Locoregional Treatment Research Articles

Thermoablative Treatment of Papillary Microcarcinomas of Thyroid.

Recently, locoregional treatment with ultrasound-guided radiofrequency has been proposed as a new, effective, and safe procedure for low-risk papillary thyroid microcarcinoma (PTC < 1 cm), not eligible or recruitable for surgery. Until now, the gold standard has been the surgery and then the active surveillance. The aim of the study is to present our experience of ultrasound-guidedthermoablation, a procedure performed before demolitive surgery and post-active surveillance. It is a non-invasive treatment that does not require general anesthesia, with a low risk of complications, hypothyroidism, and hypoparathyroidism. All nodules described on ultrasound showed a volumetric increase (follow-up from 12 to 36 months). The cytological examination in all cases showed TIR 4b and TIR 5 papillary microcarcinoma. All the patients were offered the possibility of radiofrequency thermoablation; they were all informed and gave their consent. 18G active tip electrode needles 7 or 10 mm (Amica Gen HS) were used with the moving shot method under local anesthesia in a day hospital setting. No severe complications were reported. Contrast-Enhanced Ultrasonography (CEUS) with SonoVue (CEUS Sonovue) was performed post-procedure and then at 1, 3, 6, and 12 months, which documented complete revascularization and progressive volumetric reduction of the treated area. Our experience has confirmed that radiofrequency ablation can effectively eliminate small papillary thyroid carcinomas with fewer complications. In our opinion, it is a valid alternative for the treatment of low-risk and indolent papillary thyroid microcarcinomas, even in the absence of surgical contraindications.

Evaluation of the Prognostic Role of D-dimer in Egyptian Hepatocellular Carcinoma Patients Undergoing Locoregional Treatment

Abstract Background The blood coagulation function is often abnormal in HCC patients due to hypercoagulatory state, hyperfibrinolytic state, and increased plasma D-dimer. HCC patients treated with locoregional treatment may show changes of D-dimer levels. Several studies explored the validity of D-dimer levels during locoregional treatment in HCC but definitive data are still lacking. Aim of the Work Determination of the efficacy of D-dimer profile as a prognostic marker regarding tumor features, and post interventional response in HCC subjects undergoing TACE or RFA. Patients and Methods The clinical data of 50HCC patients who underwent TACE or RFA in our hospital from October 2021 to June 2022 were collected, including the CBC, CRP Alfa-fetoproteins and plasma d-dimer level 1 week before TACE or RFA(D0), D-dimer level 1 month (D1) and 4 months(D2) after TACE or RFA. Contrast enhanced CT was performed within 1 week before locoregional treatment and was repeated 1month and 4 months after locoregional treatment to assess for treatment efficacy according to the mRECIST criteria based on change in tumor size as measured by CT scan. One month after TACE or RFA, these patients were divided into four groups according to the mRecist criteria: complete response, partial response, stationary disease and progressive disease. D0, D1 and D2 were compared between the 4 groups and the relation between D-dimer level and the efficacy of locoregional treatment was assessed. Results In patients with negative D-dimer before locoregional treatment (D0), there was no significant difference between D0 and D1 (P &amp;gt; 0.05), while patients with elevated pretreatment D-dimer levels (D0), D1 was significantly higher than D0 (P &amp;lt; 0.05) and the D1 is higher than that in patients with negative Do. Progressive rise of D-dimer levels 4months post locoregional treatment (D2) in HCC was associated with tumor progression suggesting aggressive tumor biology and poor outcome(P = 0.02). Conclusion The changes in plasma D-dimer level can be used as a potential prognostic biomarker in predicting the efficacy of locoregional treatment in HCC patients and thus, elevated D-dimer levels pre and post locoregional treatment may serve as predictors of adverse tumor profile and poor outcome.

Microwave ablation followed by cTACE in 5-cm HCC lesions: does a single-session approach affect liver function?

PurposeMicrowave ablation (MWA) and conventional transarterial chemoembolization (cTACE) are locoregional treatments commonly performed in very early, early and intermediate stages of hepatocellular carcinoma (HCC). Despite combined locoregional approaches have shown encouraging results in obtaining complete tumor necrosis, their application in a single session is poorly described.Our aim was to evaluate the safety and efficacy of single-session MWA and cTACE treatment in 5-cm HCCs and its influence on liver function.Materials and methodsAll 5-cm HCCs treated by MWA and cTACE performed in a single-session in our Interventional Radiology unit between January 2020 and December 2022 were retrospectively recorded and analyzed. Patients with poor or missing pre- and post-treatment imaging were excluded. Technical success, clinical success, and complications rate were examined as primary endpoints. Pre- and post-treatment liver function laboratory parameters were also evaluated.ResultsA total of 15 lesions (mean lesion diameter, 5.0 ± 1.4 cm) in 15 patients (11 men; mean age, 67.1 ± 8.9 years) were retrospectively evaluated. Technical and clinical success were 100% and 73%, respectively. Four (27%) cases of partial response and no cases of progressive or stable disease were recorded. AST and ALT values have found to be significantly higher in post-treatment laboratory tests. No other significant differences between pre- and post-treatment laboratory values were registered. AST and ALT pre- and post-treatment higher differences (ΔAST and ΔALT) were significantly associated with a lower clinical success rate.ConclusionMWA and cTACE single-session approach is safe and effective for 5-cm HCCs, without significant liver function impairment. A post-treatment increase in AST and ALT values may be a predictor for clinical failure.

Biodegradable Microembolics with Nanografted Polyanions Enable High-Efficiency Drug Loading and Sustained Deep-Tumor Drug Penetration for Locoregional Chemoembolization Treatment.

Transarterial chemoembolization (TACE), the mainstay treatment of unresectable primary liver cancer that primarily employs nondegradable drug-loaded embolic agents to achieve synergistic vascular embolization and locoregional chemotherapy effects, suffers from an inferior drug burst behavior lacking long-term drug release controllability that severely limits the TACE efficacy. Here we developed gelatin-based drug-eluting microembolics grafted with nanosized poly(acrylic acid) serving as a biodegradable ion-exchange platform that leverages a counterion condensation effect to achieve high-efficiency electrostatic drug loading with electropositive drugs such as doxorubicin (i.e., drug loading capacity >34 mg/mL, encapsulation efficiency >98%, and loading time <10 min) and an enzymatic surface-erosion degradation pattern (∼2 months) to offer sustained locoregional pharmacokinetics with long-lasting deep-tumor retention capability for TACE treatment. The microembolics demonstrated facile microcatheter deliverability in a healthy porcine liver embolization model, superior tumor-killing capacity in a rabbit VX2 liver cancer embolization model, and stabilized extravascular drug penetration depth (>3 mm for 3 months) in a rabbit ear embolization model. Importantly, the microembolics finally exhibited vessel remodeling-induced permanent embolization with minimal inflammation responses after complete degradation. Such a biodegradable ion-exchange drug carrier provides an effective and versatile strategy for enhancing long-term therapeutic responses of various local chemotherapy treatments.

Transcatheter Arterial Radioembolization–Induced Gastric Ulcer in an Excluded Stomach After Roux-en-Y Gastric Bypass

ABSTRACT Transcatheter arterial radioembolization (TARE) is a common locoregional treatment for hepatocellular carcinoma. It is associated with peptic ulcer disease in up to 5% of patients. A 70-year-old man with Roux-en-Y gastric bypass and liver cirrhosis with hepatocellular carcinoma treated with TARE 6 months earlier was evaluated for continued melena and was found to have an ulcer in the excluded stomach. This was successfully treated with liquid proton pump inhibitor through gastrostomy tube to the excluded stomach. This represents a unique case of successful management of TARE-induced peptic ulcer disease in the excluded stomach of a Roux-en-Y gastric bypass patient.

Diffusion-weighted magnetic resonance imaging as an early prognostic marker of chemoradiotherapy response in squamous cell carcinoma of the anus: An individual patient data meta-analysis

Background and purposeSquamous cell carcinoma of the anus (SCCA) can recur after chemoradiotherapy (CRT). Early prediction of treatment response is crucial for individualising treatment. Existing data on radiological biomarkers is limited and contradictory. We performed an individual patient data meta-analysis (IPM) of four prospective trials investigating whether diffusion-weighted (DW) magnetic resonance imaging (MRI) in weeks two to three of CRT predicts treatment failure in SCCA. Material and methodsIndividual patient data from four trials, including paired DW-MRI at baseline and during CRT, were combined into one dataset. The association between ADC volume histogram parameters and treatment failure (locoregional and any failure) was assessed using logistic regression. Pre-defined analysis included categorising patients into a change in the mean ADC of the delineated tumour volume above and below 20%. ResultsThe study found that among all included 142 patients, 11.3 % (n = 16) had a locoregional treatment failure. An ADC mean change of <20 % and >20 % resulted in a locoregional failure rate of 16.7 % and 8.0 %, respectively. However, no other ADC-based histogram parameter was associated with locoregional or any treatment failure. ConclusionsDW-MRI standard parameters, as an isolated biomarker, were not found to be associated with increased odds of treatment failure in SCCA in this IPM. Radiological biomarker investigations involve multiple steps and can result in heterogeneous data. In future, it is crucial to include radiological biomarkers in large prospective trials to minimize heterogeneity and maximize learning.

Circulating Tumor DNA Predicts Early Recurrence Following Locoregional Therapy for Oligometastatic Colorectal Cancer.

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan-Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar's test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

The Negative Impact of Sarcopenia on Hepatocellular Carcinoma Treatment Outcomes.

Hepatocellular carcinoma (HCC) represents a major global health concern, characterized by evolving etiological patterns and a range of treatment options. Among various prognostic factors, sarcopenia, characterized by loss of skeletal muscle mass, strength, and function, has emerged as a pivotal contributor to HCC outcomes. Focusing on liver transplantation, surgical resection, locoregional treatments, and systemic therapies, this review aims to analyze the impact of sarcopenia on HCC treatment outcomes, shedding light on an underexplored subject in the pursuit of more personalized management. A comprehensive literature review was conducted by searching peer-reviewed articles on sarcopenia and treatment outcomes in patients with HCC from inception up to October 2023. Sarcopenia was found to be prevalent among HCC patients, exhibiting different occurrence, possibly attributable to diverse diagnostic criteria. Notably, despite variations in studies utilizing skeletal muscle indices, sarcopenia independently correlated with lower overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS) across surgical (both transplantation and resection), locoregional, and systemic therapies, including tyrosine-kinase inhibitors (TKIs) and immune-checkpoint inhibitors (ICIs). Moreover, a link between sarcopenia and increased rate and severity of adverse events, particularly in surgery and TKIs recipients, and larger tumor size at diagnosis was observed. While baseline sarcopenia negatively influenced treatment outcomes, alterations in muscle mass post-treatment emerged as primary determinants of reduced OS. Sarcopenia, either present before or after HCC treatment, negatively correlates with response to it, across all etiologies and therapeutic strategies. Although only a few studies have evaluated the impact of supervised physical activity training on muscle mass and OS after HCC treatment, it is crucial to evaluate the presence of sarcopenia before treatment initiation, to better stratify patients' prognosis, thus performing a more tailored approach, and identify therapies able to restore muscle mass in HCC patients. Conversely, the impact of sarcopenia on HCC recurrence and extrahepatic spread remains inadequately explored.

Repeated Previous Transarterial Treatments Negatively Affect Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib

Background: Transarterial chemoembolisation (TACE) and radioembolisation (TARE) can lead to the deterioration of liver function, especially in cases of a high tumour burden, potentially lessening the benefits of subsequent systemic treatments. We aimed to verify whether a high number of previous transarterial treatments modified the outcomes of patients who received sorafenib as a frontline systemic treatment. Methods: A retrospective analysis of a large multicenter dataset containing prospectively collected data of sorafenib-treated patients was conducted. Results: Data from 696 patients were analysed, with 139 patients having received &gt;two transarterial procedures before starting sorafenib. A propensity score matched 139 identified pairs of patients. Having received &gt;two locoregional treatments was independently associated with a shorter survival (hazard ratio 1.325, 95% confidence interval 1.018–1.725, p = 0.039). This pattern was confirmed amongst responders to sorafenib, but not in progressors. A trend toward a higher rate of the permanent discontinuation of sorafenib due to liver failure (18.7 vs. 10.8%, p = 0.089) and a lower rate of eligibility for second-line treatments (24.5 vs. 17.3%, p = 0.184) was observed in patients who had received &gt;two transarterial procedures. Conclusions: Repeated endovascular treatments negatively impacted the survival of HCC patients, especially sorafenib-responders. An early switch to systemic therapies should be considered in cases that are unlikely to respond.

Evaluation of the Contrast-Enhanced Ultrasound Nonradiation Treatment Response Assessment LI-RADS v2024 Using Data From a Multi-Center Transarterial Chemoembolization Study

Rationale and ObjectiveHepatocellular carcinoma (HCC) locoregional treatment response is commonly evaluated using the Modified Response Evaluation Criteria in Solid Tumors and the American College of Radiology (ACR) Liver Reporting and Data System (LI-RADS) Treatment Response Assessment (TRA) for MRI/CT. This study aims to evaluate the diagnostic performance of the new ACR contrast-enhanced ultrasound (CEUS) Nonradiation TRA LI-RADS v2024 in HCC treated with transarterial chemoembolization (TACE). Methods and MaterialThis retrospective observational study included 87 patients treated with TACE from a previously reported cohort. At 15- and 30-days post-treatment, 68 and 72 HCC lesions were evaluated. Three blinded radiologists with different levels of CEUS experience interpreted the images independently. According to CEUS Nonradiation TRA LI-RADSv2024, both intralesional and perilesional tumor viability were evaluated and final TRA categories were as follows: TR-Nonviable, TR-Equivocal, and TR-Viable. Reference standard used was a composite of histology and imaging. Results140 HCC lesions were analyzed. At 15 days post-treatment, the sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and accuracy of TR-Viable classification ranged from 72.5-94.3%, 72.2-86.4%, 86.8-91.4%, 65.6-86.7%, 76.9-86.8%, respectively. At 30 days post-treatment, the SN, PPV, and NPV of TR-Viable classification decreased, ranging from 65.9-84.2%, 85.7-90.6%, and 59.5-73.9%, respectively, while the SP increased, ranging from 80.0-88.0%. Kappa values ranged from 0.557-0.730, indicating moderate to substantial agreement. ConclusionCEUS Nonradiation TRA LI-RADS is a reliable tool for the detection of viable tumors in lesions treated with TACE and demonstrates reproducibility across readers.

Oligo-residual disease in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer: incidence, pattern of failure, and clinical value of local consolidative therapy

ObjectivesTo investigate the feasibility and potential clinical value of local consolidative therapy (LCT) in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer (NSCLC).Materials and methodsPD-1/PD-L1 inhibitor-treated metastatic NSCLC patients with measurable disease in three academic centers were screened and those with adequate follow-up were included. Oligo-residual disease (ORD) was defined as residual tumors limited to three organs and five lesions evaluated at the best response among patients with partial response or stable disease after PD-1/PD-L1 inhibitors. Oligometastatic and multiple-metastatic disease (OMD/MMD) were similarly classified at baseline. Locoregional interventions, administered after effective treatment of PD-1/PD-L1 inhibitors and before initial disease progression, were defined as LCT. Patterns of initial progressive disease (PD) were classified as involving only residual sites (RP), only new sites (NP), or a combination of both (BP).ResultsAmong the 698 patients included, ORD was documented in 73 (47.1%) of 155 patients with baseline OMD and 60 (11.0%) of 543 patients with baseline MMD. With a median follow-up of 31.0 (range, 6.0–53.0) months, 108 patients with ORD developed initial PD, with RP, NP, and BP occurring in 51 (47%), 23 (21.3%), and 34 (31.5%), respectively. Among the 133 patients with ORD, those receiving LCT (n = 43) had longer progression-free survival (HR = 0.58, 95% CI 0.40–0.85, p = 0.01) and overall survival (HR = 0.49, 95% CI 0.30–0.79, p < 0.0001).ConclusionORD occurs with a clinically relevant frequency among PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients and LCT may provide extra survival benefits in those with ORD.

First-Line Treatments and Management of Metastatic Renal Cell Carcinoma Patients: An Italian Interdisciplinary Uro-Oncologic Group Algorithm.

The treatment landscape for metastatic renal cell carcinoma (mRCC) has undergone significant transformations in recent years. The introduction of novel combination therapies involving tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors has resulted in improved oncological outcomes compared to traditional TKI monotherapy. In this evolving paradigm, the pivotal role of the multidisciplinary tumor board is underscored, particularly in shaping the therapeutic trajectory for patients eligible for locoregional interventions like cytoreductive nephrectomy and metastasectomy. In cases where systemic treatment is deemed appropriate, the absence of direct comparisons among the various combination therapies complicates the selection of a first-line approach. The clinician is faced with the challenge of making decisions based on patient-specific factors such as performance status, risk classification according to the International Metastatic Renal Cell Carcinoma Database Consortium, comorbidities, and disease characteristics, including the number and location of metastases and tumor histology. Considering these concerns, we propose, as a member of a Tuscany Interdisciplinary Uro-Oncologic Group, an algorithm to streamline the decision-making process for mRCC patients, offering guidance to clinicians in their day-to-day clinical practice.

CINDERELLA clinical trial: Using artificial intelligence–driven healthcare to enhance breast cancer locoregional treatment decisions.

TPS621 Background: Breast cancer treatments often pose challenges in balancing efficacy with quality of life. The CINDERELLA Project pioneers an artificial intelligence (AI)-driven approach (CINDERELLA APP) for shared decision-making process, aiming to harmonise locoregional therapeutic interventions with breast cancer patients' expectations about aesthetic outcomes. The CINDERELLA clinical trial aims to establish a new standard in patient-centred care by bridging the gap between clinical treatment options and patient expectations through innovative technology. The trial focuses on evaluating the effectiveness of the CINDERELLA APP in improving patient satisfaction regarding locoregional treatment aesthetic outcomes, aligning patient expectations with real-world results, and assessing its impact on overall quality of life and psychological well-being. Methods: Trial design and statistical methods: This international multicentric interventional randomised controlled open-label clinical trial will recruit and randomise patients into two groups: one receiving standard treatment information and the other using the AI-powered CINDERELLA APP. The primary objective is to assess the levels of agreement among patients' expectations regarding the aesthetic outcome before and 12 months after locoregional treatment. The trial will also evaluate the aesthetic outcome level of agreement between the AI evaluation tool and self-evaluation. The impact of the intervention on aligning expectations with outcomes will be evaluated using the Wilcoxon signed-rank test. The improvement in classification of aesthetic results post-intervention will be measured by calculating the Weighted Cohen's kappa. Outcomes across different groups will be compared using statistical tests and bootstrap methods. CANKADO functions as the base system, allowing doctors to supervise APP content for patients and handle data gathering, while upholding principles of privacy, data security, and ethical AI practices. Intervention planned: Using the CINDERELLA APP, the patient will have access to supervised medical information approved by breast cancer experts, and the AI system will match patient's information to pictures showing the potential aesthetic outcome (spectrum of good-poor) according to different locoregional approach. Major eligibility criteria: Non-metastatic breast cancer patients eligible for either breast-conserving surgery or mastectomy with immediate reconstruction. Current enrollment: Recruitment is currently open at six study sites. The recruitment started on 8 August 2023, aiming to enroll at least 515 patients/arm. As of January 26, 2024, clinical study sites have successfully randomised 177 patients. Clinical trial information: NCT05196269 .

The Number of Positive Lymph Nodes Instead of Extranodal Extension and Nodal Diameter is an Independent Predictor of Survival and Treatment Outcome of High-Grade Parotid Gland Carcinoma

BackgroundThere is emerging evidence that current 8th edition of the American Joint Committee staging system is not sensitive enough to predict parotid gland carcinoma (PGC) survival outcomes. PurposeThe present study aimed to analyze pathological nodal factors related to survival and treatment outcomes in a cohort of patients surgically treated with PGC. Study Design, Setting, SampleWe performed a retrospective cohort study of consecutive patients surgically treated with PGC at the authors’ institution from January 1993 to December 2018. Inclusion criteria were as follows: confirmed high-grade parotid gland malignancy on histopathology, first surgical treatment to the parotid cancer with neck dissection with curative intent at the study clinic and sufficient data for review. Exclusion criteria were previous treatment in another institution, low-grade carcinomas, cases where neck dissection was not performed, incurable local disease and distant metastases at the time of first diagnosis and patients lost to follow-up. Predictor variablePredictor variable comprised pathological nodal factors grouped as the number of cervical node metastases, extranodal extension (ENE, largest diameter of nodal metastasis and involvement of parotid lymph nodes. Main outcome variablesOutcomes evaluated were overall survival (OS), disease specific survival (DSS), recurrence free survival (RFS), locoregional recurrence free survival (LRFS) and distant metastasis free survival (DMFS). OS was calculated from the day of biopsy or definitive surgery to the last known hospital follow-up date, or the date of death found in the hospital records or social security data. DSS was calculated from the day of biopsy or definitive surgery until the last known follow-up or death from PGC reported in the patient record. Patients who died from causes other than the disease being studied are not counted in this measurement. Treatment outcome was evaluated through occurrence of locoregional relapse of the disease or development of distant metastases. RFS was defined as the time from the date of biopsy or definitive surgery to the date of LRFS or DMFS reported in the patient record. Covariates.Covariates were composed of a set of heterogeneous variables grouped into the following categories: demographic, pathologic and clinical. Analyses.Unadjusted and adjusted hazard ratios for each variable were calculated with univariate and multivariable Cox regression. Statistical significance was defined at p value of <.05. ResultsThe cohort of 112 patients included 62 males (55%) and 50 (45%) females. The mean age of the patients was 60.52±15.22 years. The median follow-up time was 59 months (3-221 months). Adenoid cystic carcinoma was the most common tumor type with the incidence of 45%. Cumulative OS for the 5-and 10-year follow-up period was 75% and 61% respectively. Locoregional recurrences occurred with 27 (24%), distant metastases occurred with 25 (22%) and both were diagnosed with 5 patients (6%). The number of metastatic nodes was the most important nodal prognostic factor related to OS (p=0.02; HR = 2.67; CI = 0.03-6.35), DSS (p=0.011; HR = 2.55; CI = .61-6.83) and DMFS (p=0.005; HR = 2.85; CI = 0.12-4.76). Presence of pathological parotid nodes was associated with poorer RFS (p=0.015; HR = 3.45; CI = 0.25-6.02). Conclusion and relevanceNumber of metastatic lymph nodes, instead of extranodal extension and largest nodal diameter, was the contributing factor associated with survival and treatment outcomes of surgically treated patients with high-grade PGC. Since the main function of staging system is to predict outcomes, the significance of ENE and nodal dimension in salivary gland cancer staging system requires further clarification. Important finding in present study was that the presence of positive parotid lymph nodes was associated to locoregional treatment failure.

Neoadjuvant HPV16-specific arenavirus-based immunotherapy HB-200 plus chemotherapy followed by response-stratified de-intensification in HPV16+ oropharyngeal cancer: TARGET-HPV.

6017 Background: The role of immunotherapy in curative viral-mediated oropharyngeal cancer (OPC) remains undefined. Human papillomavirus (HPV) 16 positive (+) OPC constitutively expresses viral epitopes that drive antigen-specific anti-tumor immunity, supporting rationale for evaluating neoadjuvant HPV16 directed therapeutics in non-metastatic OPC. HB-200 is an arenavirus-based vector therapy derived from LCMV (HB-201) and Pichinde virus (HB-202) each expressing a non-oncogenic HPV16 E7E6 fusion protein to induce HPV16 specific CD8+ T-cell responses. Building on our OPTIMA II results demonstrating that neoadjuvant chemotherapy/nivolumab led to deep responses in 71% of patients who went on to receive reduced radiation (RT), we hypothesized that adding HB-200 to chemotherapy to drive HPV16-specific anti-tumor immunity would be safe and effective to further deepen responses and facilitate more de-escalation. Methods: In this Phase 1 dose escalation investigator-initiated study, patients with non-metastatic HPV16+ OPC were treated with escalating doses of HB-201 single vector (Arm A) or HB-202/201 alternating vector (Arm B) x3 with neoadjuvant carboplatin AUC5 on day 1 and paclitaxel 100mg/m2 on days 1/8/15 of a 21-day cycle for 3 cycles. Deep responders (≥50% tumor shrinkage) received transoral robotic surgery (TORS) alone or RT to 50Gy +/- cisplatin, while non-responders (&lt;50% shrinkage) received 50 or 70Gy of RT with cisplatin. Primary objective was safety/tolerability and recommended phase 2 dose of HB-200 with chemotherapy. Additional objectives included deep response rate, circulating tumor (ct) HPV-DNA dynamics, and HPV16-specific T-cell response. Results: Twenty-one patients with HPV16+ OPC were enrolled and treated (Arm A, n=9, 43%; Arm B, n=12, 57%). Median age 57, 91% male, 75% base of tongue, 52% non-smokers, and 33% stage II/III (AJCC 8th edition). ≥Grade 3 treatment-emergent adverse events (AEs) occurred in 13 (62%) of patients overall and 3 (14%) non-hematologic during neoadjuvant. There were no Grade 4 AEs reported. All patients completed neoadjuvant HB-200/chemotherapy and response-stratified locoregional treatment. Deep responses following HB-200/chemotherapy were observed in 17/21 (81%) of patients, and in 14/15 (93%) treated on higher dose levels 1 or 2 ( p=0.05). All three patients who underwent TORS had no viable tumor at time of surgery. Two patients (9%) had persistent disease following CRT and underwent salvage surgery with no evidence of disease at last follow-up. ctHPV-DNA and HPV16-specific T-cell response data will be presented at the meeting. Conclusions: Neoadjuvant HB-200/chemotherapy is safe and feasible with early efficacy signal in this setting warranting further study. Enrollment to the subsequent randomized phase II part is ongoing (NCT05108870). Clinical trial information: NCT05108870 .

Ipsilateral recurrence and breast cancer outcomes in carriers of BRCA1/2 pathogenic variants according to locoregional treatments.

e12584 Background: Our previous study of 255 breast cancer (BC) patients, carriers of BRCA1/2 pathogenic variants (PV), showed that patients who underwent mastectomy without post-mastectomy radiotherapy (PMRT) had higher rates of local recurrence (LR) than those who underwent PMRT or breast-conserving therapy (BCT). Our aim was to verify our previous findings in a larger cohort. Methods: Clinical data was extracted from the medical records of BRCA1/2 mutation carriers with BC, treated at a single institution between 1/2006-12/2022. Data extracted included demographics, tumor characteristics, disease stage, surgical and oncological treatment, use of RT and disease outcomes. Results: Overall, 481 BC patients with BRCA1/2 germline mutations were identified, 20 of them presented with synchronous bilateral disease. Median follow-up time was 75.3 months (range 12.5-211). After excluding 16 patients with metastatic de novo disease and 1 patient not operated for medical reasons, 464 patients with 484 primary tumors were analyzed. Of these, 234 (48.3%) mastectomies (84% were skin- or nipple-sparing, SSM/NSM, 16% total mastectomy) and 250 (51.7%) BCT were performed. In the non-PMRT group (n=153) there was earlier disease stage at diagnosis (77.6% of tumors were Tis and T1N0) compared to the PMRT group (n=81) and BCT group (4.9% and 45%, respectively, p&lt;0.001). All had free surgical margins. LR rate in the study cohorts was 20/153 breasts (13.1%) in the non-PMRT group compared with 1/81 breasts (1.2%) in the PMRT group (p=0.003), and 16/250 (6.4%) in the BCS group (p=0.024). All but one recurrence were invasive. Cumulative incidence of LR at 5 and 10 years was 14.1% and 15.9% in the non-PMRT, compared to 4.4% and 9.4% in BCT group, respectively (p=0.034). No significant difference in overall survival was observed (p=0.39). Conclusions: BRCA1/2 PV carriers treated with mastectomy without PMRT had higher rates of LR than those who underwent mastectomy and PMRT or BCT, despite earlier stage disease. Further studies are needed to compare these outcomes to non- BRCA1/2 carriers and find means to improve local control in these patients.

Addition of stereotactic body radiotherapy (SBRT) to systemic chemotherapy in locally advanced cholangiocarcinoma (CC) (ABC-07): Results from a randomized phase II trial.

4006 Background: Locoregional treatments for inoperable, non-metastatic CC remain undefined. Single arm phase 2 data suggested that SBRT may improve clinical outcomes. We aimed to investigate the efficacy and safety of the addition SBRT with CisGem in locally advanced inoperable CC. Methods: ABC-07 (ISRCTN:10639376) is a phase II multicentre randomized trial for patients with inoperable, histologically confirmed locally advanced CC, WHO performance status 0-1. After registration patients showing no progression after 4 cycles of CisGem were randomized (2:1) for treatment after completing six cycles: either SBRT (50 Gy in 5 fractions or 67.5 Gy in 15 fractions, based on tumour size) or two additional cycles (cycles 7 and 8) of CisGem (CG-only). Primary endpoint was progression free survival (PFS). With 80% power and a 15% one-sided alpha, the study planned to randomize 65 patients to detect a median PFS increase from 10.4 to 17.4 months. Secondary endpoints included overall survival (OS), toxicity and patterns of failure. RT quality assurance was undertaken. Results: Between March 2016 and August 2022, 16 UK centres randomized 69 patients (SBRT, 45; CG only, 24). Median age was 66 (38 to 83) yrs, 58 (84.1%) perihilar location, 48(69.6%) stent in situ, median tumor size was 3.5cm (range 0.6-10.5). The median follow-up time was 20.7 months. In the SBRT arm, 43 completed 6 cycles CisGem (96%) and 41 (91%) received SBRT. In the CG-only arm, 18 (75%) completed 8 cycles. The median PFS from randomization was 8.6 and 9.0 months in the SBRT and CG-only arms, respectively (HR: 1.00; 95% CI: 0.58,1.70; p = 0.989). The first PFS events were 7 (16%) local and 24 (53%) metastatic relapses for SBRT, versus 7 (29%) and 7 (29%) in the CG-only arm, respectively. From registration, median OS time was 23.4 (95% CI: 14.6, 27.7) months for SBRT and 17.2 (95% CI: 10.2, NR) months for CG-only arm. Post-randomization, OS was 19.4 months (11.2, 24.6) for SBRT and 14.2 (7.0, NR) months for CG-only (HR: 0.79; 95% CI: 0.41,1.51; p = 0.47). Adverse events of grade ≥3 were observed in 33 (73%) and 21 (88%) patients in SBRT and CG-only arms, respectively. Of the infections, of which biliary sepsis was common, pre-cycle 6, SBRT had 19 (42%) cases vs. 7 (29%) in CG-only; post-cycle 6, SBRT had 17 (38%) sepsis cases vs. 6 (25%) in CG-only. There was 1 Grade 3 duodenal hemorrhage and 1 death due to sepsis in the SBRT arm. Primary causes of death included disease (20, 44% vs 11, 46%), sepsis (5, 11% vs 3, 13%), and hepatic failure (0 vs 3, 13%) for the SBRT and CG-only arms, respectively. Conclusions: SBRT did not show a PFS advantage over CG-only, yet a longer median OS time and better primary tumour control were observed without safety concerns. However, more mature survival data is still needed. Clinical trial information: 10639376.

Beyond Chemoimmunotherapy in Advanced Non-Small Cell Lung Cancer: New Frontiers, New Challenges.

Chemoimmunotherapy is currently the preferred first-line treatment option for the majority of patients with advanced non-small cell lung cancer without driver genetic alterations. Most of these patients, however, will experience disease progression within the first year after treatment initiation and both patients and their physicians will be confronted with the dilemma of the optimal second-line treatment. Identification of molecular targets, such as KRASG12C, BRAFV600X, METexon14, and human epidermal growth factor receptor 2 mutations, and RET rearrangements offer therapeutic opportunities in pretreated patients with corresponding alterations. For those tumors that do not harbor oncogenic drivers, second-line treatment with docetaxel remains the current standard of care despite modest efficacy. Strategies to challenge docetaxel include the combination of immune checkpoint inhibitors (ICIs) with tyrosine inhibitors of multiple kinases or with DNA damage response inhibitors, antibody-drug conjugates, and locoregional treatments for oligoprogressive disease. Next-generation immunotherapy strategies, such as T-cell engagers, immune-mobilizing monoclonal T-cell receptors, chimeric antigen receptor cell therapy, tumor infiltrating lymphocytes, and T-cell receptor cell therapy are being currently investigated in the quest to reverse resistance to ICIs. Importantly, the advent of these new agents heralds a novel spectrum of toxicities that require both the physician's and the patient's education. Herein, we review current and future strategies aiming to outperform docetaxel after chemoimmunotherapy failure, and we provide practical information on how to best communicate to our patients the unique toxicity aspects associated with immunotherapy.

Percutaneous cryoablation of breast cancer metastases: Analysis of long-term single center experience, efficacy and outcomes.

e13105 Background: Percutaneous image-guided cryoablation is a minimally invasive loco-regional treatment modality with wide availability and advantages of minimal sedation, short recovery, and ability to continue concurrent systemic therapy. However, there is a paucity of data about its long-term effects in the treatment of metastatic breast cancer despite evidence suggesting a potential survival advantage with loco-regional therapy for oligo-metastatic disease. Methods: We conducted retrospective analysis of patients who underwent CT-guided percutaneous cryoablation for metastatic breast cancer and had at least 1 follow up post cryoablation. Patient data including demographics, cancer treatment history and outcomes were extracted by chart review after IRB approval. Descriptive analyses of overall survival (OS), progression-free survival (PFS), and time to next-line treatment (TTNL) was performed. Results: The study encompassed 37 metastatic breast cancer patients who underwent cryotherapy between 2004-2021. These ablation procedures targeted various metastatic sites, which included the liver, lung, renal, lymph nodes, subcutaneous nodules, and bone. Their median age at the time of cryoablation was 58 years (range: 34-90). Among them, 46% had triple-negative breast cancer (TNBC), 41% were HR+/HER2-, and 8% were HER2+. Prior to first cryoablation procedure, 59% of patients had received more than one line of systemic therapy, and 73% were actively undergoing systemic treatment. The median size of the metastatic lesions treated with cryoablation was 1.8 cm (range: 0.4-6.5 cm). The most frequent site for cryotherapy was the liver (38%), followed by lymph nodes (30%). For the entire cohort, median PFS, TTNL, and OS were 7.1, 14, and 65.7 months, respectively. Subgroup analysis revealed mPFS of 3.1, 7.4 and 14.2 months for TNBC, Her2+ and HR+/Her2- cohorts respectively. Subgroup analysis for OS was not reported due to the small number of events and premature follow up time. Among the 27 patients who experienced disease progression, the majority (74%) had distant progression, with 22% occurring within the same organ but outside the ablation zone. Local recurrence within the ablation zone was rare, observed in only 4% of cases. Conclusions: Percutaneous image-guided cryoablation of metastatic breast cancer lesions demonstrated durable local response, prolonged PFS, TTNL and OS. Future studies investigating cryoablation as part of a multidisciplinary treatment approach for patients with metastatic breast cancer are worthwhile to confirm disease control rate and improvement in survival.

Recent safety and efficacy findings from a phase 1b/2 open-label combination study of ASP-1929 photoimmunotherapy with anti-PD-1 therapy in EGFR-expressing advanced head and neck squamous cell carcinoma (HNSCC).

6083 Background: In the challenging landscape of advanced HNSCC, patients (pts) have overall low survival and high locoregional (LR) recurrence rates. While LR progression is a key contributor to morbidity and mortality, LR control remains low despite aggressive therapy including surgery, radiation, chemotherapy, and immunotherapy. ASP-1929 photoimmunotherapy (PIT) combines EGFR-targeting cetuximab, with a light-activatable dye, IRDye 700DX, and a laser light for localized drug activation. This novel approach has demonstrated rapid and selective tumor necrosis in preclinical studies, and a manageable safety profile in HNSCC early clinical trials. Phase I/II and preclinical data indicate a potential synergy in anti-tumor activity of PIT when combined with anti-PD-1 therapy. Here we present updated interim evaluation findings based on a recent data cut from this study initially presented at the 2023 American Head and Neck Society meeting. Methods: A phase 1b/2 open-label study of pts with recurrent locally advanced (rLA) and/or metastatic (m) HNSCC evaluating the safety and efficacy of ASP-1929 PIT in combination with anti-PD-1 (pembrolizumab) therapy (NCT04305795). Pts with measurable disease by modified RECIST 1.1, at least 1 lesion accessible to light illumination, combined positive score (CPS) ≥1, and who were not candidate for LR therapy could be eligible for the study. Treatment included ASP-1929 PIT (infusion day 8, target tumors illuminated 24±4 hours later) plus anti-PD-1 (days 1&amp;22) during a 6-week cycle for up to 24 months. Primary objectives: safety/tolerability; objective response rate (ORR). Secondary objectives: overall survival (OS); progression-free survival (PFS); duration of response (DOR). Planned sample size: 26 HNSCC pts. Results: Of the 19 r/m HNSCC pts enrolled, 18 pts received both study therapies (PIT-evaluable). Data cut-off was August 31, 2023 (previously reported data cut-off: October 4, 2022). Efficacy results updated for the 18 PIT-evaluable pts: ORR of 33.3% (95% CI 13.3-59.0), including 4 CRs (22.2%) and 2 PRs (11.1%). Median OS not reached; 24-month OS rate estimate was 52.4% (95%CI 25.9-73.4). No change in median PFS, 2.9 months (95%CI 1.4-14.6). Median DOR was not reached at data cut-off (range 2.8+ to 18.0+ months). Safety data remained consistent with the data previously presented. Most common serious adverse reactions were dysphagia (10.5%) and tongue edema (10.5%). There were two grade 4 events: laryngeal edema (PIT-related) and tumor hemorrhage due to advanced disease, and no fatal events. Conclusions: ASP-1929 PIT in combination with anti-PD-1 therapy was generally well tolerated. Initial data demonstrate promising overall survival and response rates with this combination therapy in pts with rLA and/or m HNSCC lacking LR treatment options. Clinical trial information: NCT04305795 .