Locoregional Therapy In Patients Research Articles

Neoadjuvant Nivolumab Plus Chemotherapy Followed By Response-Adaptive Therapy for HPV+ Oropharyngeal Cancer

Immune checkpoint inhibitors improve survival in recurrent and/or metastatic head and neck cancer, yet their role in curative human papillomavirus-positive oropharyngeal cancer (HPV+ OPC) remains undefined. Neoadjuvant nivolumab and chemotherapy followed by response-adaptive treatment in HPV+ OPC may increase efficacy while reducing toxicity. To determine the deep response rate and tolerability of the addition of neoadjuvant nivolumab to chemotherapy followed by response-adapted locoregional therapy (LRT) in patients with HPV+ OPC. This phase 2 nonrandomized controlled trial conducted at a single academic center enrolled 77 patients with locoregionally advanced HPV+ OPC from 2017 to 2020. Data analyses were performed from February 10, 2021, to January 9, 2023. Addition of nivolumab to neoadjuvant nab-paclitaxel and carboplatin (studied in the first OPTIMA trial) followed by response-adapted LRT in patients with HPV+ OPC stages III to IV. Primary outcome was deep response rate to neoadjuvant nivolumab plus chemotherapy, defined as the proportion of tumors with 50% or greater shrinkage per the Response Evaluation Criteria in Solid Tumors 1.1. Secondary outcomes were progression-free survival (PFS) and overall survival (OS). Swallowing function, quality of life, and tissue- and blood-based biomarkers, including programmed death-ligand 1 (PD-L1) expression and circulating tumor HPV-DNA (ctHPV-DNA), were also evaluated. The 73 eligible patients (median [range] age, 61 [37-82] years; 6 [8.2%] female; 67 [91.8%] male) started neoadjuvant nivolumab and chemotherapy. Deep responses were observed in 51 patients (70.8%; 95% CI, 0.59-0.81). Subsequent risk- and response-adaptive therapy was assigned as follows: group A, single-modality radiotherapy alone or transoral robotic surgery (28 patients); group B, intermediate-dose chemoradiotherapy of 45 to 50 Gray (34 patients); and group C, regular-dose chemoradiotherapy of 70 to 75 Gray (10 patients). Two-year PFS and OS were 90.0% (95% CI, 0.80-0.95) and 91.4% (95% CI, 0.82-0.96), respectively. By response-adapted group, 2-year PFS and OS for group A were 96.4% and 96.4%, and group B, 88.0% and 91.0%, respectively. Lower enteral feeding rates and changes in weight, as well as improved swallowing, were observed among patients who received response-adapted LRT. Pathologic complete response rate among patients who underwent transoral robotic surgery was 67.0%. PD-L1 expression was nonsignificantly higher for deeper responses and improved PFS, and ctHPV-DNA clearance was significantly associated with improved PFS. This phase 2 nonrandomized controlled trial found that neoadjuvant nivolumab and chemotherapy followed by response-adapted LRT is feasible and has favorable tolerability, excellent OS, and improved functional outcomes in HPV+ OPC, including among patients with high-risk disease. Moreover, addition of nivolumab may benefit high PD-L1 expressors, and sensitive dynamic biomarkers (eg, ctHPV-DNA) are useful for patient selection. ClinicalTrials.gov Identifier: NCT03107182.

Personalizing Locoregional Therapy in Patients With Breast Cancer in 2024: Tailoring Axillary Surgery, Escalating Lymphatic Surgery, and Implementing Evidence-Based Hypofractionated Radiotherapy.

The management of axillary lymph nodes in breast cancer is continually evolving. Recent data now support omitting axillary lymph node dissection (ALND) in most patients with metastases in up to two sentinel lymph nodes (SLNs) during upfront surgery and those with residual isolated tumor cells after neoadjuvant chemotherapy (NACT). In the upfront surgery setting, ALND is still indicated, however, in patients with clinically node-positive breast cancer or more than two positive SLNs and, after NACT, in case of residual micrometastases and macrometastases. Omission of the sentinel lymph node biopsy (SLNB) can be considered in many postmenopausal patients with small luminal breast cancer, particularly when axillary ultrasound is negative. Several randomized controlled trials (RCTs) are currently aiming at eliminating the remaining indications for ALND and also establishing omission of SLNB in a broader patient population. The movement to deescalate axillary staging is in part because of the association between ALND and lymphedema, which is swelling of an extremity because of lymphatic damage and obstructed lymphatic drainage. To reduce the risk of developing this condition, patients undergoing ALND can undergo reverse mapping of the axilla and immediate reconstruction or bypass of the lymphatics from the involved extremity. Decongestion and compression are the foundation of conservative treatment for established lymphedema, while lymphovenous bypass and lymph node transfer are surgical procedures to address the physiologic dysfunction. Radiotherapy is an essential component of breast locoregional therapy: more than three decades of radiation research has optimized treatment according to patient's risk of local recurrence while substantially reducing the number of treatment visits. High-quality RCTs have shown the efficacy and safety of hypofractionation-more than 2Gy radiation dose per treatment (fraction)-significantly reducing the burden of radiotherapy treatment for many patients with breast cancer. In 2024, guidelines recommend no more than 15-16 fractions for whole-breast and nodal radiotherapy, with some recommending five fractions for whole-breast radiotherapy. In addition, simultaneous integrated boost (SIB) has been shown to be noninferior to sequential boost with regards to ipsilateral breast tumor recurrence with similar or reduced long-term side effects, also reducing overall treatment length. Further RCTs are underway investigating other indications for five fractions, including SIB and regional node irradiation, such that, in future, it may be possible for the majority of breast radiotherapy patients to be treated with a 1-week course. This manuscript serves to outline the latest updates on axillary surgical staging, lymphatic surgery, and evidence-based radiotherapy in the treatment of breast cancer.

Survival and time off chemotherapy after locoregional therapy for patients with metastatic pancreatic adenocarcinoma

Survival and time off chemotherapy after locoregional therapy for patients with metastatic pancreatic adenocarcinoma

Examining the treatment journey of patients diagnosed with hepatocellular carcinoma (HCC) using retrospective real-world data in British Columbia, Canada.

e16111 Background: Hepatocellular carcinoma (HCC) is a complex disease with treatments that may include locoregional therapy (LRT), systemic therapy and liver transplant. Using retrospective real-world data from a tertiary care hospital in British Columbia (BC). We examined characteristics, treatment pathways, survival and relevant healthcare costs of HCC patients. Methods: This was a retrospective, real-world data study using data from two existing chart review studies (called MOTION and HCC) and the BC Transplant database. The Canadian province of British Columbia has a population of 5.0 million who receive medical coverage under the Medical Services Plan. “MOTION” collected data on patients who received LRTs between 2004 and 2017, while “HCC” collected data on patients who received systemic therapies between 2000 and 2019. MOTION and HCC and Transplant data were linked and patients were assigned a unique study number and personal health information (PHI) was removed. Start and stop dates for LRT and systemic therapies were used to determine treatment patterns. Treatment costs were provided by BC Cancer’s Pharmacy department, medical oncology visits were assumed to be monthly while patients were on systemic treatment, LRT costs were based on departmental expenditures, and the cost of a liver transplant was provided by the regional health authority. Analyses used descriptive statistics for baseline characteristics, duration and costs (in 2021 Canadian dollars) and Kaplan-Meier curves for survival. Results: There were 417 and 413 patients from the HCC and MOTION databases respectively, in which 63 patients were in both (referred to as the “common” group). Median age (years) at diagnosis was 64, 62 and 62 for HCC, MOTION and common groups respectively, while the proportion who were female was 17.5%, 18.2% and 15.9%. Median overall survival (mOS) from diagnosis was 21, 33 and 28 months for the HCC, MOTION and common groups, respectively. From start of systemic treatment, mOS was 9 months for the HCC group, 29 months from first LRT for patients in the MOTION group, and 26 months for the common group from first treatment. Treatment and cost results were based only on the common group: mean length of follow-up from diagnosis was 34.6 ± 26.2 months and mean time from diagnosis to first treatment was 4.7 ± 4.2 months. DEB-TACE was most frequently the first LRT, often received 3 rounds of LRT before starting systemic treatment, in which sorafenib was given mostly as first line systemic therapy. When including only costs related to LRTs, systemic therapies, medical oncology visits and liver transplants, the mean cost per patient was $94,419, resulting in $51,649 mean cost per patient per year. Conclusions: The linkage of HCC-related LRT, systemic and transplant databases provided detailed results related to the treatment patterns, survival and costs of HCC patients in Canada.

The Safety and Effectiveness of Hepatic Transarterial Embolic Locoregional Therapy in Patients with Contraindications to Hepatectomy after Portal Vein Embolization

The safety and effectiveness of hepatic transarterial embolic locoregional therapy (LRT) was assessed, including transarterial chemoembolization (TACE) and transarterial radioembolization (TARE), in patients who underwent portal vein embolization (PVE) before major hepatectomy in whom surgery was then contraindicated. Adverse events (AEs) were graded according to the Society of Interventional Radiology classification of AEs. Tumor response was assessed based on the Response Evaluation Criteria In Solid Tumors 1.1. Overall survival (OS) and progression-free survival (PFS) were estimated. Fifteen patients underwent 37 transarterial LRTs (25 TACEs, 11 TAREs, and 1 bland embolization), most (73%) with hepatocellular carcinoma. Eleven AEs occurred in 7 patients, including 2 Grade 3/5 (severe) and 2 Grade 4/5 (life-threatening) events. The best response was partial response in 4 (27%) and stable disease in 10 (66%) patients. The median OS and PFS were 42 (95% CI, 35–49 months) and 33 months (95% CI, 24–42 months), respectively. In conclusion, hepatic transarterial LRT can be considered as a therapeutic option in patients with contraindicated liver surgery after PVE.

Retrospective analysis of colorectal cancer patients with metachronous initially unresectable liver metastases (and no other) achieving no evidence of disease after first-line comprehensive therapy: a multicenter real-world study.

To explore the optimal timing of locoregional therapy in patients with colorectal cancer (CRC) recurrence after radical resection and initially unresectable liver metastases but no other metastases and whether maintenance therapy should be performed after achieving no evidence of disease (NED). This study was jointly carried out in six medical institutions in China to collect the clinical data of patients with primary CRC from January 2015 to December 2021. Research participants were identified according to the inclusion criteria of this study for statistical analysis of the clinical characteristics and recurrence time. 625 patients CRC with metachronous initially unresectable liver metastases but no other metastases were enrolled. Multivariate analysis showed that the number of metastases in the liver and the time from the start of first-line chemotherapy to locoregional therapy significantly affected the progression-free survival (PFS, P < 0.05) following the first-line treatment, and continued maintenance therapy reduced the risk of tumor progression in the patients (P < 0.05). Furthermore, stratified analysis showed that the median PFS of patients with 3-5 metastases in the liver was maximized when the time from the start of first-line chemotherapy to locoregional therapy was 3-4months. Patients with > 6 metastases in the liver should extend the duration between the start of first-line chemotherapy and locoregional therapy to more than four months. Similarly, with the significant increase in the number of metastases in the liver, subsequent maintenance therapy significantly extended the PFS of the patients. The overall therapeutic plan in patients with CRC recurrence after radical resection and initially unresectable liver metastases but no other metastases should consider the individual patients' situations, especially the number of metastases in the liver at initial recurrence.

First-in-man histotripsy of hepatic tumors: the THERESA trial, a feasibility study

Rationale Current hepatic locoregional therapies are limited in terms of effectiveness and toxicities. Given promising pre-clinical results, a first in-human trial was designed to assess the technical effectiveness and safety profile of histotripsy, a noninvasive, non-thermal, non-ionizing focused ultrasound therapy that creates precise, predictable tissue destruction, in patients with primary and secondary liver tumors. Methods A multicenter phase I trial (Theresa Study) was performed in a single country with 8 weeks of planned follow-up. Eight of fourteen recruited patients were deemed eligible and enrolled in the study. Hepatic histotripsy, was performed with a prototype system (HistoSonics, Inc., Ann Arbor, MI). Eleven tumors were targeted in the 8 patients who all had unresectable end-stage multifocal liver tumors: colorectal liver metastases (CRLM) in 5 patients (7 tumors), breast cancer metastases in 1 (1 tumor), cholangiocarcinoma metastases in 1 (2 tumors), and hepatocellular carcinoma (HCC) in 1 (1 tumor). The primary endpoint was acute technical success, defined as creating a zone of tissue destruction per planned volume assessed by MRI 1-day post-procedure. Safety (device-related adverse events) through 2 months was a secondary endpoint. Results The 8 patients had a median age of 60.4 years with an average targeted tumor diameter of 1.4 cm. The primary endpoint was achieved in all procedures. The secondary safety profile endpoint identified no device-related adverse events. Two patients experienced a continuous decline in tumor markers during the eight weeks following the procedure. Conclusions This first-in-human trial demonstrates that hepatic histotripsy effectively destroys liver tissue in a predictable manner, correlating very well with the planned histotripsy volume, and has a high safety profile without any device-related adverse events. Based on these results, the need for more definitive clinical trials is warranted. Trial Registration: Study to Evaluate VORTX Rx (Theresa). NCT03741088. https://clinicaltrials.gov/ct2/show/NCT03741088 KEY POINTS Histotripsy, a new noninvasive, non-thermal, non-ionizing focused ultrasound therapy, safely created a zone of tissue destruction in the liver that correlated very well with the pre-defined planned tissue destruction volume. In this first human trial histotripsy was well tolerated with no histotripsy device-related adverse events and its primary endpoint of acute technical success was achieved in all 8 enrolled patients with primary or secondary liver tumors. This new locoregional therapy for patients with liver tumors is safe and effective, warranting further trials.

Safety and efficacy of durvalumab plus bevacizumab in unresectable hepatocellular carcinoma: Results from the phase 2 study 22 (NCT02519348).

436 Background: The phase 2 Study 22 trial (NCT02519348) investigated durvalumab (anti-programmed cell death ligand-1 [PD-L1] antibody) and tremelimumab (anti-cytotoxic T-lymphocyte associated antigen 4 antibody) as monotherapy, or durvalumab in combination with tremelimumab or bevacizumab (anti-vascular endothelial growth factor [VEGF] antibody), for the treatment of patients with unresectable hepatocellular carcinoma (uHCC). Results of Study 22 that evaluated durvalumab and tremelimumab as monotherapy or in combination were reported previously. PD-L1 inhibition plus VEGF inhibition with bevacizumab may exhibit an additive effect to improve clinical activity. Herein, we report results from a single-arm cohort of Study 22, evaluating durvalumab plus bevacizumab as first-line treatment in patients with uHCC. Methods: Patients with uHCC who had not received any prior systemic therapy were administered durvalumab 1120 mg plus bevacizumab 15 mg/kg once every 3 weeks. Adequate endoscopic therapy according to institutional standards was required for patients with a history of gastrointestinal bleeding for &gt;12 months or those at high risk for esophageal varices. The primary endpoint was safety. Secondary endpoints included confirmed objective response rate (ORR; assessed by blinded independent central review [BICR] according to RECIST v1.1), duration of response (DoR; RECIST v1.1 by BICR) and overall survival (OS). Results: At the data cut-off (November 6, 2020), 47 patients were allocated to receive treatment. Median total treatment duration was 6.2 months (durvalumab) and 4.1 months (bevacizumab). Thirty-three (70.2%) patients experienced an adverse event possibly related to treatment (TRAE). Grade 3 or 4 TRAEs occurred in 4 (8.5%) patients; serious TRAEs occurred in 5 (10.6%) patients, including gastric ulcer perforation, ascites, and liver tumor rupture, possibly related to bevacizumab, and raised creatinine and pneumonitis, possibly related to durvalumab. There were 3 (6.4%) discontinuations and no deaths associated with TRAEs. Objective responses (RECIST 1.1 by BICR) were confirmed in 10 patients (ORR, 21.3%; 95% CI, 10.7–35.7); median DoR (RECIST 1.1 by BICR) was not reached. Median OS was not reached (95% CI, 12.52 months–non-estimable). Conclusions: Durvalumab plus bevacizumab was well tolerated and showed promising clinical activity in patients with uHCC. Durvalumab with or without bevacizumab in combination with transarterial chemoembolization is being investigated as locoregional therapy in patients with HCC not amenable to curative treatment in the phase 3 EMERALD-1 study (NCT03778957), and durvalumab with or without bevacizumab is being investigated in patients with HCC at high risk of recurrence after curative treatment in the phase 3 EMERALD-2 study (NCT03847428). Clinical trial information: NCT02519348.

Locoregional Therapy in De novo Metastatic Breast Cancer: A Retrospective Cohort Study.

Objective: Whether locoregional therapy (LRT) should be performed in patients with de novo metastatic breast cancer (dnMBC) has been debated. Here we report the survival outcomes of LRT in patients with dnMBC, focusing on the association of surgical timings and surgical margins with survival in this patient population. Methods: The retrospective study included patients with dnMBC in our hospital, between March 1, 2007 and December 31, 2017. Overall survival (OS) was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan–Meier methods. Results: A total of 153 patients were included, of whom 87 underwent LRT and 66 systemic therapy alone (STA). LRT showed a significant OS benefit over STA (HR, 0.62; 95% CI, 0.39 to 0.99; P = .043). The OS of LRT group and STA group were 39 months (95% CI, 33.6 to 44.4 months) and 24.6 months (95% CI, 20.6 to 28.6 months), respectively. The benefit was consistent across most subgroups. The OS of patients undergoing surgery was better than that of patients without surgery (HR, 0.58; 95% CI, 0.35 to 0.94; P = .0001), and there was difference in survival improvement at different surgical timings (surgery before chemotherapy, during chemotherapy, and after chemotherapy) (P = .0001). The survival benefit of surgery after chemotherapy was significantly greater than that of the other 2 options (HR, 0.77; 95% CI, 0.63 to 0.94). Moreover, compared with patients with positive margins, the OS of patients with negative margins was significantly improved (HR, 0.22; 95% CI, 0.13 to 0.37; P < .001). Conclusions: Our results suggest that LRT is associated with improved OS in women with dnMBC, and patients who had surgery after systemic chemotherapy with negative surgical margins, are expected to benefit more.

P-229 Systematic review and pooled analysis of locoregional therapies in patients with intrahepatic cholangiocarcinoma

Locoregional treatments (LRT) including radioembolisation (SIRT), transarterial chemo-embolisation (TACE), hepatic arterial infusion (HAI) of chemotherapy, external beam radiotherapy (EBRT) and ablation, have been studied for the management of intrahepatic cholangiocarcinoma (iCC). The aim of this systematic review was to provide outcome benchmarks for clinical trial design.

Liver Transplantation Outcomes in a U.S. Multicenter Cohort of 789 Patients With Hepatocellular Carcinoma Presenting Beyond Milan Criteria.

The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down-staged (DS) with locoregional therapy (LRT). We evaluated post-LT outcomes, predictors of down-staging, and the impact of LRT in patients with beyond-MC HCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002-2013). Clinicopathologic characteristics, overall survival (OS), recurrence-free survival (RFS), and HCC recurrence (HCC-R) were compared between patients within MC (n=3,570) and beyond MC (n=789) who were down-staged (DS, n=465), treated with LRT and not down-staged (LRT-NoDS, n=242), or untreated (NoLRT-NoDS, n=82). Five-year post-LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n=324; 60.2% and 53.8%; overall P<0.001). DS patients had superior RFS (60% vs. 54%, P=0.043) and lower 5-year HCC-R (18% vs. 32%, P<0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5-year HCC-R of 15.5% in DS/<5cm and 39.1% in NoDS/>5cm, P<0.001). Multivariate predictors of down-staging included alpha-fetoprotein response to LRT, pathologic tumor number and size, and wait time >12months. LRT-NoDS had greater HCC-R compared with NoLRT-NoDS (34.1% vs. 26.1%, P<0.001), even after controlling for clinicopathologic variables (hazard ratio [HR]=2.33, P<0.001) and inverse probability of treatment-weighted propensity matching (HR=1.82, P<0.001). In LT recipients with HCC presenting beyond MC, successful down-staging is predicted by wait time, alpha-fetoprotein response to LRT, and tumor burden and results in excellent post-LT outcomes, justifying expansion of LT criteria. In LRT-NoDS patients, higher HCC-R compared with NoLRT-NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.

4:21 PM Abstract No. 236 Survival outcomes of elderly patients with hepatocellular carcinoma treated with loco-regional therapy: a 20-year single-center experience

To describe survival data of elderly patients with hepatocellular carcinoma (HCC) treated with loco-regional therapy (LRT) and to compare the survival outcomes of “transplantable” LRT patients with patients with HCC outside the criteria for liver transplantation (LT). We retrospectively reviewed the clinical and tumor information of 743 consecutive patients older than 65 years at time of HCC diagnosis treated with LRT from 1998 to 2018 at a single center. This study included only patients with HCC and a known diagnosis date and excluded patients treated surgically prior to LRT or eventually underwent LT. The primary endpoint was overall survival. To establish Milan criteria status, each patient was assessed for size and number of tumors at diagnosis. Patients included in this study, both within and outside Milan criteria radiologically, were ultimately not transplant candidates due to a variety of clinical and social reasons. Results were analyzed using a Kaplan-Meier method and a univariate Cox regression model. Two hundred and eighty-five patients met the inclusion criteria (age 72.5 ± 5.6). The 1, 3, and 5-year overall survival for the total cohort was 70.7%, 34.8%, and 23.2%. One hundred and fifty-five (54%) patients were within Milan criteria, 98(34%) were not, and 33 were unknown. There were no significant differences in age at first procedure between the two groups (P = 0.8464). The 1, 3, and 5-year overall survival after LRT for patients within Milan versus outside Milan criteria were 77.9% versus 62.0%, 43.7% versus 23.3%, and 35.4% versus 8.75%, respectively (P <0.001, hazards ratio: 1.93, 95% confidence interval [1.37-2.71]). Liver transplantation remains the best therapeutic option for elderly patients with HCC that can be transplanted. For patients that are not transplant candidates, LRT is a viable alternative. As expected, overall survival rate is heavily impacted by stage of initial disease, further research is needed to identify and develop better therapeutic strategies for patients with advanced disease.Tabled 1GroupAge1-Year OS (95% CI)3-Year OS (95% CI)5-Year OS (95% CI)Within Milan72.2 ± 5.977.9% (71.3%-85.1%)43.7% (35.4%-54.1%)35.4% (26.2%-47.8%)Outside Milan72.4 ± 5.063.3% (54.0%-74.2%)23.3% (14.4%-37.8%)8.75% (3.17%-24.2%) Open table in a new tab

Contrast-Enhanced Ultrasound in the Short-Term Evaluation of Hepatocellular Carcinoma after Locoregional Treatment

Background: Contrast-enhanced ultrasound (CEUS) with second-generation contrast agents performed 1 month after hepatocellular carcinoma (HCC) treatment is almost as sensitive as contrast-enhanced computed tomography (CECT) in depicting the residual tumor. However, the efficacy of CEUS performed early after the procedure is still debated. Aim: We evaluated the diagnostic accuracy (DA) of CEUS for the assessment of tumor response shortly after locoregional therapy in patients with unresectable HCC. Methods: Ninety-four patients with 104 HCC lesions who were scheduled to receive percutaneous ethanol injection, radiofrequency ablation, transcatheter arterial chemoembolization, or combined treatment were enrolled in this study. With CECT at 1-month as the reference standard, the DA of CEUS performed 48-h after the procedure was evaluated. Patients were followed-up to look for tumor or disease progression. Results: Based on CECT findings, 43/104 lesions were diagnosed as having residual viability after 1 month. CEUS performed 48 h after treatment detected residual tumor in 34/43 nodules with treatment failure at CECT with a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 79.1, 96.7, 94.4, 86.8, and 89%, respectively. There was a high degree of concordance between CEUS and CECT (kappa coefficient = 0.78). A hyperemic halo was detectable in 35 lesions without a statistically significant difference between concordant and discordant cases. In patients with uninodular disease responders according to 48 h CEUS had a significantly longer mean overall survival and time to progression compared to nonresponders. Conclusion: CEUS performed 48 h after treatment can be considered a reliable modality for the evaluation of the real extent of necrosis and has prognostic value in the assessment of HCC.

Locoregional therapies in patients with recurrent intrahepatic cholangiocarcinoma after curative resection

Background:Hepatectomy is one potential treatment for intrahepatic cholangiocarcinoma (IHCC). Recurrent rate is high after curative resection and most recurrences occur within residual liver parenchyma. The aim of this study was to elucidate the impact of different treatment modalities on recurrent diseases in patients with IHCC after primary liver resection.Methods:Between February 1999 and December 2015, we retrospectively identified patients who received curative resection for IHCC. Patients who experienced recurrences were included. Locoregional therapies included re-hepatectomy, radiofrequent ablation, and transhepatic arterial chemoembolization. These patients were categorized into three groups: intrahepatic recurrence without locoregional therapies (group A), intrahepatic recurrence with locoregional therapies (group B) and extrahepatic metastases (group C).Results:Forty-three patients were included and there were 12, 15, and 16 patients in groups A, B, and C, respectively. The median disease-free survival times were 8.3, 9.1, and 8.7 months in groups A, B, and C (p = 0.099). The median after-recurrence overall survival times (period between recurrence and death/censor) were 6.4, 34.0, and 8.3 months in groups A, B, and C (p = 0.001). Locoregional therapies showed favorable benefit in multivariant analysis (hazard ratio: 0.274, confidence interval: 0.083–0.908, p = 0.010).Conclusion:Locoregional therapies offered favorable benefits for patients with recurrent intrahepatic cholangiocarcinoma.

Safety and efficacy of locoregional therapy for metastatic pancreatic ductal adenocarcinoma to the liver: a single-center experience.

Many patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with liver metastatic disease (mPDAC), and few are surgical candidates. Interventional oncology (IO) locoregional therapies (LRT) have proven beneficial in other primary and metastatic hepatic malignancies. Systemic chemotherapy is the standard of care for patients with mPDAC. This study assessed the safety and efficacy of LRT including thermal ablation, chemoembolization, and radioembolization for mPDAC. A retrospective analysis was performed of 28 patients with mPDAC referred to IR clinic for consideration of LRT from 01/2006 to 08/2017, of whom 20 underwent treatment. Laboratory values were analyzed at 0, 3, and 6 months post-treatment. Imaging response was evaluated at 1, 3, and 6 months post-intervention by modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Adverse events (AE) were classified by CTCAE v5.0. Overall survival (OS) from the diagnosis of PDAC, survival from the time of mPDAC diagnosis, and survival from the time of LRT were calculated. Median OS (mOS) was 25 months. Median survival from time of mPDAC diagnosis and post LRT were 16.25 and 9.7 months, respectively. At one month post-intervention, 12 of 17 patients demonstrated disease response (CR or PR per mRECIST). Survival among responders was 9 months vs. 6 months for patients with stable or progressive disease (P=0.08). There were two grade 3 AE which included post-embolization syndrome and transient renal failure. Chemotherapy was briefly delayed in one of these patients, but ultimately resumed. The use of LRT in patients with mPDAC is safe. Additionally, no significant chemotherapy limiting toxicities were observed. Responders to therapy demonstrated a survival benefit trend in this small and heterogeneous cohort. Further investigations with randomized trials are warranted.

The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma.

Checkpoint inhibitors have recently been approved for the treatment of patients with hepatocellular carcinoma (HCC). However, biomarkers, which will help identify patients responding to therapy, are missing. We recently tested the combination of anti-CTLA4 treatment (tremelimumab) with loco-regional therapy in patients with HCC and reported a partial response rate of 26%. Here, we report updated survival analyses and results from our immune monitoring studies on peripheral blood mononuclear cells (PBMCs) and tumors from these patients. Tremelimumab therapy increased CD4+-HLA-DR+, CD4+PD-1+, CD8+HLA-DR+, CD8+PD-1+, CD4+ICOS+ and CD8+ICOS+ T cells in the peripheral blood of the treated patients. Patients with higher CD4+PD1+ cell frequency at baseline were more likely to respond to tremelimumab therapy. PD-1 expression was increased on alpha fetal protein (AFP) and survivin-specific CD8 T cells upon tremelimumab treatment. An increase of tumor infiltrating CD3+ T cells were also seen in these patients. Immunosequencing of longitudinal PBMC showed that one cycle of tremelimumab significantly decreased peripheral clonality, while no additional effects were seen after loco-regional therapy. In summary, we observed a clear activation of T cell responses in HCC patients treated with tremelimumab and identified potential biomarkers which will help identify patients responding to immunotherapy with anti-CTLA4.

Abstract 4094: Oncopig and human hepatocellular carcinoma cell lines exhibit similar response to liver cancer chemotherapy agents

Abstract Preclinical animal models represent pivotal tools to develop novel therapeutics. While murine models are commonly used in preclinical drug research, many agents that show promise in mouse studies ultimately fail in human clinical trials. In contrast to mice, pigs share many genetic, physiological, and metabolic similarities with humans, which may facilitate relevant investigation of drug pharmacokinetic and therapeutic analyses. The Oncopig Cancer Model (OCM) is a novel transgenic swine platform that recapitulates human cancer through development of site/cell specific tumors after Cre recombinase induced expression of heterozygous KRASG12D and TP53R167H transgenes. Given similar drug metabolism between pigs and humans, we propose that the OCM can address unmet clinical needs by facilitating translation of results obtained in preclinical murine studies to human clinical practice. In order to investigate the feasibility of using the OCM for drug screening, we tested the hypothesis that OCM and human hepatocellular carcinoma (HCC) cell lines exhibit similar responses to chemotherapy agents commonly used in clinical settings. Responses to four cytostatic (sorafenib) and cytotoxic (doxorubicin, cisplatin, mitomycin C) HCC chemotherapies were compared between OCM derived porcine HCC cell lines and three representative human HCC cell lines (SNU-387, SNU-475, HepG2). Results of MTT time course assays (3x performance) revealed that OCM HCC and human HCC cell lines displayed similar sensitivities to all four chemotherapies when exposed to comparable, clinically relevant concentrations for 72 hours. Sorafenib had a cytostatic effect at 10-20 µM in all four cells lines tested, consistent with clinically relevant, 3-15 µM systemic therapeutic concentrations. Doxorubicin, usually administered at 1-5 µM for locoregional therapy in patients, had comparable half maximal inhibitory concentrations (IC50) for pHCC (0.19 µM), HepG2 (0.45 µM), and SNU-387 (0.94 µM), but was higher for SNU-475 (3.31 µM). Mitomycin C had similar IC50 for pHCC (1.77 µM), HepG2 (1.73 µM), and SNU-475 (2.93 µM), but was higher for SNU-387 (7.91 µM). Finally, IC50 for cisplatin was nearly identical for pHCC (7.54 µM) and HepG2 (8.34 µM), but higher for SNU-387 (25.89 µM) and SNU-475 (16.57 µM). These results show clinically relevant similarities in response to the tested chemotherapy agents between pHCC and HepG2 (the most widely used human HCC cell line for in vitro investigations). Notably, differential drug responses observed between human HCC cell lines are consistent with previous studies, and are likely reflective of differential pathway alterations driving oncogenesis in these lines. These results indicate the OCM represents a valuable tool for screening promising chemotherapy agents, providing a novel large animal bridge between preclinical investigation in small animal models and human clinical trials. Citation Format: Mario F. Neto, Eileena F. Giurini, Hanna H. Chen, Jordan L. Newson, Lawrence B. Schook, Kyle M. Schachtschneider, Ron C. Gaba. Oncopig and human hepatocellular carcinoma cell lines exhibit similar response to liver cancer chemotherapy agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4094.

Abstract No. 525 Liver transplantation rates for hepatocellular carcinoma: is there a sex-related difference?

To determine if there exists a sex-related difference in the rate of liver transplantation (LT) and locoregional therapy for patients with hepatocellular carcinoma (HCC) exception points in the United States. Retrospective evaluation of the UNOS STAR database was performed evaluating all adult patients with HCC meeting T2 criteria listed for LT between 2005 and 2015. Patient demographics, probability of LT, wait time to LT, and locoregional therapy rates were evaluated. A total of 14,844 patients (76.8% male) were included. Median age for men was 58 years (IQR: 54-62 years) compared to 60 years of age for women (IQR: 55-65 years), p < 0.001. Median height for men was 175 cm (range, 170-180 cm) compared to 160 cm for women (range, 157- 165 cm), p < 0.001. Within 3-years of listing for LT, the probability of LT was 79.8% for men compared to 78.2% for women (p < 0.001). Median time to LT for men was 3.6 months (range, 1.3-7.5 months) compared to 4.1 months for women (range, 1.6-8.4 months), p<0.001. There was no significant difference in locoregional therapy rates between men and women, p = 0.63. Women have a longer wait time to and a lower probability of LT, despite similar rates of locoregional therapies. The likelihood of female sex and smaller stature may result in a lower probability of LT. Additional MELD exception points for women may help bridge this sex-related disparity.

Selective internal radiation therapy using yttrium-90 resin microspheres in patients with unresectable hepatocellular carcinoma: a retrospective study.

Selective internal radiation therapy (SIRT) with yttrium-90 resin (Y-90 resin) microspheres has been used as a locoregional therapy for patients with unresectable hepatocellular carcinoma (HCC). We examined patient and disease characteristics that might affect survival after Y-90 resin, as well as treatment tolerability. Data from patients with unresectable HCC treated with Y-90 resin at a single institution were reviewed retrospectively. Survival was assessed with Kaplan-Meier curves and log-rank tests. Response was evaluated with the response evaluation criteria in solid tumors (RECIST) criteria. Adverse events (AEs) were noted, and laboratory values were graded with CTCAE v3.0. Data from 111 patients were analyzed. AEs occurred in 23 patients at 1 week after treatment and in 46 at 3 months. At 6 months, 13 patients had a complete response and 13 had a partial response. Factors associated with longer overall survival (OS) included early-stage disease [27.8 months for patients with Barcelona-Clinic Liver Cancer (BCLC) A vs. 9.2 months for BCLC C]; treatment with other locoregional therapies (69.0 vs. 11.4 months); and lack of bilobar disease (23.5 vs. 9.4 months), portal vein thrombosis (16.2 vs. 8.6 months), ascites (16.6 vs. 10.3 months), and treatment with sorafenib (17.2 vs. 10.3 months). In six patients, Y-90 resin was used as a bridge to liver transplantation, which greatly improved survival (69.0 vs. 12.1 months). Several characteristics may prove useful for selecting patients likely to respond well to Y-90 resin. These results should be confirmed in prospective studies.

Role of Diffusion Weighted Imaging in Assessment of Tumor Response After Loco-regional Therapy in Patients of Hepato-Cellular Carcinoma

Background and Aim: Diffusion Weighted Imaging (DWI) has been found to be useful in liver mass characterisation. Its role in post-treatment evaluation has not been adequately explored. While dynamic contrast-enhanced magnetic resonance imaging (DCE—MRI) is the standard of evaluation for post-treatment response, DWI can potentially differentiate between viable and non-viable tissue and hence may be useful. This study was designed to evaluate the sensitivity and specificity of DWI in response assessment after loco-regional therapy for HCC. Methods: A prospective study was done between January 2009 and January 2017. Patients of HCC who presented to our liver clinic and undergoing loco-regional therapy [trans- arterial chemo-embolisation (TACE)/ablation techniques including radio-frequency ablation (RFA), percutaneous acetic acid injection (PAI)] were included. Four weeks post-treatment, DCE-MRI was performed using VIBE sequences to ascertain treatment response of index mass, based on m-RECIST criteria and DWI to look for presence/absence of diffusion restriction. DCE-MRI was the gold-standard. If partial response (PR) was detected on DCE-MRI, a repeat session of the earlier treatment was done followed by repeat DCE-MRI at 4 weeks (each evaluation being one observation). Results: HCC patients (n = 44) including 33 males, 11 females, having mean age 51.8 ± 14.6 years were included and underwent repetitive evaluation of 62 nodules. Post-therapeutic (54 TACE, 4 RFA and 4 PAI) response evaluation was done. DCE-MRI showed contrast enhancement in 15/62(24.2%) nodules (PR), while diffusion restriction was seen in 13/15(86.7%) of these nodules. No enhancement was seen in 47/62(75.8%) nodules (complete response), of which 37/47(78.7%) showed no restriction, while 10/47(21.3%) showed restricted diffusion. DWI thus showed a sensitivity of 86.7% and specificity of 78.7%. Conclusion: DWI shows good sensitivity and moderate specificity for assessing response in HCC after loco-regional therapy. Although DWI cannot be a standalone for post- treatment response assessment, it may be useful as an adjunct to DCE-MRI. The authors have none to declare.