98.0%, 91.4%, and 69.0% (P &lt; 0.001), and 91.3%, 86.8%, and 57.4% (P &lt; 0.001), respectively. Multivariable analyses suggested that the Tα1 + anti-PD-1 antibodies treatment improved the RFS and OS more than the non-anti-PD-1 antibodies + Tα1 treatment (hazard ratio (HR): 0.174, 95% confidence intervals (CI): 0.089–0.340, P &lt; 0.001 and HR: 0.240, 95% CI: 0.084–0.683, P = 0.008, respectively). Subgroup analysis demonstrated significant RFS and OS benefits for patients with HCC and vascular invasion treated with Tα1 + anti-PD-1 antibodies. Grade 1 and 2 toxicities included rash/pruritus (21.5%), diarrhea (18.5%), and reactive cutaneous capillary endothelial proliferation (RCCEP)(15.4%). Grade 3 toxicities included RCCEP (1.5%), diarrhea (1.5%), rash/pruritus (0.8%), edema (0.8%), hepatitis (0.8%), nausea/vomiting (0.8%), and hypothyroidism (0.8%). No grade 4/5 toxicities or severe adverse events were detected. Conclusions: Combining anti-PD-1 antibodies with Tα1 as adjuvant therapy is safe, improving postoperative prognosis in patients with HCC and HRRFs after hepatectomy, proving more effective than anti-PD-1 antibodies alone.

Interferon-gamma signature as prognostic and predictive marker in macroscopic stage III melanoma

BackgroundA substantial proportion of patients with macroscopic stage III melanoma do not benefit sufficiently from adjuvant anti-PD-1 therapy, as they either recur despite therapy or would never have recurred. To...

Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma.

Liver cancer, specifically hepatocellular carcinoma (HCC), is the sixth most common cancer and the third leading cause of cancer mortality worldwide. The development of effective systemic therapies, particularly those involving immune-checkpoint inhibitors (ICIs), has substantially improved the outcomes of patients with advanced-stage HCC. Approximately 30% of patients are diagnosed with earlystage disease andcurrently receive potentially curative therapies, such as resection, liver transplantation or local ablation, which result in median overall survival durations beyond 60 months. Nonetheless, up to 70% of these patients will have disease recurrence within 5 years of resection or local ablation. To date, the results of randomized clinical trials testing adjuvant therapy in patients with HCC have been negative. This major unmet need has been addressed with the IMbrave 050 trial, demonstrating a recurrence-free survival benefit in patients with a high risk of relapse after resection or local ablation who received adjuvant atezolizumab plus bevacizumab. In parallel, studies testing neoadjuvant ICIs alone or in combination in patients with earlystage disease have also reported efficacy. In this Review, we provide a comprehensive overview of the current approaches to manage patients with earlystage HCC. We also describe the tumour immune microenvironment and the mechanisms of action of ICIs and cancer vaccines in this setting. Finally, we summarize the available evidence from phase II/III trials of neoadjuvant and adjuvant approaches and discuss emerging clinical trials, identification of biomarkers and clinical trial design considerations for future studies.

Adjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial

Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88−1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73−2.38; p = 0.44). Grade 3−4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p < 0.001). In conclusion, while adjuvant nDC treatment in stage IIIB/C melanoma patients generated specific immune responses and was well tolerated, no benefit in RFS was observed.

Anti-HER2 therapy response assessment for guiding treatment (de-)escalation in early HER2-positive breast cancer using a novel deep learning radiomics model

ObjectivesAnti-HER2 targeted therapy significantly reduces risk of relapse in HER2 + breast cancer. New measures are needed for a precise risk stratification to guide (de-)escalation of anti-HER2 strategy.MethodsA total of 726 HER2 + cases who received no/single/dual anti-HER2 targeted therapies were split into three respective cohorts. A deep learning model (DeepTEPP) based on preoperative breast magnetic resonance (MR) was developed. Patients were scored and categorized into low-, moderate-, and high-risk groups. Recurrence-free survival (RFS) was compared in patients with different risk groups according to the anti-HER2 treatment they received, to validate the value of DeepTEPP in predicting treatment efficacy and guiding anti-HER2 strategy.ResultsDeepTEPP was capable of risk stratification and guiding anti-HER2 treatment strategy: DeepTEPP-Low patients (60.5%) did not derive significant RFS benefit from trastuzumab (p = 0.144), proposing an anti-HER2 de-escalation. DeepTEPP-Moderate patients (19.8%) significantly benefited from trastuzumab (p = 0.048), but did not obtain additional improvements from pertuzumab (p = 0.125). DeepTEPP-High patients (19.7%) significantly benefited from dual HER2 blockade (p = 0.045), suggesting an anti-HER2 escalation.ConclusionsDeepTEPP represents a pioneering MR-based deep learning model that enables the non-invasive prediction of adjuvant anti-HER2 effectiveness, thereby providing valuable guidance for anti-HER2 (de-)escalation strategies. DeepTEPP provides an important reference for choosing the appropriate individualized treatment in HER2 + breast cancer patients, warranting prospective validation.Clinical relevance statementWe built an MR-based deep learning model DeepTEPP, which enables the non-invasive prediction of adjuvant anti-HER2 effectiveness, thus guiding anti-HER2 (de-)escalation strategies in early HER2-positive breast cancer patients.Key Points• DeepTEPP is able to predict anti-HER2 effectiveness and to guide treatment (de-)escalation.• DeepTEPP demonstrated an impressive prognostic efficacy for recurrence-free survival and overall survival.• To our knowledge, this is one of the very few, also the largest study to test the efficacy of a deep learning model extracted from breast MR images on HER2-positive breast cancer survival and anti-HER2 therapy effectiveness prediction.

Pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: Final analysis of distant metastasis-free survival in the phase 3 KEYNOTE-716 study.

LBA9505 Background: Adjuvant pembrolizumab significantly improved distant metastasis-free survival (DMFS) and recurrence-free survival (RFS) in patients with resected stage IIB or IIC melanoma versus placebo. We present the protocol-specified final DMFS analysis from KEYNOTE-716 (NCT03553836). Methods: Eligible patients were ≥12 years old with resected stage IIB or IIC cutaneous melanoma per American Joint Committee on Cancer, 8th edition, guidelines and a negative sentinel lymph node biopsy. In part 1 of the study, patients were randomly assigned (1:1) to pembrolizumab 200 mg (2 mg/kg up to 200 mg for pediatric patients) or placebo every 3 weeks for up to 17 cycles (~1 year) or until disease recurrence, unacceptable toxicity, or withdrawal. Randomization was stratified by T category for adults (T3b vs T4a vs T4b), with a separate stratum for pediatric patients. The primary end point was RFS per investigator review. DMFS per investigator review was a secondary end point. The protocol-specified final DMFS analysis was based on a target of 195 DMFS events. No formal hypothesis testing was performed because DMFS and RFS end points were met at previous interim analyses. The data cutoff date for this analysis was January 4, 2023. Results: Overall, 976 patients were randomly assigned to receive pembrolizumab (n = 487) or placebo (n = 489). Median duration of follow-up (time from randomization to the data cutoff date) was 39.4 months (range, 26.0-51.4). Compared with placebo, adjuvant pembrolizumab improved DMFS (medians: not reached; hazard ratio [HR], 0.59 [95% CI, 0.44-0.79]) and RFS (medians: not reached; HR, 0.62 [95% CI, 0.49-0.79]). The 36-month DMFS rate was 84.4% with adjuvant pembrolizumab versus 74.7% with placebo; the 36-month RFS rate was 76.2% with adjuvant pembrolizumab versus 63.4% with placebo. DMFS benefit with adjuvant pembrolizumab over placebo was observed regardless of cancer stage at baseline (stage IIB HR, 0.62 [95% CI, 0.42-0.92]; stage IIC HR, 0.57 [0.36-0.88]). Similar results were observed with RFS (stage IIB HR, 0.58 [95% CI, 0.43-0.79]; stage IIC HR, 0.65 [95% CI, 0.45-0.94]). No new safety signals were observed. Conclusions: With a median follow-up of 39.4 months, adjuvant pembrolizumab for resected stage IIB and IIC melanoma continued to show DMFS and RFS benefit over placebo, with no new safety signals. Clinical trial information: NCT03553836 .

Abstract CT224: mRNA-4157, a personalized cancer vaccine, in combination with pembrolizumab, demonstrates trend for improved recurrence free survival compared to pembrolizumab alone in adjuvant melanoma patients across tumor mutational burden subgroups

Abstract Background: The open-label randomized Phase 2 mRNA-4157-P201/Keynote-942 trial met its primary endpoint of prolonged recurrence free survival (RFS) in patients with resected high-risk stage III/IV melanoma. Tumor immunogenicity provides a favorable landscape for inflammatory processes associated with clinical benefit to checkpoint inhibitors (ICI) and tumor mutational burden (TMB) has been shown to be an independent predictor of treatment outcomes in patients treated with ICI therapy. mRNA-4157 is a novel mRNA-based personalized cancer vaccine which encodes up to 34 patient-specific tumor neoantigens. Here we report analyses of baseline biopsies from the trial to explore the novel mechanism of action hypothesized to augment endogenous anti-tumor responses and generate immunity to additional tumor neoantigens. Methods: Paraffin-embedded formalin-fixed baseline tumor core biopsies underwent whole exome sequencing (WES) and whole transcriptome sequencing. According to the established WES genomic score for pembrolizumab, the TMB high threshold utilized for analysis was 175/exome (10 mutations/megabase per F1CDx). The distribution of TMB expression in baseline tumor samples across study arms and their association with the primary RFS endpoint was evaluated. The association with RFS of other markers of inflamed tumors, including those established for pembrolizumab (e.g. gene expression profile (GEP) and PD-L1 expression) was also assessed. Results: The RFS benefit of mRNA-4157 and pembrolizumab combination compared to pembrolizumab monotherapy observed in the intention-to-treat population was maintained with a similar treatment effect magnitude across both high (HR = 0.65; 95% CI: 0.3, 1.5) and low (HR = 0.59; 95% CI: 0.3,1.4) TMB subpopulations. In line with observations from historical data for pembrolizumab, improved RFS was observed in high TMB compared to low TMB patient subgroups in the pembrolizumab monotherapy arm. The trend for increased RFS benefit in the high TMB subpopulation was maintained in the mRNA-4157 and pembrolizumab study arm. Additional subgroup analyses (e.g. GEP and PD-L1) were assessed and will be discussed. Conclusions: Our results indicate that mRNA-4157 demonstrates improvements in RFS irrespective of TMB status when administered in combination with pembrolizumab compared to pembrolizumab monotherapy in patients with resected high-risk cutaneous melanoma. The novel mechanism of action of mRNA-4157 may both deepen the activity of pembrolizumab and broaden the population of patients that can benefit from immune therapy. The association between TMB and mRNA-4157 treatment effect will be further explored in upcoming planned studies. Citation Format: Ryan J. Sullivan, Matteo Carlino, Jeffrey S. Weber, Tarek Meniawy, Matthew H. Taylor, Kevin Kim, Meredith McKean, Georgiana V. Long, Mark Faries, C. Lance Cowey, Andrew Pecora, Geoffrey T. Gibney, Jason Luke, Sajeve Thomas, Vasudha Sehgal, Igor Feldman, Praveen Aanur, Michelle Brown, Robert S. Meehan, Celine Robert-Tissot, Adnan Khattak. mRNA-4157, a personalized cancer vaccine, in combination with pembrolizumab, demonstrates trend for improved recurrence free survival compared to pembrolizumab alone in adjuvant melanoma patients across tumor mutational burden subgroups [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT224.

MP63-03 EFFICACY AND SAFETY OF a NOVEL 450 NM BLUE DIODE LASER VERSUS PLASMAKINETIC ELECTROCAUTERY FOR THE TRANSURETHRAL RESECTION OF NON-MUSCLE INVASIVE BLADDER CANCER: THE PROTOCOL AND RESULT OF a MULTICENTRE RANDOMIZED CONTROLLED TRIAL

You have accessJournal of UrologyCME1 Apr 2023MP63-03 EFFICACY AND SAFETY OF a NOVEL 450 NM BLUE DIODE LASER VERSUS PLASMAKINETIC ELECTROCAUTERY FOR THE TRANSURETHRAL RESECTION OF NON-MUSCLE INVASIVE BLADDER CANCER: THE PROTOCOL AND RESULT OF a MULTICENTRE RANDOMIZED CONTROLLED TRIAL Kaijie Wu, Lianhua Zhang, Shuai Jiang, Tianhai Lin, YI Luo, and Dalin He Kaijie WuKaijie Wu More articles by this author , Lianhua ZhangLianhua Zhang More articles by this author , Shuai JiangShuai Jiang More articles by this author , Tianhai LinTianhai Lin More articles by this author , YI LuoYI Luo More articles by this author , and Dalin HeDalin He More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003321.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To be the first to apply a novel 450 nm blue diode laser in transurethral resection of bladder tumour (TURBt) to treat patients with non-muscle invasive bladder cancer (NMIBC) and evaluate its efficacy and safety during the preoperative period compared to the conventional plasmakinetic electrocautery. METHODS: Randomized controlled trials (RCTs) in five medical centres were conducted from October 2018 to December 2019. Patients with NMIBC were randomized to the blue laser or plasmakinetic electrocautery group for TURBt. As the first study to evaluate this novel blue laser device, the primary outcome was the effective resection rate of bladder tumours, including effective dissection and haemostasis. The secondary outcomes were the perioperative records, including operation time, postoperative indwelling catheter time, hospital stay length, blood loss, reoperation rate, wound healing and adverse events. RESULTS: A total of 174 patients were randomized to either the blue laser group (85 patients) or plasmakinetic electrocautery group (89 patients). There was no statistical significance in the clinical features of bladder tumours, including tumour site, number and maximum lesion size. Both the blue laser and plasmakinetic electrocautery could effectively dissect all visible bladder tumours. The operation time for patients in the blue laser group was longer (p=0.001), but their blood loss was less than that of patients in the control group (p=0.003). There were no differences in the postoperative indwelling catheter time, hospital stay length, reoperation rate or other adverse events. However, the patients undergoing TURBt with the blue laser showed a faster wound healing at 3 months after operation. CONCLUSIONS: The novel blue laser could be effectively and safely used for TURBt in patients with NMIBC, and this method was not inferior to plasmakinetic electrocautery during the perioperative period. However, TURBt with the blue laser may provide the benefit to reduce preoperative blood loss and accelerate postoperative wound healing. Moreover, longer follow-up to confirm recurrence-free survival benefit was required. Source of Funding: This study was fifinancially supported by the National Key Research and Development Program (2019YFC0121501) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e871 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kaijie Wu More articles by this author Lianhua Zhang More articles by this author Shuai Jiang More articles by this author Tianhai Lin More articles by this author YI Luo More articles by this author Dalin He More articles by this author Expand All Advertisement PDF downloadLoading ...

MP14-16 LATE CELL CYCLE SIGNATURES STRATIFY GEMDOCE RESPONSES FOR BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 Apr 2023MP14-16 LATE CELL CYCLE SIGNATURES STRATIFY GEMDOCE RESPONSES FOR BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER Andrew Gabrielson, Gabriel Epstein, Mingxiao Feng, Sunil Patel, Max Kates, and Woonyoung Choi Andrew GabrielsonAndrew Gabrielson More articles by this author , Gabriel EpsteinGabriel Epstein More articles by this author , Mingxiao FengMingxiao Feng More articles by this author , Sunil PatelSunil Patel More articles by this author , Max KatesMax Kates More articles by this author , and Woonyoung ChoiWoonyoung Choi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003234.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) are commonly treated with intravesical gemcitabine and docetaxel chemotherapy (GEMDOCE). However, studies evaluating biomarkers of GEMDOCE response in BCG-unresponsive NMIBC have been limited. Docetaxel is a microtubule-stabilizing agent that induces cell cycle arrest and apoptosis through mitotic catastrophe. We evaluated whether early and late cell cycle signatures were associated with GEMDOCE response in BCG-unresponsive NMIBC tumors. METHODS: We performed a retrospective study of patients with BCG-unresponsive NMIBC who underwent intravesical GEMDOCE. Monthly maintenance therapy was given for 52% of patients with a 3-month complete response. RNAseq and DNA panel sequencing were performed on FFPE tissues from pre-treatment TURBT samples. Gene set variation analysis (GSVA) was performed to calculate gene set enrichment scores with cell cycle and immune signatures. Cluster analysis was performed to assess whether cell-cycle signatures and other gene signatures were associated with response and recurrence-free survival. RESULTS: A total of 30 patients with BCG-unresponsive NMIBC were included, of whom 63% (19) experienced disease recurrence. Cluster analysis with cell cycle signatures yielded 2 clusters with high expression of either late (cluster 1) or early (cluster 2) cell cycle signatures (Figure 1). Tumors enriched with late cell cycle signatures showed significant recurrence-free survival benefit compared to tumors with high expression of early cell cycle signatures (Figure 2). TP53 alterations were enriched in cluster 1 which demonstrated a clinical benefit from GEMDOCE. In contrast to prior work from our lab on BCG-treated tumors, response in GEMDOCE-treated tumors was not associated with immune signatures. CONCLUSIONS: These early data suggest that there may be molecular signatures that stratify patients with BCG-unresponsive NMIBC treated with GEMDOCE. Further expansion of these cohorts in both BCG-naïve and BCG-unresponsive cohorts is ongoing. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e188 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrew Gabrielson More articles by this author Gabriel Epstein More articles by this author Mingxiao Feng More articles by this author Sunil Patel More articles by this author Max Kates More articles by this author Woonyoung Choi More articles by this author Expand All Advertisement PDF downloadLoading ...

Adjuvant therapy with nivolumab versus placebo in patients with resected stage IIB/C melanoma (CheckMate 76K)

Patients with resected stage IIB/C melanoma are at high risk of recurrence with outcomes similar to patients with resected stage IIIB disease. Adjuvant NIVO has shown benefit in patients with resected stage III-IV melanoma. The phase 3 CheckMate 76K (NCT04099251) trial compared adjuvant NIVO vs PBO in patients with completely resected stage IIB/C melanoma. Patients aged ≥12 years were stratified by T category and randomized 2:1 to receive NIVO 480 mg or PBO, intravenously Q4W for 12 months. The primary endpoint was recurrence-free survival (RFS); safety was a key secondary endpoint. Overall, 790 patients were randomized to NIVO (526) vs PBO (264); 61% had stage IIB and 39% had stage IIC disease. Minimum follow-up was 8 months (median: 15.8 months NIVO; 15.9 months PBO); 66/526 (13%) vs 69/264 (26%) had a recurrence event. At this interim analysis, CheckMate 76K met the primary endpoint: NIVO significantly reduced the risk of recurrence vs PBO (stratified HR, 0.42; 95% CI, 0.30-0.59; stratified P&lt;0.0001); 12-month RFS rates for NIVO vs PBO were 89% (95% CI, 86-92) vs 79% (74-84); substage rates were 93% vs 84% (IIB) and 84% vs 72% (IIC). RFS benefit was observed across predefined subgroups. For NIVO, 5% of all patients had distant recurrences and 2% regional; for PBO, it was 12% and 8%. Grade 3-4 treatment-related adverse events (TRAEs) for NIVO vs PBO were 10% vs 2%; any-grade TRAEs leading to discontinuation were 15% vs 3%. There was one treatment-related death (0.2%) with NIVO (heart failure and acute kidney injury). Adjuvant NIVO significantly improved RFS vs PBO and decreased the risk of recurrence or death by 58% in patients with resected stage IIB/C melanoma, with efficacy benefit across subgroups. The safety results were similar to the known anti–PD-1 monotherapy profile with no new safety signals. NIVO is an effective adjuvant treatment option with a clinically meaningful benefit in resected stage IIB/C melanoma. Encore presentation from Society of Melanoma Research, September 2022.

Efficacy and safety of a novel 450 nm blue diode laser versus plasmakinetic electrocautery for the transurethral resection of non-muscle invasive bladder cancer: The protocol and result of a multicenter randomized controlled trial.

To be the first to apply a novel 450 nm blue diode laser in transurethral resection of bladder tumor (TURBt) to treat patients with non-muscle invasive bladder cancer (NMIBC) and evaluate its efficacy and safety during the preoperative period compared to the conventional plasmakinetic electrocautery. Randomized controlled trial (RCT) in five medical centers was designed as a non-inferiority study and conducted from October 2018 to December 2019. Patients with NMIBC were randomized to the blue laser or plasmakinetic electrocautery group for TURBt. As the first study to evaluate this novel blue laser device, the primary outcome was the effective resection rate of bladder tumors, including effective dissection and hemostasis. The secondary outcomes were the perioperative records, including surgical time, postoperative indwelling catheter time, hospital stay length, blood loss, reoperation rate, wound healing and adverse events. A total of 174 patients were randomized to either the blue laser group (85 patients) or plasmakinetic electrocautery group (89 patients). There was no statistical significance in the clinical features of bladder tumors, including tumor site, number and maximum lesion size. Both the blue laser and plasmakinetic electrocautery could effectively dissect all visible bladder tumors. The surgical time for patients in the blue laser group was longer (p=0.001), but their blood loss was less than that of patients in the control group (p=0.003). There were no differences in the postoperative indwelling catheter time, hospital stay length, reoperation rate or other adverse events. However, the patients undergoing TURBt with the blue laser showed a faster wound healing at 3 months after operation. The novel blue laser could be effectively and safely used for TURBt in patients with NMIBC, and this method was not inferior to plasmakinetic electrocautery during the perioperative period. However, TURBt with the blue laser may provide the benefit to reduce preoperative blood loss and accelerate postoperative wound healing. Moreover, longer follow-up to confirm recurrence-free survival benefit was required.

Role of Adjuvant Regional Nodal Irradiation in Resected Melanoma: A Secondary Analysis of SWOG S1404

<h3>Purpose/Objective(s)</h3> Results from TROG 02.01 demonstrated that adjuvant radiotherapy (RT) in high-risk melanoma patients is associated with improved locoregional control (LRC). The aim of our study is to evaluate the role of adjuvant RT in standard risk (SR), high risk (HR) and ultra-high risk (UHR) melanoma patients in the immunotherapy era. S1404 randomized resected stage III and stage IV melanoma patients to standard of care adjuvant immunotherapy or pembrolizumab after surgery. <h3>Materials/Methods</h3> We retrospectively analyzed the data for 1239 patients enrolled in S1404. We stratified the patients according to SR (no high-risk features), HR (defined according to TROG 02.01 trial) and UHR (extracapsular extension with 5 or more positive nodes or 4 cm or greater nodal size). Recurrence free survival (RFS) and time to regional recurrence (TtRR) were primary outcomes; distant metastasis free survival (DMFS) was a secondary outcome. RFS was estimated using the Kaplan-Meier method and associations with the outcome were evaluated using Cox regression models. TtRR and DMFS were estimated with cumulative incidence curves and associations with the outcome were evaluated using cause-specific regression models. <h3>Results</h3> Of 1239 patients analyzed, 136 patients (11%) completed RT. The most common RT regimen used was 30 Gy/5 fractions (37%) followed by 48 Gy/20 fractions (31%). Fifty three percent of patients were HR per TROG02.01. More HR patients received RT compared to SR (16 % versus 6%; p-value <= 0.001). Among the patients who received RT 76/136 (56%) were advanced stage (Stage IIIC/ resected Stage IV) compared with those who did not 390/1103 (35%); p value <= 0.001. Similarly macroscopic lymph node involvement was significantly higher in RT group, 89/136 (65%) versus 457/1103 (41%); p value <=0.001. TtRR was significantly longer for patients who completed RT (all comers: 9% RR @ 4 year no RT vs 1% @ 4 year with RT; p value = 0.015). For high-risk patients, TtRR was longer for patients who received RT regardless of PD1 status (12% RR @ 4 year no RT vs 2% @ 4 year with RT; p value = 0.009). No significant difference in value of RT was seen based on anatomic nodal site, study arm or BRAF mutation status. Among patients treated with pembrolizumab, a trend toward RFS benefit was seen in patients treated with RT (HR = 1.54, 95% confidence interval 0.94-2.53; p=0.085). There was no significant difference in DMFS between those who completed RT versus not. <h3>Conclusion</h3> Our study validated the results of previous studies and suggests consideration of adjuvant RT in high-risk patients regardless of planned adjuvant immunotherapy for improved LRC. We recommend the use of adjuvant RT in patients with macroscopic nodal involvement with extracapsular extension or with heavy nodal burden even in the immunotherapy era.

Benefit of adjuvant chemotherapy for resected pathologic N1 non-small cell lung cancer is unrecognized: A subgroup analysis of the JBR10 trial

Adjuvant chemotherapy is underutilized in clinical practice, in part, because its anticipated survival benefit is limited. We evaluated the impact of AC on overall and recurrence-free survival among completely resected pN1 NSCLC patients enrolled in the North American Intergroup phase III (JBR10) trial. A post-hoc subgroup analysis of pN1 NSCLC patients was performed. Participants were randomized to cisplatin+vinorelbine (AC) (n = 118) or observation (n = 116) following complete resection. The primary endpoint was overall survival (OS). The secondary endpoint was recurrence free survival (RFS). Kaplan-Meier methods were used to compare OS and RFS between the two treatment groups. Cox regression was used to identify factors associated with OS and RFS endpoints. Both groups had similar baseline characteristics. AC patients had improved 5-year OS (AC 61.4% vs observation 41.0%, log-rank p = .008) and 5-year RFS (AC 56.2% vs observation 39.9%, log-rank p = .011) rates compared to observation. Cox regression analyses confirmed the OS (HR 0.583, 95% CI 0.402-0.846, p = .005) and RFS (HR 0.573, 95% CI 0.395-0.830, p = .003) benefit associated with AC. AC was associated with a lower risk (HR 0.648, 95% CI 0.435-0.965, p = .0326) and a lower cumulative incidence (Subdistribution Hazard Ratio [SHR], 0.67, 95% CI 0.449-0.999, p = .0498) of lung cancer deaths. In the JBR10 trial, treatment with AC conferred a significant OS and RFS advantage over observation for pN1 NSCLC patients. These data suggest that pN1 NSCLC patients may experience a disproportionately greater clinical benefit from AC than the 6% survival advantage estimated by the LACE meta-analysis.

Outcomes in patients with resected stage IIIA melanoma treated with adjuvant nivolumab or monitored with observation: A real-world study.

e21534 Background: Nivolumab is approved in the United States and other countries as an adjuvant treatment for patients with completely resected stage III–IV melanoma based on results of the phase 3 CheckMate 238 trial, though the trial enrolled a limited number of patients with stage IIIA disease (AJCC-8). The objective of this real-world study is to describe characteristics, treatment patterns, and outcomes of patients with resected stage IIIA melanoma (AJCC-8) treated with adjuvant nivolumab or monitored with observation. Methods: In this retrospective, chart-review study, physicians from Cardinal Health’s proprietary Oncology Provider Extended Network (OPEN) extracted data from electronic health records of patients who had undergone complete surgical resection of stage IIIA melanoma between Jan. 1, 2018, and Dec. 31, 2019. Recurrence-free survival (RFS) and overall survival (OS) were evaluated from the date of resection and compared between the adjuvant nivolumab and observation cohorts using log-rank tests and adjusted Cox proportional hazards models (covariates included age, sex, race, region, payer type, ECOG PS, and Charlson Comorbidity Index). Discontinuations and deaths due to adjuvant nivolumab toxicity were assessed. Results: This study included 171 patients treated with adjuvant nivolumab and 38 patients monitored with observation. In the adjuvant nivolumab and observation cohorts, respectively, mean age was 57.4 and 68.1 years; most patients were male (59% and 68%) and white (90% and 87%); and median follow-up from resection was 20.7 and 25.0 months. Sentinel lymph node tumor burden of &lt; 1 mm was reported in 12% (n = 20) and 16% (n = 6) of patients in the adjuvant nivolumab and observation cohorts, respectively. The scheduled treatment course with adjuvant nivolumab was completed by 91% of patients (n = 155). RFS and OS rates were numerically higher with adjuvant nivolumab than with observation (Table). There was a trend toward RFS and OS benefit with adjuvant nivolumab versus observation (unadjusted RFS HR 0.53, 95% CI 0.26–1.09; adjusted RFS HR 0.62, 95% CI 0.28–1.40; unadjusted OS HR 0.55, 95% CI 0.19–1.57; adjusted OS HR 0.81, 95% CI 0.25–2.61). Discontinuation of adjuvant nivolumab due to toxicity occurred in 2% of patients (n = 4); no treatment-related deaths were reported. Conclusions: These real-world results confirm that patients with resected stage IIIA melanoma (AJCC-8) have a good prognosis. Treatment with adjuvant nivolumab may provide modest survival benefit over observation in this population, though increased sample size and additional follow-up are warranted.[Table: see text]

Real-world outcomes and prognostic factors in uterine leiomyosarcom: A single center experience from India.

e17620 Background: Uterine leiomyosarcoma (uLMS) is a rare and aggressive malignancy with dismal prognosis, often diagnosed incidentally after surgery for presumed benign disorders. There is a dearth of prospective data particularly in Indian women owing to its rarity. Published studies differ about prognostic factors, and the role of adjuvant treatment in uLMS. Methods: Prospectively maintained uterine cancer electronic database was used to include uLMS patients with adequate clinical information who underwent treatment between January 1, 2012 and December 31, 2021. Progression-free survival (PFS) and overall survival (OS) were calculated for the entire population, while recurrence-free survival (RFS) was calculated for the patients who had curative intent treatment. Various potential prognostic factors were tested using univariate and multivariate analysis. Results: Among 44 identified patients of uLMS, 32 women with sufficient information were included in the study. Majority of the patients had early stage disease at diagnosis including 19 (59.4%) patients with FIGO stage I tumors. Twenty three (71.9%) patients were diagnosed incidentally after surgery. Curative intent treatment was offered to 26 patients (81.3%) while 6 (18.7%) patients had palliative treatment. Median tumor size was 9 cm (interquartile range [IQR] 7-15), and the median mitotic count was 16 per 10 high power fields (hpf) (IQR, 12-25). Eleven patients (34.3%) received adjuvant chemotherapy while 15 patients (46.9%) remained on surveillance. After a median follow-up of 63.8 months, 22 patients (68.8%) had disease recurrence and 23 (71.9%) patients had died. Lung was the most common site (64.3%) of recurrence, followed by bone (18.8%), and abdominal cavity (12.5%). The median PFS and OS for the whole population were 20.7 months (95% confidence interval [CI] 13.7 - 27.7) and 28 months (95% CI 19.7 - 36.3) respectively. The 5-year PFS estimate was 20% while the 5-year survival probability was 25%. Stage specific 5-year OS probabilities for stage I, II, III, and IV were 45%, 40%, 20%, and 8% respectively. Patients who received adjuvant chemotherapy had longer RFS than those who were observed after primary surgery (median 59·9 months [95% CI 19.5–100.3] vs 20.5 months [95% CI 15.8-25.3]; hazard ratio [HR] 0·13 [95% CI 0.02-0.85; p = 0·03). Lower stage (FIGO stage I-II) (HR 0.15 [95% CI 0.03-0.67]; p = 0.013), and lower mitotic count (&lt; 15/10 hpf) (HR 0.13 [95% CI 0.03-0.61]; p = 0.01) were independent prognostic factors associated with better survival. Conclusions: This 10-year experience of uLMS from an Indian tertiary care cancer center shows poor survival across stages with a high rate of recurrence. Only stage and mitotic count were found to be independent prognostic factors. The finding of RFS benefit with adjuvant chemotherapy warrants larger prospective studies to evaluate the role of adjuvant therapy in uLMS.

What Is the Impact of Mammalian Target of Rapamycin Inhibitors on Hepatocellular Carcinoma Recurrence After Liver Transplantation.

We read with great interest the article by Lee et al1 regarding the pooled data from 2 randomized trials evaluating the 24 mo safety and efficacy of mammalian target of rapamycin inhibitor (mTORi) everolimus with reduced tacrolimus (EVR with reduced tacrolimus, n = 387) versus standard tacrolimus (n = 385) regimen after liver transplantation (LT). Interestingly, the authors found that the recurrence of hepatocellular carcinoma (HCC) was numerically lower, although not statistically significant, in patients transplanted beyond Milan with EVR with reduced tacrolimus than in patients with standard tacrolimus (5.9% versus 23.1%; P = 0.215), whereas no difference was found in those within Milan criteria (2.9% versus 2.1%; P = 1.0). The authors mentioned that these findings were similar to our meta-analysis,2 but in fact, in our study,2 we had found that the rate of HCC recurrence was significantly lower in LT recipients under mTORi than in those under calcineurin inhibitors (CNIs; tacrolimus or cyclosporine), but only in those with pre-LT HCC within Milan criteria (mTORi: 3.8% versus CNIs: 9.2%; P = 0.03); comparatively, the rate of HCC recurrence was similar among patients transplanted for HCC outside Milan criteria (mTORi: 29.5% versus CNIs: 29.2%; P = 1.0). Indeed, our findings were confirmed in the SiLVER randomized trial,3 in which sirolimus (another mTORi) showed a benefit only in low-risk LT recipients (ie, those with HCC within Milan criteria pretransplant). Although Lee et al1 did not provide any explanation, these discordance results could not be attributed to different anti neoplastic properties between sirolimus and EVR. (In fact, in our meta-analysis, HCC recurrence was significantly more frequently observed in patients who received sirolimus than in those who received EVR [10.5% versus 4.1%; P = 0.02]). The absence of any clear benefit from EVR administration regarding HCC recurrence might be attributed to the relatively low rates of HCC recurrence in both groups under the mTORi and the mTORi-free regimens at 24 mo (3.3% and 6.3%, respectively).1 Interestingly, in the SiLVER study,3 the recurrence-free survival at 24 mo was 83% in the group under mTORi and 77% in the mTORi-free group, which was possibly related to the lower proportion of patients with HCC within Milan criteria, compared with the study by Lee et al1 (eg, in the group under mTORi: 65.1% versus 82.9%, respectively). Nevertheless, longer follow-up would be useful in the study by Lee et al1 to overcome this limitation, as in the SiLVER study,3 recurrence-free survival benefit was evident in the first 3 to 5 y, especially in low-risk patients. Finally, it would be useful to provide the trough levels of CNIs, particularly during the first month after LT,4 as well as the trough levels of mTORi in those with and without HCC recurrence, as we recently showed that the recipients with mean trough levels of EVR ≥6 ng/mL at 7 to 12 mo post-LT, compared with those with EVR <6 ng/mL, had decreased HCC recurrence rates (log-rank: 2.3; P = 0.007).5