Radiological Response Research Articles

Evaluation of clinical and pathological responses of HER-2 positive locally advanced breast cancer patients after neoadjuvant therapy and surgery

Purpose: This study aimed to compare the effectiveness and toxicity of neoadjuvant dual Human epidermal growth factor receptor-2 (HER-2) blockade combined with chemotherapy in advanced breast cancer.
 Materials and Methods: Patients with HER2-positive breast cancer who received trastuzumab (T)+ pertuzumab (P) with weekly neoadjuvant paclitaxel or docetaxel were included in the study. Patients’ age, clinical stage, histological reports, ki-67 index, toxicity profiles, and the state of the pathological and radiological response following neoadjuvant therapy were evaluated. 
 Results: All 40 patients were women (mean age 50.9) and the overall rate of pathological complete responses was 62.5% (25/40). The rates of non-responsive patients and grade 2 neuropathy were statistically significantly higher in the group receiving P+T+Weekly Paclitaxel. When SUV values were analyzed based on hormone positivity, it was found that they decreased dramatically in both groups and were statistically significant. The logistic regression analysis developed to predict the precise response status to therapy was found to be significant.
 Conclusion: When comparing the agents used in dual HER-2 targeted therapies, patient response rates and toxicity profiles may differ. Ductal carcinoma in situ (DCIS) and molecular subtype were found to be significant variables in the developed logistic regression model.

Evaluation of Neurofibromatosis Type 1 Associated Optic Pathway Gliomas

Background/Aims: Optic pathway gliomas (OPGs) are low-grade gliomas histologically represented by pilocytic astrocytoma (PA) in 90% of cases, can develop from any part of the visual pathways such as optic nerve, chiasm, optic tract, or optic radiations which frequently involve the hypothalamus. OPGs account for 3–5% of childhood central nervous system (CNS) tumors and about 2% of pediatric glial lesions. OPGs are believed to be the most prevalent intracranial tumor in patients with neurofibromatosis type 1 (NF-1) and can occur in 15–20% of NF-1 cases. The aim of this study is to evaluate the clinical features and treatment response in patients diagnosed with optic glioma and NF-1.
 Methods: All cases diagnosed with OPG and received treatment in the Pediatric Oncology Department, between January 2015 to January 2021 were retrospectively evaluated. Inclusion criteria include children and adolescents with OPG aged between 0 and 18 years. The medical records (gender, age, tumor entity, tumor location) of patients, as well as their treatment history and magnetic resonance imaging (MRI) scans, were examined. The diagnosis of OPG was made clinically and radiologically by the tumor board. The recommendations of the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group were used in the diagnosis and evaluation of treatment response. Patients received intravenous chemotherapy with SIOP LGG 2004 (vincristine- carboplatin) with or without bevacizumab (10 mg/kg, started every 2 weeks), therapy or vinblastine (3 mg/m2, weekly). 
 Results: This study included 27 cases during the study period from January 2015 to January 2021. In this study there were 14 male (51.8 %) and 13 female (48.1 %) patients. The median age was 4.8 (range: 0.5–14.9) years. Biopsy was performed in three patients and the diagnosis was low-grade glioma (pilocytic astrocytoma) for all of them. Chemotherapy was administered to 22 cases in total. Twelve patients received vincristine-carboplatine, 5 patients received vincristine-carboplatin with bevacizumab and 5 patients received vinorelbine. Radiological response was evaluated in all 22 patients at 3 months MRI. No patient had a radiological complete respons, 11 patients (50%) had partial response, 2 patients (9%) presented with a progressive disease, showing an increase in measurements of 35% and 9 patients(40.9%) had stable disease at the 3-month evaluation.
 Conclusions: Systemic and visual problems play a significant role in the selection of treatment for pediatric patients with optic gliomas. An essential treatment option for improving symptoms and reducing tumor size is systemic chemotherapy. A crucial therapy option for enhancing vision is bevacizumab for the patients with NF-associated OPG.

Teriflunomide and Epstein-Barr virus in a Spanish multiple sclerosis cohort: in vivo antiviral activity and clinical response.

Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been associated with multiple sclerosis (MS). Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing forms of MS. In the preclinical Theiler's murine encephalitis virus model of MS, the drug demonstrated an increased rate of viral clearance versus the vehicle placebo. Furthermore, teriflunomide inhibits lytic EBV infection in vitro. 1. To evaluate the humoral response against EBV and HHV-6 prior to teriflunomide treatment and 6 months later. 2. To correlate the variation in the humoral response against EBV and HHV-6 with the clinical and radiological response after 24 months of treatment with teriflunomide. 3. To analyze the utility of different demographic, clinical, radiological, and environmental data to identify early biomarkers of response to teriflunomide. A total of 101 MS patients (62 women; mean age: 43.4 years) with one serum prior to teriflunomide onset and another serum sample 6 months later were recruited. A total of 80 had been treated for at least 24 months, 13 had stopped teriflunomide before 24 months, and 8 were currently under teriflunomide therapy but with less than 24 months of follow-up. We analyzed the levels of the viral antibodies titers abovementioned in serum samples with ELISA commercial kits, and the levels of serum neurofilament light chain (Nf-L). Antiviral antibody titers decreased for EBNA-1 IgG (74.3%), VCA IgG (69%), HHV-6 IgG (60.4%), and HHV-6 IgM (73.3%) after 6 months of teriflunomide. VCA IgG titers at baseline correlated with Nf-L levels measured at the same time (r = 0.221; p = 0.028) and 6 months later (r = 0.240; p = 0.017). We found that higher EBNA-1 titers (p = 0.001) and a higher age (p = 0.04) at baseline were associated with NEDA-3 conditions. Thus, 77.8% of patients with EBNA-1 >23.0 AU and >42.8 years (P50 values) were NEDA-3. Treatment with teriflunomide was associated with a reduction of the levels of IgG antibody titers against EBV and HHV-6. Furthermore, higher EBNA-1 IgG titers prior to teriflunomide initiation were associated with a better clinical response.

How the Underlying Etiology of Cirrhosis Impacts Response to SBRT

In the US, incidence rates of hepatocellular carcinoma (HCC) have more than tripled and death rates have doubled since 1980. In 2022, it is expected for 41,260 new cases to be diagnosed with 30,520 deaths. Many etiologies contribute to the development of HCC including alcoholic cirrhosis, cryptogenic cirrhosis, HCV, HBV, NASH, and genetic disorders like hereditary hemochromatosis. An increasing number of patients are not candidates for curative options such as resection or transplant and the role of alternative liver directed as therapies has increased. SBRT has emerged as a safe and effective option, but there is little known about the outcomes related to the etiology of the HCC. The purpose of this study is to characterize the rates of toxicity and efficacy between different HCC etiologies in patients who were treated with SBRT. A single institutional database was compiled of all patients with HCC who were treated with SBRT. Patients with HCC etiologies of HCV, alcoholic cirrhosis, or NASH cirrhosis who received SBRT and monitored with liver function tests and imaging (MRI or CT) and were not transplanted were included Demographic information, disease etiology, all treatment courses, lab values, radiologic response, and follow-up were collected on all patients. SPSS was used to analyze the data. Consecutive patients (n = 37, 43 courses of radiation) who received SBRT between 2013- January 2022 were included. Most patients were male (n = 32, 86.5%) and average age was 64.73 ± 7.42 years (range: 50-82 years). A majority of patients had either HCV or HCV and alcoholic cirrhosis (n = 28, 75.7%) and there were no baseline difference in child Pugh score, tumor size, or number of prior treatments. Most patients were treated with 50Gy/5 fx (n = 26, 70.3%) with 5 others being treated with 45Gy/5fx to meet mean liver constraints. Most patients had a decrease in ALT (n = 22, 59.5%) while almost half of patients had a decrease in AFP (n = 14, 48.3%) at average follow-up of 11.84 ± 5.35 months. There was a significant correlation between HCC etiology and change in bilirubin with patients with HCV being more likely to have increases in total bilirubin (χ2 (6) = 17.5, p < 0.01). Patients with HCV induced cirrhosis may be more fragile and have a significant increased risk of toxicity after SBRT based on total bilirubin changes. Most patients did have a decrease in ALT showing potential for some improvement in liver function with SBRT. However, almost half of patients have some biologic efficacy with SBRT independent of HCC etiology. Further studies should include looking at the biologic differences in the etiologies and what treatment liver-directed therapies may be best for each population.

A Novel Strategy to Enhance Radiotherapy Efficacy: Results from the Prospective Phase I Clinical Trial of MR-Guided Focused Ultrasound-Stimulated Microbubbles (MRgFUS+MB) Treatment for Breast Cancer

Preclinical in vitro and in vivo studies have demonstrated that tumor cell death can be enhanced 10- to 40-fold when radiotherapy (RT) is combined with focused-ultrasound (FUS)-stimulated microbubbles (MB) treatment. MBs are gas microspheres used as intravascular contrast agents. The acoustic exposure of MBs within the target volume causes bubbles cavitation that induces perturbation of tumor vasculature. This activates apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy, which would otherwise require high-dose radiotherapy (>8-10 Gy/fraction) to be activated. Subsequent irradiation of an MB-sensitized tumor causes increased anoxic tumor killing, which occurs in addition to canonical RT-induced DNA damage. Given the compelling results of preclinical data, we conducted a phase I clinical trial of magnetic resonance (MR)-guided FUS-stimulated MBs (MRgFUS+MB) treatment for breast cancer patients (pts). We report the safety and efficacy results of this new radio enhancement treatment. This is a single-center, single-arm, investigator-initiated phase 1 clinical trial (NCT04431674). We included pts with stage I-IV breast cancer with tumor in situ for whom breast or chest wall RT was deemed adequate by a multidisciplinary team. Pts were excluded if they had contraindications for contrast-enhanced MR or MB administration. Pts underwent 2-3 MRgFUS+MB treatments throughout the RT course. We used an MR-coupled FUS-device operating at 500 KHz and 540 kPa peak negative pressure to deliver the treatment. The FUS sonicated intravenously administrated MB within the MR-guided target volume. Pts were monitored for 30-min post-procedure and subsequently treated with RT. The primary outcome was acute toxicity per Common Terminology for Adverse Events V5.0. Secondary outcomes were radiological response at 3 months and local control (LC) at 1 year. Kaplan-Meier method was used to estimate local control. All pts signed a written consent form before study participation. We enrolled 18 females with 20 primary breast cancer treated with MRgFUS+MB therapy. The median age was 60 years (range, 44-90). The molecular subtypes consisted of basal-like (n = 3/20), luminal (n = 11/20), and HER2-enriched (n = 6/20). The prescribed dose was 20 Gy/5 fractions (n = 8/20), 30-35 Gy/5 fractions (n = 7/20), 30-40 Gy/10 fractions (n = 3/20), and 66 Gy/33 fractions (n = 2/20). The median follow-up was 9 months (range, 0.3-29). All pts completed the planned MRgFUS+MB treatments. The only MRgFUS+MB treatment-related toxicity consisted of Grade 1 allergic reaction (mild cough) 30 minutes after the last MB injection. All worst acute toxicities were radiation dermatitis (Grade 3 = 2/20, Grade 2 = 2/20, Grade 1 = 14/20). At 3 months, 75% had partial (n = 6/20) or complete (n = 9/20) response, with a single progression. The LC rate at 1 year was 86%. MRgFUS+MB was a safe and efficient treatment that provided durable responses.

Preoperative Radiotherapy of Soft Tissue Sarcoma with Simultaneous Integrated Boost: A Phase II Study

Neoadjuvant radiotherapy to 50 Gy in 25 fractions is delivered in operable Soft Tissue Sarcoma (STS) patients to downstage the tumor and improve resectability, although at the expense of increased risk of wound dehiscence. Nonetheless, clear margin resection (R0) may not be achieved in tumors located in proximity of critical structures such as the neurovascular bundle (NVB), resulting in impaired local control. The aim of this study is to increase R0 rate through addition of an IMRT boost to the potential sites of suboptimal resection in STS patients receiving neoadjuvant RT. We report hereby the dosimetric results and safety results from the first 5 patients enrolled in this trial. We designed a prospective monocentric interventional single-arm Phase II study enrolling locally advanced STS eligible for surgery. RT is administered in 25 daily fractions to include the MRI-based Gross Tumor Volume (GTV) and peritumoral tissue at risk of microscopic spread (CTV1) to a dose of 50 Gy (2Gy/fraction), with SIB (Simultaneous Integrated Boost) intensification to the tumor/dissection plane interface (CTV2) to a dose of 60 Gy (2.4 Gy/fraction). CTV2 delineation is approved by both a Radiation Oncologist and Surgeon. A margin of 0.5 cm is applied to both CTV to obtain PTV1 and PTV2. Concurrent anthracyclines-based chemotherapy (ChT) is allowed up to 3 cycles. Primary endpoint is R0 resection rate. Secondary endpoints include pathologic complete response rate, objective response rate, overall survival, local and distant progression-free survival, acute and chronic toxicity rate. To assess an increase in R0 rate from 81% to 97% assuming β = 80% e α = 0.05, 33 patients will be included. Dose constraints are summarized in Table1. At least 95% of the PTV1 and PTV2 should be covered by 95% the prescription dose up to a maximum allowed dose of 107%. Five patients were included. Tumor was located in the limbs and in the trunk in respectively 4 and 1 patient. Mean age was 47 years (range: 19-67). Concurrent chemotherapy was performed in 2 patients. Mean GTV size was 228.6 cm3 (range: 59.8-314.5). Mean PTV coverage by the 95% of the dose prescription was 98% (95-100) and 97% (95-100) in PTV1 and PTV2, respectively. Mean PTV1 and PTV2 Dmax were 61.6 Gy (range: 59-63) and 64.1 Gy (range:63-66), in both cases below the 107% threshold. Mean Bone Dmax was 55 Gy (56.6-61.8 Gy). Dmax to the skin corridor exceeded 20 Gy in 1 patient (range 12.5-58.1). While the NVB was overlapping the PTV2 in all cases, Dmax was below 66 Gy. At the time of this report, no Grade ≥3 acute skin toxicity was observed. Two patients underwent surgery with a radiological partial response (RECIST) and pathological complete response. No major wound complication was reported. Planning goals of the first 5 enrolled patients are achieved in most cases. Preliminary results show a benign safety profile and promising tumor response rate.

Volumes Changes in Adrenal Metastases during Delivery of 5-Fraction Stereotactic Magnetic Resonance-Guided Adaptive Radiotherapy

Stereotactic MR-guided adaptive radiotherapy (SMART) improves adrenal target coverage and reduces organ at risk doses. Changes in adrenal tumor volumes were observed during contouring for daily-adaptive planning. We hypothesized that such changes in GTV may correlate with long-term outcomes. An Ethics approved institutional database was accessed for details of 5-fraction adrenal SABR treatments on a 0.35T MR-Linac between 2016-2023. Volumetric MR-scans were acquired at baseline, and prior to each of 5 fractions. Manually contoured GTVs were accessed. Volume changes between simulation and first fraction (ΔPF1), as well as between first and subsequent fractions (ΔF1F2 to ΔF1F5) were computed. Daily relative adrenal volume change (DRVC) and the absolute volume change (DAVC) before treatment, were calculated by dividing ΔPF1 by the number of days between simulation and F1. Paired Wilcoxon tests were used to compare volumes at different timepoints. Univariate linear regression (LinR) models were created to study per-treatment volume changes. A logistic regression (LogR) analysis explored associations between baseline characteristics and volumetric changes with radiological complete response (CR) at the date of last news. Adrenal SMART in 5 fractions of either 8 or 10Gy was delivered to 70 patients. The median interval between simulation and F1 was 13 days (range, 2-35), and 13 days between F1-F5 (range, 9-31). Solitary metastasis comprised 44%; metastases were mainly from non-small cell lung (64%) or renal (9%) primaries. Concurrent systemic therapy (± 3 months) was delivered in 41% of patients. Mean baseline GTV at simulation and F1 were respectively 38.5 and 41.4cc (p<0.001). Mean ΔPF1 was +9.1% (-10.2% to +50.1%) or +2.9cc (-4.4 to +27.4cc). Mean DRVC was +0.8% per day (-1.0% to +8.4%), and did not correlate with histology, GTV or concurrent systemic treatment. Mean DAVC was +0.26cc per day (-0.31 to +2.4cc), and was associated with GTV size (p = 0.04). In total, 47% of adrenal GTVs decreased in volume at F5 compared to F1. A ≥10% increase in GTV was observed in 39% of patients during SMART. GTV variations of ≥20% occurred in 36% patients at some point during SMART. At a median follow-up of 20.3 months, radiological CR was seen in 23% of 64 evaluable patients. Radiological CR was significantly associated with baseline GTV (p = 0.03) and ΔF1F5 (p = 0.03), but not DRVC (p = 0.6) or ΔF1F3 (p = 0.3). Local relapses were seen in 6% of patients. Changes in adrenal volumes during SMART were common, with variations ≥20% occurring in 36% patients. The probability of a radiological CR correlated with both baseline GTV size and median relative volume decline between fractions 1 and 5. These changes support use of daily SABR plan adaptation.

Single-Fraction Pre-Operative Stereotactic Radiosurgery for Early-Stage Breast Cancer: Pathological Findings

to assess pathological results after single-fraction pre-operative stereotactic radiosurgery of early-stage breast cancer. A phase 2 clinical trial to investigate the feasibility of pre-operative radiosurgery for early-stage breast cancer was conducted. Eligible patients are women older than 50 years, with histologically proven breast invasive ductal carcinoma, hormonal receptors positive/human epidermal grow factor receptor 2 negative, any grade, tumor size < 3cm, unifocal, with no nodal involvement, and suitable for breast conservative surgery. An expert radiologist injected ultrasound-guided a fiducial marker to precisely identify tumor positioning. The Planning Target Volume (PTV) is created by adding a 3mm margin to the Gross Tumor Volume (GTV). A single fraction of 30-33 Gy is delivered to 95% of PTV. Patients had a breast MRI scan 6-12 weeks after treatment to evaluate the rate of radiological response. Surgery was performed at 9 to 16 weeks after irradiation. From January 2022 to December 2022, 33 patients underwent single-fraction radiosurgery, of whom 29 had breast conserving surgery (BCS). BCS was performed at 9-10 weeks for the first 14 patients, at 14-16 weeks for 13 patients, and at 18-19 weeks for 2 patients. The pathological response was defined as complete response (pCR) if no residual tumor cells were found, partial response (pPR), or no response. The pPR were also subdivided into 3 subgroups according to the rate of residual disease: < 10%, 10-50%, and > 50%. Two patients (7%) achieved pCR, both treated with 33 Gy and operated at 14 weeks. Twenty-five patients (86%) had pPR, of which 7 patients (24%) had residual disease < 10%, 9 patients (31%) between 10-50% and 9 patients (31%) over 50%. Two patients (7%) had no pathological response. All patients had sentinel lymph node biopsy at the time of surgery. Positive micrometastatic nodal involvement was found in 3 patients (11%), of which 2 patients (7%) had macrometastases (pN1a) and received subsequent axillary lymph node dissection. All patients had negative surgical margins. Not any acute and sub-acute surgical complications were observed. Single-fraction pre-operative stereotactic radiosurgery for early-stage breast cancer leads to a high rate of complete or partial pathological response with surgery performed at 2-4 months following irradiation.

Advanced Hepatocellular Carcinoma Patients with Poor Access to Systemic Therapy Treated with Definitive Stereotactic Body Radiation Therapy: A Single-Institution Experience in Latin America

The standard treatment for patients with advanced hepatocellular carcinoma (aHCC) is systemic therapy with or without stereotactic body radiation therapy (SBRT). We present our experience using SBRT as a definitive treatment for aHCC patients with poor access to systemic therapy. We performed a retrospective review of patients treated with SBRT at the largest institution in Santiago, Chile between June 2016 and September 2022. All patients were deemed unsuitable for another locoregional treatment by the tumor board. We registered demographic, clinical and treatment characteristics. Additionally, treatment response rates using mRECIST criteria, overall survival (OS), local control (LC) and treatment toxicity were reported. We performed a multivariate analysis of variables using Cox proportion hazard ratio for OS and logistic regression for LC. A total of 59 patients were included (41 males and 18 females; median age: 70 years [range: 38 - 85 years]), with a total of 63 treatment courses. Most common etiologies of chronic liver disease were nonalcoholic fatty liver disease (23%) and chronic alcohol consumption (20%). Most patients were classified as Child-Pugh Class A (80%). Barcelona Clinic Liver Cancer (BCLC) stage was 2%, 11%, 49% and 38% for stages 0, A, B and C, respectively, while macrovascular invasion was present in 10 (18%) of patients. Forty-six patients (73%) had been subjected to prior locoregional therapy and only 5 patients (8,5%) received systemic therapy after SBRT. Median tumor size was 7 cm. (range: 0.95 - 32 cm). Median radiation dose was 40 Gy (range: 26.5 - 50 Gy) in 5 fractions. Evaluation of radiological response was performed in 46 patients (79%), with complete response, partial response, stable disease and progressive disease in 41%, 43%, 7% and 9% of the cohort, respectively. With a median follow-up of 9 months (range: 0 - 58), 34 patients (58%) died with a median OS of 10.8 months (range: 0 - 28 months). At 12 months, OS was 65.2% (95% CI: 50.9 - 76.3) and at 24 months was 40.7% (95% CI: 26.2 - 54.6) In multivariate analysis tumor size (as a continuous variable) was the only significant variable for LC (OR 2.9 [CI 1.1 - 5.3; p 0.03]) and for OS (HR 3.4 [CI 1.3 - 6.7; p< 0.01]). Four patients developed grade 3 toxicity (3 thrombocytopenia and 1 duodenal ulcer) and only two treatments were suspended definitively. Despite systemic therapy is the standard treatment for aHCC, a minor proportion of patients received the standard of care. SBRT is safe, feasible and a well-tolerated treatment option for aHCC with good clinical outcomes. To our knowledge, this is the first cohort reported of patients with aHCC treated with SBRT in Latin America.

Role of Stereotactic Body Radiation Therapy in Portal Vein Tumor Thrombosis in Hepatocellular Carcinoma: A Prospective Single Institute Experience

Patients diagnosed with Hepatocellular carcinoma (HCC) complicated with portal vein tumor thrombosis (PVTT) have a limited number of treatment options available and are associated with an overall poor prognosis. With the recent developments in the field of radiation therapy, the role of radiotherapy particularly Stereotactic Body radiotherapy (SBRT) has increased as a loco-regional therapy for HCC. This study was planned to evaluate the role of SBRT in Locally advanced HCC complicated with PVTT and its role as loco-regional therapy. We conducted a prospective study that included patients diagnosed with HCC complicated with PVTT Child-Turcotte Pugh (CTP) Class A/B with a maximum score of 7, diagnosed on triple phase Contrast-Enhanced - MRI unsuitable for other ablative procedures. Patients with Bilirubin levels > 4 mg/dl, active Hepatitis, CTP score >7, normal liver volume <700cc or history of prior radiotherapy were excluded from the study. Patients underwent a contrast enhanced 4D-CT simulation with abdominal compression and were planned for SBRT using VMAT technique. Patients were followed-up as per Institute protocol. CECT or MRI for a radiological response was done for response assessment using mRECIST criteria version 1.1. A baseline MRI was done at one-month post-SBRT to understand any RT changes in the liver and to differentiate from tumor progression during the response assessment at three months. A total of 22 patients with HCC were recruited and received SBRT to PVTT, with a dosage between 30-42 Gy over 6 fractions treated on alternate days. Patients were assessed post-treatment with triphasic CE-MRI every 3 months as per institute protocol. Five patients had achieved Complete response in form of Portal vein recanalization. Three patients had Partial response to the treatment. Seven patients maintained stable disease status whereas six patients had disease progression during the entire course of treatment. The response rate (CR+PR) to treatment was 36.3% at the time of analysis. The Overall Response rate (CR+PR+SD) was 69%. No grade 3 or 4 toxicities were observed and treatment was tolerated well by patients. Kaplan-Meier method was applied to calculate the survival probability at various follow-up intervals. The median time for overall survival was 25 months ((95% CI: 15-35). Out of the 22 subjects included in the study, 6 patients died. There was a 78% survival probability at 12 months and a 68% survival probability at 18 months of follow-up. This prospective single-arm study demonstrated the vital role of SBRT in the treatment of Hepatocellular carcinoma with Portal vein tumor thrombosis and its efficacy in terms of achieving excellent local control with relatively lesser toxicities compared with existing treatment modalities. Patients have shown benefit post-treatment in terms of thrombus reduction and restoration of Portal vein flow making them suitable for further treatment like Resection or TACE.

Combination of transarterial radioembolization with atezolizumab and bevacizumab for intermediate and advanced staged hepatocellular carcinoma: A preliminary report of safety and feasibility

PurposeThe IMbrave150 Phase III trial demonstrated the superiority of atezolizumab and bevacizumab (Atezo/Bev) over sorafenib for unresectable hepatocellular carcinoma (HCC). The present study aims to evaluate the feasibility of TARE in combination with Atezo/Bev for the treatment of intermediate and advanced staged HCC. MethodsA retrospective review at a single institution was performed between May 2021 and December 2022. Patients who received TARE using yttrium-90 (Y90) with concomitant or sequential Atezo/Bev systemic treatment were included. The following outcomes were retrieved: overall survival (OS), radiologic tumor response, progression-free survival, technical adverse events related to TARE, and toxicity based on the National Cancer Institute–Common Terminology Criteria for Adverse Events version 5.0. ResultsTen consecutive patients with intermediate (n ​= ​4) and advanced stage HCC (n ​= ​6) were treated with TARE and sequential/concomitant Atezo/Bev. Tumor control was achieved in all TARE-treated target lesions (100%). Overall disease progression occurred in 4 patients with PFS of 78.8% and 66.7% at 6- and 12- months, respectively. Two patients died at follow-up, with 6-month and 12-month OS rates of 90.0% and 77.1%, respectively. Three (75%) patients with intermediate stage disease were downstaged into Milan criteria. One patient developed grade 3 transaminitis and hypoglobulinemia, while Atezo/Bev was switched to Lenvatinib in another patient due to immunotherapy related myositis. ConclusionThis study demonstrates the initial safety and feasibility of combined TARE with Atezo/Bev for intermediate/advanced stage HCC. Further prospective studies with larger sample sizes are warranted.

Assessment of CT perfusion indices of the clinicoradiological response to anti-tubercular therapy in patients with intestinal tuberculosis

To explore the possibility of using a novel technique, CT perfusion imaging, to monitor the response to anti-tubercular therapy (ATT) in patients with intestinal tuberculosis. A prospective observational study was performed in adults with treatment naive-intestinal tuberculosis. Clinical, endoscopic, and conventional radiological findings of patients were compared at baseline and post-ATT. CT perfusion imaging was performed with recording of six perfusion parameters (blood flow, blood volume, mean transit time, time to peak, maximum peak intensity, and permeability/blood flow extraction). Twenty-two patients (13 women, 59%) with a median age of 25 years were recruited. The terminal ileum and ileocaecal junction were the most frequent sites of involvement (59%), with multiple segments of the intestine being involved in 16 patients (73%). Median duration of ATT was 6 months (range 6-10 months). Complete clinical response was observed in 22/22 (100%) patients, endoscopic response in 12/12 (100%) patients, and radiological response in 10/13 (76%) patients. There was a significant decrease in mean blood flow, blood volume, maximum peak intensity, and an increase in mean transit time and time to peak on follow-up CT perfusion imaging performed after 6 months of ATT. Significant alterations in CT perfusion parameters were demonstrated following treatment, consistent with a decline in inflammation and vascularity. CT perfusion imaging of the bowel is a novel means to assess the radiological response to ATT in intestinal tuberculosis, although at the cost of a higher dose of radiation exposure.

THREE FRACTION STEREOTACTIC RADIOTHERAPY (SRT) FOR VESTIBULAR SCHWANOMMA: THE WESSEX EXPERIENCE

Abstract AIMS Retrospective review of SRT for vestibular schwannoma. University Hospital Southampton treat tumour vol umes max 2.5cm in diameter without brainstem compression with 21Gy/3#. This reviews the experience of local control and toxicity profile in our centre and the impact of limiting dmax. METHOD Retrospective analysis of patients treated for radiologically diagnosed vestibular schwannoma from 2019 to present. Patient notes, audiograms, imaging and radiotherapy planning system were reviewed for data collection. No patients were removed from analysis due to missing data. RESULTS 36 patients have been treated with three fraction SRT. Median age 68 (47-83). PTV volume from 1.03cm3 to 5.52cm3 (median 2.37cm3). All patients have radiologically stable disease to date, with 14 patients (38.9%) having objective tumour response on imaging. 9 patients had serviceable hearing at baseline and 1 remained serviceable at follow up. 7 (19.4%) patients experienced treatment-related toxicity. 6 patients reported facial nerve toxicity in which 4 (66.7%) this was self-limiting with full recovery. 2 patients had persistent facial nerve symptoms (House-Brackmann score 2, and 3 respectively). Those with dmax &amp;lt;26Gy (n=15) experienced this less with only 1 patient experiencing facial nerve toxicity (House-Brackmann score 2). CONCLUSIONS Three fraction SRT provides excellent local control with high levels of objective radiological response in tumours up to 4cm3, however, long term follow-up is required. This treatment has acceptable toxicity with most symptoms resolving spontaneously. Permanent facial nerve toxicity was seen in 2 (5.6%) of patients. By limiting dmax to &amp;lt;26Gy the rate of facial nerve toxicity is reduced significantly.

Randomized Controlled Trial of Neoadjuvant Short-Course Radiotherapy Followed by Consolidation Chemotherapy Versus Long-Course Chemoradiotherapy in Locally Advanced Rectal Cancer: Comparison of Overall Response Rates.

Management of locally advanced rectal cancer (LARC) is evolving with current emphasis on the addition of chemotherapy to short course radiotherapy (SCRT). We primarily aimed to analyse the difference in overall response rates between SCRT with sequential chemotherapy and standard long-course chemoradiotherapy (LCCRT)in LARC. After randomization, patients in arm A received 45Gy in 25 fractions over 5weeks with concurrent capecitabine while patients in arm B received 25Gy in 5 fractions over 1week followed by 3 cycles of CAPOX (capecitabine and oxaliplatin) chemotherapy. Clinical and radiological response assessment was made after the completion of neoadjuvant treatment, a week prior to surgery. Adjuvant chemotherapy was added to complete 6months of peri-operative chemotherapy. Surgery was performed between 8 and 10weeks of completion of radiation treatment in both arms. Of the 33 patients recruited in this study between February 2020 to July 2021, 17 patients were randomized to arm A and 16 to arm B. The rates of complete tumour regression were 23.1% in arm A versus 35.7% in arm B (p-value = 0.683). Pathological complete response (pCR) rate was 20% arm A versus 30% in arm B (0.446). A higher number of patients in arm B experienced grade 3 diarrhoea, whereas acute skin toxicity was seen only in arm A. SCRT had fewer treatment interruptions compared to LCCRT. SCRT followed by three cycles of CAPOX chemotherapy in the neoadjuvant setting is comparable to LCCRT in terms of tumour response. This may be a better alternative regimen with fewer treatment interruptions in a resource-limited setting.

Prognostic impact of post-treatment FDG PET/CT in anal canal cancer: A prospective study

Background and purposeThe aim of our prospective study was to assess the prognostic value of 18F-FDG PET/CT performed two months post treatment for anal canal neoplasm. Population and methodsConsecutive patients with histologically proved anal cancer, with 18F-FDG PET/CT pre and two months post treatment were included. Patients were not previously treated for this neoplasm and then received radiotherapy ± chemotherapy. Clinical and pathologic data were collected and for 18F-FDG PET/CT visual and quantitative analysis (standardized uptake value, metabolic volume) were performed; response was classified according to EORTC and PERCIST criteria. The results were assessed for disease free survival and local recurrence free survival using the log-Rank test ResultsFrom December 2014 to September 2019, 94 consecutive patients were screened and 78 were included in this study. Median follow-up was 51 months. Two months post treatment, 37 patients (47.4%) had a complete radiological response according to both EORTC and PERCIST criteria, 66 patients (84.6%) had a clinical complete response. For disease free survival, the prognostic value of complete response was statistically significant (p=0.02) with 18F-FDG PET/CT and with clinical examination (p<0.001). For local recurrence free survival, the prognostic value with 18F-FDG PET/CT was lower (p=0.04) than clinical examination (p < 0.007). ConclusionWhile clinical examination remains the gold standard for post treatment evaluation in anal cancer, 18F-FDG PET/CT has a statistically significant prognostic value. These two assessments could be combined to improve early evaluation.

P17.09.B REIRRADIATION AS A SALVAGE THERAPY FOR LOCAL GLIOBLASTOMA RECURRENCE

Abstract BACKGROUND There is a lack of successful strategies to treat glioblastoma (GB) recurrences. Reirradiation is one of them, but it only can be considered in a few patients with localized relapses. This review aims to analyse the role of reirradiation in this setting and the management difficulties associated with this strategy. MATERIAL AND METHODS We have retrospectively reviewed the outcome of GB patients treated with surgery and the standard Stupp regimen, that have received stereotactic radiotherapy (RT) at the time of a local in-field relapse in our centre, during the period from 2005 to 2022. RESULTS 44 patients have been identified. The recurrence occurred at a median time of 9.7 months (m) after the end of the first RT. It was the first relapse in 89% of patients, and RT was given exclusively in 47.7% of cases. In the remaining patients, RT was combined with other treatments. The median maximum diameter of the relapse was 13.5 mm. Treatment schemes were mainly two: 35 Gy in 3.5 Gy daily fractions (52%) and 20 Gy in 5 Gy daily fractions (39%). Acute toxicity was mild, with worsening of previous neurological symptoms in only 15% of patients. After a median follow-up of 15 m, radiological responses were observed in 40% of patients, with a remarkable number of distant progressions in less than 6m (32.5%). The median time to progression was 4.8 m, being longer for patients treated at first relapse, females and with a Karnofsky index (KI) &amp;gt;70. The diameter of the relapse showed a tendency to impact in time to progression, but no differences for RT dose, RT scheme or type of strategy (exclusive RT vs combined) have been detected. The median overall survival after reirradiation was 14.9 m. Related prognostic factors were KI &amp;gt;70, size of the relapse (maximum diameter &amp;lt;25 mm) and reirradiation given at first relapse. Radiological changes after reirradiation were commonly observed (47% of patients); differentiating them from true local progression was often difficult. CONCLUSION Reirradiation is a feasible and safe therapeutic option to treat localized GB relapses, able to control the disease for a few months in selected patients, especially those with first recurrences and small lesions. Further studies must be performed to improve the radiological evaluation in these patients and to determine the optimal combination with other treatment modalities.

P04.01.B MEK INHIBITORS IN PEDIATRIC RECURRENT SYMPTOMATIC UNRESECTABLE LOW-GRADE GLIOMAS HARBORING MAPK ALTERATION: A SINGLE CENTER EXPERIENCE

Abstract BACKGROUND Treatment of inoperable, recurrent, progressive pediatric low-grade gliomas (pLGGs) remains controversial. Recent studies focused on aberrant activation of the mitogen-activated protein kinase (MAPK) pathway, due to gain of function mutations in RAS or BRAF genes or loss or inactivation of NF1. Selumetinib and trametinib, orally bioavailable and selective MEK1/MEK2 inhibitors (MEKi), act on MAPK pathway. In April 2020 the US Food and Drug Administration and in June 2021 the European Medicines Agency approved selumetinib for inoperable plexiform neurofibromas in Neurofibromatosis type 1 (NF1). We evaluated MEKi efficacy and safety in pLLGs harboring MAPK alteration. MATERIAL AND METHODS From July 2021 to February 2023 eight patients (5 females, 3 males, median age 8 years, range 4-18) were admitted to our hospital for symptomatic, recurrent, inoperable pLGGs (location: 3 hypothalamic-optic chiasm region, 2 posterior fossa, 1 temporo-mesial, 1 quadrigeminal plate, 1 diffuse leptomeningeal; MAPK alteration: 3 NF1 inactivation, 4 KIAA1549/BRAF gene fusion, 1 RNF130/BRAF fusion). MEKi were administered (6 selumetinib, 2 trametinib) after disease progression for failure of previous treatments (6 partial resection, 7 multiple chemotherapies, 2 radiotherapy). MRI assessment was performed every 4 months and radiological response was defined in accordance with RAPNO criteria. RESULTS At first evaluation, 3/8 patients (37,5%) showed a partial radiological response (-64,96% mean volume reduction, range 52,61%-77,19%) and 4/8 (50%) stable disease (0-41.67% volume decrease). Disease progression was observed in a patient heavily pretreated for acute leukemia. One patient with leptomeningeal spreading showed progressive disease at second evaluation. Median time to progression has not yet been reached. Six of 8 patients experienced at least one toxicity. The most frequent toxicities reported were mucocutaneus disorders (rash, mucositis, eczema). Three patients presented creatine phosphokinase (CPK) increase (one grade 2 with rapid normalization after therapy discontinuation). All patients on trametinib had to reduce treatment dose (for skin toxicity or increasing blood pressure). CONCLUSION MEKi, selumetinib and trametinib, represent promising strategies in children with recurrent/progressive LGGs harboring MAPK alterations. In our small series, the treatment was effective and well tolerable in patients with localized disease and without other risk factors. The most common toxicities were CPK elevation and rash. Further studies are needed to identify patients who may benefit most from MEKi treatment and to establish whether such treatments are superior to chemotherapy in front line setting for MAPK altered pLGGs.

P09.03.A DEVELOPMENT OF A CORE OUTCOME SET FOR USE IN ADULT PRIMARY GLIOMA PHASE III INTERVENTIONAL TRIALS - A MIXED METHODS STUDY

Abstract BACKGROUND Glioma patients’ high symptom burden and the poor prognosis of high grade glioma has emphasised quality of survival and overall health-related quality of life (HRQOL) throughout the disease trajectory in clinical trials. Patient-reported outcomes (PROs) allow insight into how investigative treatment affects patients’ perceived functioning, complementing other outcome data (e.g. survival, radiological response) in clinical decision-making. Creating robust evidence requires effective data synthesis and meta-analyses across trials, underpinned by consistent trial outcome measurement, analysis and reporting. However, a standard ontology is lacking in cancer clinical trials, and brain tumours specifically, and selective outcome reporting is common. Core outcome set (COS) development is one means to improve data synthesis. The COBra project aimed to develop a COS for use in glioma phase III trials in support of those goals. Given stakeholder interest in PROs and prioritising the patient perspective, we also undertook initial exploration of which items could be patient reportable. MATERIAL AND METHODS A COS for adult primary glioma phase III interventional trials was developed through: (1) trial registry review and systematic review of qualitative studies; (2) interviews with glioma patients and caregivers; (3) outcome list de-duplication; (4) two-round Delphi process and outcome list rating; (5) a consensus meeting to finalise the COS. Patient-reportable COS outcomes were identified by cross-referencing the final COS outcomes with outcomes and PRO measures (PROMs) reported in the trial registry review. Activities were guided by UK Patient and Public Involvement standards and public contributors were core research team members. RESULTS A COS consisting of 19 outcomes grouped into seven outcome domains (Survival, Adverse Events, Activities of Daily Living, HRQOL, Seizure Activity, Cognitive Function and Physical Function) was finalised for use in glioma trials using this structured approach. Mapping PROMs identified in the registry review suggests that sub-domains of 6/7 outcome domains in the final COS can be patient-reported (adverse events, activities of daily living, HRQOL, seizure activity, neurocognitive function, physical function). Other currently unidentified instruments may also be suitable. Further research will identify appropriate measurement tools, promote accessible PRO delivery, and validate this COS for wider use. CONCLUSION A COS for glioma trials was developed, comprising seven outcome domains. Development of this COS coincides with growing regulatory interest in patient-reported data. To optimise data synthesis and prioritise the patient perspective, opportunities to collect data in this way should be promoted and taken. As such, this COS could be considered for use in registrational trials after further validation.

P11.35.B STEREOTACTIC RADIOTHERAPY FOR VESTIBULAR SCHWANOMMAS: THE WESSEX EXPERIENCE

Abstract BACKGROUND Review of SRT for vestibular schwannoma (VS) within Wessex region led by University Hospital Southampton (UHS). UHS treat tumour volumes max 2.5cm in diameter without brainstem compression with 21Gy/3#. We reviewed the experience of local control and toxicity profile in our centre comparing with 1 and 5 fraction SRT schedules. We present three fraction SRT as an appropriate fractionation schedule. MATERIAL AND METHODS This is a retrospective analysis of patients treated for radiologically diagnosed vestibular schwannoma from 2019 to present. Patient notes, audiograms, imaging and radiotherapy planning system were reviewed for data collection. No patients were removed from analysis due to missing data. RESULTS 84 patients have been treated with SRT for VS. Median age 66 (39-94). 12Gy/1# (1#) in 36 patients, 21Gy/3# (3#) in 36 patients, 25Gy/5# (5#) in 12 patients. In the 1# group PTV volume 0.31cm3-4.44cm3 (median 1.12cm3), in the 3# group PTV volume from 1.03cm3 to 5.52cm3 (median 2.37cm3), in the 5# group 2.05cm3-5.44cm3 (median 4.12cm3). All patients have radiologically stable disease to date. Objective radiological response noted in 14 patients (38.9%) in 3# group this is higher than any other group and statistically significant (p=0.016). Pre-treatment serviceable hearing only in a minority of patients. Treatment related toxicity was seen in 27% in the 1# group, 19% of patients within the 3# group, and 33% in the 5# group. This was mostly mild and self-limiting. Facial nerve toxicity was seen in 8.3% of the 1# group, 16.7% of 3# group, and 33.3% of the 5# group. However, this was only persistent in 2 patients in 1# group (5.6%), 2 patients in the 3# group (5.6%), and 1 (8.3%) in the 5# group. There is no statistical difference in toxicity between any group using Chi squared test. In 3# group, when Dmax limited to &amp;lt;26Gy (n=15), the frequency of facial nerve toxicity reduces to 1 (2.78%). CONCLUSION Three fraction SRT provides excellent local control with high levels of objective radiological response in tumours up to 4cm3, however, long term follow-up is required. This treatment has acceptable toxicity which is not significantly different from alternative fractionation schedules and is improved by limiting Dmax to &amp;lt;26Gy.

Longitudinal monitoring of response to chemotherapy in patients with malignant pleural mesothelioma by biomarkers.

The aim of the study was to longitudinally investigate the serum levels of mesothelin, sestrin1, hyaluronan synthase 2 (HAS2), midkine, and high mobility group box 1 (HMGB1) before and after chemotherapy and at the time of relapse in malignant pleural mesothelioma (MPM) patients treated with chemotherapy and to compare the changes in biomarker levels with radiological treatment outcome. A total of 64 MPM patients treated with chemotherapy were enrolled in the study and longitudinally followed for changes in biomarker levels in response to treatment. Biomarkers evels were measured in serum using a human ELISA kit. Relative and absolute changes in biomarker levels were compared with the best radiological overall response at each time point. Median survival was 20.0 ± 2.4 (15.3-24.7) months in patients with partial and complete response, 17.0 ± 1.0 (15.0-19.0) months in patients with stable disease, and 9.0 ± 1.0 (7.0-11.0) months in patients with progressive disease. A significant decrease in serum levels of mesothelin, midkine, and HMGB1 was observed in patients with radiologically partial and complete responses to chemotherapy (p< 0.001, p= 0.016, and p= 0.039, respectively). In these patients, mesothelin levels decreased by 15%, midkine levels by 7%, and HMGB1 levels by 15%. In addition, HMGB1 serum levels were found to significantly increase by 15% in patients with radiologically progressive responses to chemotherapy compared to pretreatment serum levels (p= 0.035). In patients with partial and complete response to chemotherapy, mesothelin levels increased by 15%, midkine by 12%, and sestrin1 by 8% when the disease recurred (p= 0.004, p= 0.004 and p= 0.044, respectively). Biomarkers may be useful in the longitudinal monitoring of response to treatment in MPM. However, the results of our study should be validated in larger groups with sufficient case numbers from multicenter institutions.