Systemic Chemotherapy Research Articles

Gastric transcatheter chemoembolization combined with systemic chemotherapy vs. systemic chemotherapy alone for patients with advanced gastric cardiac cancer presenting with dysphagia: A case control study.

The present study aimed to assess the effectiveness of gastric transcatheter chemoembolization (GTC) combined with systemic chemotherapy (SYS) compared with SYS alone in managing dysphagia, and improving the quality of life (QoL) and nutritional status of patients with advanced gastric cardiac cancer (AGCC). A retrospective review was performed using data from consecutive patients with AGCC who experienced dysphagia and underwent either SYS alone or SYS combined with GTC from January 2018 to December 2022. Propensity score matching (PSM) analysis was performed to address potential confounding factors. Ogilvie dysphagia scores were used to assess dysphagia, the Functional Assessment of Cancer Therapy-General 7 (FACT-G7) was used to assess QoL, and the Patient-Generated Subjective Global Assessment (PG-SGA) was used to evaluate nutritional status. After PSM, a total of 228 patients were included in the analysis, with 114 in each group. At 4 and 8 weeks after the initial treatment, the GTC + SYS group demonstrated significantly lower median Ogilvie scores compared with the SYS alone group (P<0.001). Similarly, the median PG-SGA score at 4 weeks after the initial treatment was 2.0 in the GTC + SYS group and 6.0 in the SYS alone group. The median FACT-G7 scores in the GTC + SYS group was 13.0, compared with 10.5 in the SYS alone group. These differences remained significant at 8 weeks (P<0.001). In conclusion, the addition of GTC to SYS may more effectively and promptly relieve dysphagia, improve nutritional status and enhance QoL compared with SYS alone in patients with AGCC presenting with dysphagia.

Benefits of adjuvant treatment with the Pingxiao capsule in patients with early breast cancer: A single‑center retrospective cohort study.

Early breast cancer (EBC) is cancer that has not spread beyond the breast or the axillary lymph nodes. The present retrospective cohort study investigated the efficacy and safety of the Pingxiao capsule (PXC), which contains a formula of traditional Chinese herbs, as adjuvant therapy in patients with EBC in a single Chinese academic medical center. Patients with EBC who had received surgery and chemotherapy were analyzed and divided into the PXC and non-PXC groups. Disease-free survival (DFS) time, overall survival (OS) time, demographic characteristics and adverse events were examined. Kaplan-Meier survival curves were used to compare the differences in DFS and OS. A total of 371 participants with a median age of 54 years were included in this study. The median DFS time of all patients was 101 months. The overall DFS rate was 72.1% in the PXC group compared with 63.6% in the non-PXC group. For women with hormone receptor-negative tumors, the DFS rate in the PXC group was significantly higher than that in the non-PXC group, irrespective of node status. Adjuvant treatment with PXC for ≥3 months was associated with significantly longer median DFS time compared with that in the non-PXC group. In addition, the incidence of neutropenia rated to be grade 2 or higher was significantly lower in the PXC group compared with that in the control group, and a markedly, but non-significantly, lower prevalence of nausea was observed in PXC group (0 vs. 4.1%). In conclusion, PXC as an adjuvant therapy along with chemotherapy is associated with prolonged DFS times in patients with EBC when compared with chemotherapy alone. The therapeutic value of combined PXC and systemic chemotherapy should be further elucidated by rigorous prospective clinical trials.

Randomized phase II/III trial of gemcitabine plus nab-paclitaxel versus concurrent chemoradiotherapy with S-1 as neoadjuvant treatment for borderline resectable pancreatic cancer: GABARNANCE study.

LBA4014 Background: No randomized controlled trials have compared systemic chemotherapy and chemoradiotherapy as neoadjuvant therapy for borderline resectable pancreatic cancer (BRPC). We attempted to determine which of the two could become established as standard neoadjuvant therapy for BRPC. Methods: This was an open-label, multicenter, randomized controlled phase II/III trial comparing two neoadjuvant treatments (UMIN-CTR 000026858): gemcitabine (GEM) plus nab-paclitaxel (nab-P) (group A, GEM 1000 mg/m2 IV + nab-P 125 mg/m2 IV on days 1, 8, and 15, 2 cycles) and concurrent chemoradiotherapy (50.4 Gy/28 fractions) with S-1 (80 mg/m2) on the irradiation days (group B). After the neoadjuvant therapy, patients (pts) underwent surgical resection if R0/R1 resection was judged as being possible, followed by postoperative adjuvant S-1 therapy for 6 months. The key eligibility criteria included patients aged 20 to 79 years with histologically proven adeno(squamous)carcinoma, centrally confirmed BRPC, PS 0-1, and no prior treatment for BRPC. The primary endpoint of the phase III part was overall survival (OS). A total of 110 pts (65 events) was required to detect a 17% difference in the 2-year OS [hazard ratio (HR) of 0.70] with a two-sided alpha level of 10% and power of 70%. Results: A total of 112 pts were randomly assigned to the trial treatments between June 2017 and December 2022 (group A/B: 56/56 pts). The median OS was 23.1 months in group A and 31.5 months in group B. No statistically significant difference in the OS was observed between the two arms (HR 0.758, 95% CI: 0.472-1.219, p = 0.2518), but a large late separation of the Kaplan-Meier curves was observed after 18 months. The difference in the 2-year OS between the groups was 14.6% (group A: 48.2%, group B: 62.8%); the separation continued until the end of the observed survival curves. A similar late separation in the PFS was seen after around 12 months, but the difference in the PFS was not statistically significant (median PFS: Group A, 12.6 months, Group B, 11.1 months; HR 0.805; 95% CI: 0.535-1.212; p = 0.2565). The R0 resection rate did not differ between the two groups (group A, 60.7%; group B, 57.1%). The tumor response rate was higher in Group A (group A, 16.1%; group B, 8.9%), but the pathological response rate was higher in group B (group A, 14.3%; group B, 30.4%). Neutropenia and thrombocytopenia were observed more frequently in group A, while anorexia was observed more frequently in group B. Both treatments were well-tolerated. Conclusions: A delayed survival advantage, in terms of both the OS and PFS, of concurrent chemoradiotherapy with S-1 was observed, without any additional toxicity burden. An updated analysis with longer-term efficacy/toxicity data is planned to verify the advantage of neoadjuvant chemoradiotherapy. Clinical trial information: UMIN-CTR 000026858.

HOXB2 promotes cisplatin resistance by upregulating lncRNA DANCR in ovarian cancer

Ovarian cancer (OV) is a highly fatal malignant disease that commonly manifests at an advanced stage. Drug resistance, particularly platinum resistance, is a leading cause of treatment failure because first-line systemic chemotherapy primarily relies on platinum-based regimens. By analyzing the gene expression levels in the Cancer Genome Atlas database, Genotype-Tissue Expression database, and Gene Expression Omnibus datasets, we discerned that HOXB2 was highly expressed in OV and was associated with poor prognosis and cisplatin resistance. Immunohistochemistry and loss-of-function experiments on HOXB2 were conducted to explore its role in OV. We observed that suppressing HOXB2 could impair the growth and cisplatin resistance of OV in vivo and in vitro. Mechanical investigation and experimental validation based on RNA-Seq revealed that HOXB2 regulated ATP-binding cassette transporter members and the ERK signaling pathway. We further demonstrated that HOXB2 modulated the expression of long non-coding RNA DANCR, a differentiation antagonizing non-protein coding RNA, and thus influenced its downstream effectors ABCA1, ABCG1, and ERK signaling to boost drug resistance and cancer proliferation. These results verified that high expression of HOXB2 correlated with platinum resistance and poor prognosis of OV. Therefore, targeting HOXB2 may be a promising strategy for OV therapy.

Efficacy and safety of different chemotherapy regimens in patients with disseminated pancreatic cancer over 65 years old

Aim. To evaluate the effectiveness and tolerability of systemic chemotherapy in elderly patients with metastatic pancreatic cancer (mPC) in real clinical practice.Materials and methods. The study included patients with mPC over 65 years of age who received first-line chemotherapy at the N. N. Blokhin National Medical Research Center of Oncology for the period from 2004 to 2023. Any previous antitumor chemotherapy for mPC was an exclusion criterion. The primary endpoint was 1-year overall survival (OS), and the secondary endpoints were ORR, median progression-free survival, median OS, chemotherapy tolerability.Results. The study included 148 patients aged 65 to 86 years with mPC who received first-line chemotherapy. Median progression-free survival among the entire population was 5.2 months. One-year OS among all patients was 32 %. The 1-year OS in mFOLFIRINOX group was 43.4 % and in gemcitabine group – 19.6 %. In a subgroup analysis, median OS with combination treatment was higher than in the gemcitabine monotherapy group (median OS 8.4 months vs. 6.8 months, p = 0.009). Patients with ECOG 2–3 also benefited from combination chemotherapy. Median OS was 8.9 months versus 3.9 months in gemcitabine (p = 0.008). The frequency of an objective response with triple chemotherapy was 66.1 %. In 30.8 % of cases, grade 3–4 neutropenia developed with mFOLFIRINOX, but febrile neutropenia developed only in three patients (5.8 %). The incidence of grade 3–4 adverse events was low, and these chemotherapy regimens were well tolerated.Conclusion. Conducting a triple chemotherapy regimen in elderly patients with mPC is an effective treatment option with an acceptable range of toxicity.

Pharmacokinetic evaluation of paclitaxel, albumin-binding paclitaxel, and liposomal-encapsulated albumin-binding paclitaxel upon gastric subserosal administration.

Introduction: Systemic chemotherapy is typically administered following radical gastrectomy for advanced stage. To attenuate systemic side effects, we evaluated the effectiveness of regional chemotherapy using paclitaxel, albumin-paclitaxel, and liposome-encapsulated albumin-paclitaxel via subserosal injection in rat models employing nuclear medicine and molecular imaging technology. Method: Nine Sprague Dawley rats were divided into three groups: paclitaxel (n = 3), albumin-paclitaxel nano-particles (APNs; n = 3), and liposome-encapsulated APNs (n = 3). [123I]Iodo-paclitaxel ([123I]I-paclitaxel) was synthesized by conventional electrophilic radioiodination using tert-butylstannyl substituted paclitaxel as the precursor. Albumin-[123I]iodo-paclitaxel nanoparticles ([123I]APNs) were prepared using a desolvation technique. Liposome-encapsulated APNs (L-[123I]APNs) were prepared by thin-film hydration using DSPE-PEG2000, HSPC, and cholesterol. The rats in each group were injected with each test drug into the subserosa of the stomach antrum. After predetermined times (30min, 2, 4, 8h, and 24h), molecular images of nuclear medicine were acquired using single-photon emission computed tomography/computed tomography. Results: Paclitaxel, APNs, and L-APNs showed a high cumulative distribution in the stomach, with L-APNs showing the largest area under the curve. Most drugs administered via the gastric subserosal route are distributed in the stomach and intestines, with a low uptake of less than 1% in other major organs. The time to reach the maximum concentration in the intestine for L-APNs, paclitaxel, and APNs was 6.67, 5.33, and 4.00h, respectively. Conclusion: These preliminary results imply that L-APNs have the potential to serve as a novel paclitaxel preparation method for the regional treatment of gastric cancer.

Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Nonsquamous EGFR-Wildtype Non-Small Cell Lung Cancer in the Phase II LUMINOSITY Trial.

Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. In total, 172 patients with nonsquamous EGFR-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

PIPAC in patients with peritoneal metastases from gastrointestinal tract (PIPOX01): An open label, non-comparative phase 1/2 dose escalation and expansion trial

BackgroundDespite modern systemic chemotherapy, survival remains poor for patients with advanced isolated peritoneal metastases from the gastrointestinal tract. We aimed to assess the safety and efficacy of pressurized intraperitoneal aerosol chemotherapy (PIPAC) with oxaliplatin. Patients and methodsWe conducted a phase 1/2, open label, non-comparative, dose escalation and expansion trial of PIPAC with oxaliplatin in patients with a peritoneal cancer index (PCI) of more than 5, 13 and 15 for respectively a gastric, small bowel and colorectal primary cancer, and who had received at least three months of systemic chemotherapy. PIPAC cycle lengths were 4–6 weeks with systemic chemotherapy allowed 15 days after each PIPAC. PCI and oxaliplatin tumor concentration were assessed every PIPAC cycle. The main endpoints were tolerability, tumor response, and survival. ResultsBetween 2017 and 2020, 34 patients were enrolled in three centers, in this phase 1/2 study, of whom 25 were evaluable at the recommended dose determined in the phase I trial (90 mg/m2 plus systemic 5-FU). Before inclusion, patients received a median of 2 [1–4] chemotherapy lines and had a median PCI of 22.5 [7–29]. At this dose, the safety profile showed acceptable tolerability. Eight patients (32 %) had grade 3/4 treatment-related adverse events. Minor (grade 1/2) adverse events were mainly abdominal pain (n = 19, 76 %) and nausea (n = 16, 64 %). Median PFS was 6.1 months and median OS was 13 months. ConclusionIn patients with advanced and refractory peritoneal metastasis, PFS of 6.1 months is encouraging. A prospective randomized phase II study is required.

Intensive locoregional therapy before liver transplantation for colorectal cancer liver metastasis: A novel pretransplant protocol.

We describe a novel pre-liver transplant (LT) approach in colorectal liver metastasis, allowing for improved monitoring of tumor biology and reduction of disease burden before committing a patient to transplantation. Patients undergoing LT for colorectal liver metastasis at Cleveland Clinic were included. The described protocol involves intensive locoregional therapy with systemic chemotherapy, aiming to reach minimal disease burden revealed by positron emission tomography scan and carcinoembryonic Ag. Patients with no detectable disease or irreversible treatment-induced liver injury undergo transplant. Nine patients received liver transplant out of 27 who were evaluated (33.3%). The median follow-up was 700 days. Seven patients (77.8%) received a living donor LT. Five had no detectable disease, and 4 had treatment-induced cirrhosis. Pretransplant management included chemotherapy (n = 9) +/- bevacizumab (n = 6) and/or anti-EGFR (n = 6). The median number of pre-LT cycles of chemotherapy was 16 (range 10-40). Liver-directed therapy included Yttrium-90 (n = 5), ablation (n = 4), resection (n = 4), and hepatic artery infusion pump (n = 3). Three patients recurred after LT. Actuarial 1- and 2-year recurrence-free survival were 75% (n = 6/8) and 60% (n = 3/5). Recurrence occurred in the lungs (n = 1), liver graft (n = 1), and lungs+para-aortic nodes (n = 1). Patients with pre-LT detectable disease had reduced RFS ( p = 0.04). All patients with recurrence had histologically viable tumors in the liver explant. Patients treated in our protocol (n = 16) demonstrated improved survival versus those who were not candidates (n = 11) regardless of transplant status ( p = 0.01). A protocol defined by aggressive pretransplant liver-directed treatment and transplant for patients with the undetectable disease or treatment-induced liver injury may help prevent tumor recurrence.

Efficacy and safety of arterial FOLFOX chemotherapy plus anti-PD-(L)1 immunotherapy as first-line treatment for unresectable intrahepatic cholangiocarcinoma: A propensity score matched analysis.

e16189 Background: This study aimed to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) plus anti-programmed death (ligand)-1 [PD-(L)1] immunotherapy compared to systemic chemotherapy (SCT) plus anti-PD-(L)1 immunotherapy as first-line treatment for patients with unresectable intrahepatic cholangiocarcinoma (uICC). Methods: In this retrospective study, unresectable treatment-naive ICC patients who were treated with HAIC plus anti-PD-(L)1 immunotherapy [HAIC+αPD-(L)1] or SCT plus anti-PD-(L)1 immunotherapy [SCT+αPD-(L)1] were included. The clinical characteristics, therapeutic outcomes and adverse events (AEs) of patients between the two groups were compared. The propensity score matching (PSM) was performed to minimize biases between groups. Results: From January 2019 to January 2023, a total of 182 patients were enrolled, including 147 patients in HAIC+αPD-(L)1 group and 35 patients in SCT+αPD-(L)1 group. After PSM, 61 and 26 patients were included in the HAIC+αPD-(L)1 and SCT+αPD-(L)1 groups, respectively. The HAIC+αPD-(L)1 group showed longer median overall survival (OS) and progression free survival (PFS) than the SCT+αPD-(L)1 group (OS: 14.5 vs 10.5 months, P = 0.019; PFS: 6.4 vs 10.1 months, P = 0.020). The disease control rate of HAIC+αPD-(L)1 group were higher than those of SCT+αPD-(L)1 group (91.8% vs 69.2%, P = 0.007). The overall incidence of adverse events (AEs) was comparable between the two groups, but the HAIC+αPD-(L)1 group showed a lower incidence of grade 3~4 AEs related to anemia, weight loss and fatigue. Conclusions: HAIC plus anti-PD-(L)1 immunotherapy had acceptable toxic effects and might improve outcomes compared to SCT plus anti-PD-(L)1 immunotherapy as first-line treatment for patients with uICC.

PIPAC in patients with peritoneal metastases from gastrointestinal tract (PIPOX): An open label, non-comparative phase 1/2 dose escalation and expansion trial.

e15561 Background: Withmodern systemic chemotherapy, survival remain poor for patient withadvanced isolated peritoneal metastases from gastrointestinal tract. We aimed to assess the safety and efficacy of PIPAC to oxaliplatin in combination or not with systemic chemotherapy. Methods: We did a phase 1/2, open label, non-comparative, dose escalation and expansion trial of PIPAC to oxaliplatin forpatients with peritoneal cancer index (PCI) more than 5, 13 and 15 for respectively a gastric, small bowell and colorectal cancer primary; who had received at least three months of systemic chemotherapy. PIPAC cycle lengths was 4 to 6 weeks with systemic chemotherapy allowed 15 days after each PIPAC. PCI and oxaliplatin concentration tumor was assessed every PIPAC cycles. Main endpoints were, tolerability, tumor response and survival. Results: Between2017 to 2020, 34 for patients were enrolled in three centers, in this phase 1/2 study of whom 25 were evaluable at recommanded dose of phase I of 90 mg/m2 plus systemic 5-FU. At this dose, safety profile showed acceptable tolerability. 8 patients (32%) had grade 3/4 treatment related adverse event. Minors (grade 1/2) adverse events were mainly abdominal pain (n = 19, 76%) and nausea (n = 16, 64%). Before inclusion patients received a median of 2 [1-4] chemotherapy lines and had a median PCI of 22.5 [7-29]. Median PFS was 6.1 months and median OS was 13 months. Conclusions: In patients with advanced and refractory peritoneal metastasis, PFS of 6.1 months is encouraging. A prospective randomized phase II study is required. Clinical trial information: NCT03294252 .

CRS-HIPEC following neo-adjuvant pressurized intraperitoneal aerosol chemotherapy (PIPAC) with systemic chemotherapy in primarily advanced inoperable epithelial ovarian cancer: An ISPSM collaborative study.

e17504 Background: PIPAC has shown improved objective response rate with improved quality of life in combination with IV chemotherapy when compared to IV chemotherapy alone in salvage situations. Methods: All patients with primarily inoperable advanced epithelial ovarian cancer not been able to receive optimal IV chemotherapy or not responding to first line of chemotherapy who could not undergo CRS-HIPEC were challenged with PIPAC &amp; IV chemotherapy as a salvage situation after discussion in MDT. Patients who subsequently underwent CRS-HIPEC were analysed to study their clinical characteristics, extent of disease and peri-operative outcomes. PIPAC was given with Cisplatin 15mg/m2 and doxorubicin 3mg/m2. Intravenous chemotherapy was given within one week of PIPAC. Each cycle was repeated once in 4-5 weeks. Patients who underwent subsequently CC0 cytoreduction got HIPEC with Injection cisplatin 100mg/m2. All outcomes were prospectively entered in the registry and analysed retrospectively. Results: 120 PIPAC applications were done in 45 patients. 30 patients received 3 cycles of PIPAC with IV chemotherapy given within one week of PIPAC. Mean PCI initially was 25±5 with nearly 55% of them having ECOG 2 performance status and mean ascities volume of 500±55 ml . Out of 45 patients 28 underwent CRS-HIPEC subsequently. Mean age 54.5±10.74, PCI 15±5, duration of surgery 9.6±1.2 hrs. The mean drop in PCI who completed 3 PIPAC with IV chemotherapy was 10±3. Out of 45 patients nearly 60% showed PRGS 1, 25% PRGS 2 and 15% PRGS 3. 30.4% had total peritonectomy, 12.7% had multivisceral resection, 30% required diaphgramatic resections, 25%required mesentric stripping, 45.8% had one bowel resections and stoma rate was 4.5%. Overall G3-G5 morbidity was 25.4% with major ones being post-operative intra-abdominal collection (21.8%), electrolyte imbalance (16.4%), pulmonary (16.4%) followed by hematological (12.7%). The 30 day mortality was 3.8%. During PIPAC + IV chemotherapy no significant grade 3-4 morbidity was seen. Conclusions: Neo-adjuvant PIPAC with Intravenous chemotherapy might be a promising combination for inducing good response rates in advanced epithelial ovarian carcinoma. CRS-HIPEC following neo-adjuvant PIPAC + IV chemotherapy is safe, feasible and tolerable. PIPAC repeated every 4-5 weeks along with systemic chemotherapy provides a ideal scenario to monitor &amp; assess response to loco regional and systemic chemotherapy.

Survival outcomes with curative intent hyperthermic intraperitoneal chemotherapy (HIPEC) for gastric cancer with peritoneal metastasis.

e16070 Background: The prognosis of gastric cancer with peritoneal metastasis (GC-PM) remains dismal. Despite the many studies evaluating hyperthermic intraperitoneal chemotherapy and cytoreductive surgery (HIPEC-CRS) for GC-PM in various treatment settings, its curative role in combination with systemic chemotherapy remains unclear. Methods: To determine the survival benefit of CRS-HIPEC in patients with GC-PM, we conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines on primary studies from January 1, 2010 to December 31, 2023. Inclusion criteria were studies involving adults with GC and histologically proven PM who received curative intent gastrectomy, D2 lymphadenectomy, and systemic chemotherapy. Exclusion criteria were studies involving patients with GC without PM involvement and HIPEC utilized strictly for prophylactic purposes. The primary endpoint was overall survival (OS), with a focus on 1-year, 2-year, and 3-year survival outcomes. We performed a random effects meta-analysis of risk ratios using RevMan and assessed heterogeneity using I2. Results: Of 452 studies identified, we included 5 studies and a total of 524 patients with survival outcome of CRS-HIPEC and standard chemotherapy were compared. We observed significantly better OS for patients who received CRS+HIPEC compared to those who received systemic chemotherapy without CRS-HIPEC (odds ratio (OR) 0.50, 95% CI [0.39-0.65], I2= 3%, P &lt; 0.00001). Further analysis demonstrated improved 1-year OS (OR 0.53, 95% CI [0.30-0.93], I2= 45%, p = 0.03), 2-year OS (OR 0.53, 95% CI [0.35-0.81], I2= 0%, p = 0.003), and 3-year OS (0.35, 95% CI [0.14-0.84], I2= 21%, p = 0.02). Low heterogeneity (3%) amongst all the groups suggests that variations within the subgroups did not impact the homogeneity of the dataset. Conclusions: Overall, use of CRS and HIPEC in addition to systemic chemotherapy resulted in statistically significant improvement in OS up to year 3 compared to standard palliative chemotherapy alone in patients with GC-PM. Further studies are warranted to evaluate HIPEC in the curative attempt setting, specifically in combination with emerging targeted therapies.

RNA expression profiling of peritoneal metastasis from pancreatic cancer treated with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an experimental treatment option in peritoneal metastasis from pancreatic cancer (PM-PC). Aims were to examine mRNA profile of fibrosis due to response after systemic chemotherapy and PIPAC (Regression) compared to treatment-naïve PM-PC and chronic cholecystitis-related peritoneal fibrosis (Controls). Peritoneal biopsies (PBs) from PM-PC patients who had undergone systemic chemotherapy and PIPAC were evaluated with Peritoneal Regression Grading Score (PRGS). We extracted RNA from PBs with Regression (PRGS 1, n=11), treatment-naïve PM-PC (n=10), and Controls (n=10). Profiling of 800 mRNAs was performed (NanoString nCounter, PanCancer Immuno-Oncology 360 (IO-360) and 30 additional stroma-related mRNAs). Regression vs. PM-PC identified six up-regulated and 197 down-regulated mRNAs (FDR≤0.05), linked to TNF-αsignaling via NF-kB, G2M checkpoint, epithelial-mesenchymal transition, estrogen response, and coagulation. Regression vs. Controls identified 43 significantly up-regulated mRNAs, linked to interferon-α response, and down-regulation of 99 mRNAs, linked to TNF-α signaling via NF-kB, inflammatory response, epithelial-mesenchymal transition, KRAS signaling, and hypoxia (FDR≤0.05). In regressive fibrosis of PM-PC after systemic chemotherapy and PIPAC (Regression), downregulation of mRNAs related to key tumor biological pathways was identified. Regression also showed transcriptional differences from unspecific, benign fibrosis (Controls). Future studies should explore whether mRNA profiling of PBs with PM from PC or other primaries holds prognostic or predictive value.

Prognostic factors for patients with sarcoma with brain metastases.

e23542 Background: Sarcomas arise in mesenchymal tissue occurring anywhere in the body with a propensity to metastasize often to the lung, liver, and bones. The brain is a rare site of metastasis with increasing incidences found in those relapsing after prolonged disease control with treatment. Brain metastases development has been associated with dismal prognoses, and more data is necessary to assess factors for improved outcomes of patients. Methods: The retrospective cohort includes 81 patients diagnosed with sarcomas metastasizing to the brain treated at five sarcoma centers between 1/1998 and 12/2021. Demographic data, characteristics and presentation of brain metastases, and treatment modalities for malignancy were identified and analyzed. Results: In total, there were 45 men and 36 women with the mean age of diagnosis being 43 years. Upon presentation, 89% of patients were symptomatic with the most common presenting symptom being focal neurological deficits (37.9%) and headaches (22.1%). At the time of analysis, 58 patients (71.6%) had died of metastatic sarcoma, 16 patients (19.8%) were alive with disease, and 3 patients (3.7%) were alive without evidence of disease. The most frequent histologies were leiomyosarcoma (12.3%) and undifferentiated pleomorphic sarcoma (12.3%). In 70.4% of patients, the tumor also had metastasized to the lung. Median time from sarcoma diagnosis to brain metastases was 1.9 years (range: 0-34.6 yrs). Median time from diagnosis of brain metastases until death was 6 months (range: 0.5-330 mo). Treatment modalities of brain metastasis varied widely with 18 patients (22.2%) undergoing whole brain radiation therapy (WBRT), 11 (13.6%) undergoing systemic chemotherapy and WBRT, and 10 (12.3%) undergoing combined surgery, systemic chemotherapy, and stereotactic radiosurgery. In multivariate analysis, the variables identified as statistically significant for predicting improved survival outcomes included surgery (HR 0.30) and chemotherapy (HR 0.24), but not radiation therapy. In patients undergoing surgery or chemotherapy, the median survival time after brain metastasis diagnosis was markedly improved, with 13.9 months and 12 months respectively versus the overall patient median of 6 months. In patients undergoing radiation therapy, there was significantly improved survival with stereotactic radiosurgery (SRS, mOS 11.6mo) as opposed to whole brain radiation therapy (WBRT, mOS 8.3mo) probably due to decreased mean number of brain metastases found in those necessitating SRS (3.2) compared to WBRT (5.7). Conclusions: Together, our findings identify that patients with metastatic sarcoma to the brain have poor prognoses, often have concurrent metastasis, and have median survival of only 6 months. However, there were significantly improved outcomes with interventions such as surgery, chemotherapy, or SRS, suggesting that aggressive treatments are warranted despite the overall poor prognosis.

The impact of metformin on clinical outcomes of metastatic colorectal cancer with known molecular profile treated with cytotoxic chemotherapy or immune checkpoint inhibitor.

e15580 Background: Colorectal cancer (CRC) is the third most common cancer in the US, with a dismal 5-year OS of 13% in mCRC. Concomitant metformin with chemotherapy or immune checkpoint inhibitors (ICIs) revealed improved outcomes in various cancers. Metformin's anti-cancer effects stem its effects on cancer metabolism, cell cycle modulation, cancer stem cells, gut microbiota, immunomodulatory properties. The aim of this retrospective study was to study the impact of concomitant metformin use with the type of systemic therapy (chemotherapy or ICIs) in CRC. Methods: CRC tumors were analyzed by NGS of DNA (592-gene) and RNA (whole transcriptome) at Caris Life Sciences. MSS was assessed by NGS, with MSI-H and MSS patients subcategorized by concomitant metformin use with ICI or with chemotherapy, respectively. Real-world OS, derived from insurance claims data, was calculated from the time of CRC sample collection to the last contact. Hazard ratio (HR) was calculated using the Cox proportional hazards model, with p values calculated using the log-rank test. Results: The study cohort included 31,083 CRC cases (male: female = 1.2, age: 80% &gt; = 50 years). Common molecular alterations included TP53 (73.6%), APC (77.6%), KRAS (47.4%), CTNNB1 (2.0%), and HER2 amplification (1.7%). 1,503 patients were MSI-H (4.83%), 21,330 as MSS (68.6%), and 8,250 indeterminate. MSI-H patients receiving concurrent ICI/metformin had similar OS (52.7 vs. 55.4 months, HR = 0.78, 95% CI: 0.41 – 1.51, p = 0.462). Conversely, OS was increased in MSS patients on concomitant chemotherapy and metformin (38.1 vs 31.1 months, HR = 0.77, 95% CI: 0.69 – 0.86, p &lt; 0.00001). In comparing real-world OS between left-sided and right-sided colorectal cancer (CRC), regardless of metformin use, multivariate analysis incorporating molecular alterations revealed longer OS for left-sided MSS CRC compared to right-sided (HR = 0.80, 95% CI: 0.76 – 0.84, p &lt; 0.00001). However, further improvement in OS was associated with concurrent metformin use in both right-sided and left-sided tumors. Conclusions: In this retrospective analysis of real-world clinical outcomes, patients receiving concomitant metformin and cytotoxic chemotherapy had improved clinical outcomes in MSS CRC compared to those not on concurrent metformin. However, the concurrent use of metformin with ICIs in MSI-H CRC did not show an impact on clinical outcomes given low sample size. These results add to the existing body of literature on the potential benefits of metformin in the context of MSS CRC and underscore the importance of a prospective controlled study of concurrent metformin use with systemic chemotherapy in metastatic CRC. Limitations of this study involves the potential inclusion of cases with prior metformin use, small sample size, retrospective analyses, and the lack of control for the patients with type II DM.

METAPANC, intensified treatment in patients with oligometastatic pancreatic cancer: Multimodal surgical treatment versus systemic chemotherapy alone—A prospective randomized controlled multicenter phase III trial.

TPS4207 Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal overall survival rate due to early metastasis and high therapy resistance. The successful introduction of intensified chemotherapeutic regimen such as FOLFIRINOX (FFX) has significantly increased response rates, disease control and overall survival. Current standards recommend systemic chemotherapy but no surgical approach in metastatic PDAC. FFX has the highest rates of response and overall survival and is a current standard of care in patients with metastatic PDAC and good performance status. Extensive surgical interventions with synchronous or metachronous metastasectomy is not recommended according to current guidelines. Retrospective data suggest beneficial outcomes in patients with hepatic oligometastasis, though prospective data from randomized clinical trials are not available. Methods: METAPANC is a prospective randomized controlled multicenter phase III trial evaluating survival and quality of life after multimodal therapy with perioperative modified FOLFIRINOX (mFFX) chemotherapy (two times 4 cycles prior to resection of the primary tumor and resection of the metastases), followed by 4 cycles of adjuvant mFFX chemotherapy (Arm A) vs. mFFX (without surgery), as standard of care first-line treatment (Arm B). Patients are eligible for randomization after 8 cycles of mFFX if they have at least stable disease on imaging according to RECIST V1.1 (Response Assessment I after 4 cycles and Response Assessment II after 8 cycles of mFFX). Patients with progressive disease will be excluded from the study. This clinical trial will focus on a well-defined patient collective with resectable PDAC and metastatic load limited to the liver with a maximum of three metastases. Patients with metachronous liver metastatic status can also be included, but must have completed adjuvant chemotherapy at least 6 months before start of study treatment. In patients randomized into Arm A with metastatic lesions located in the center of the liver local ablative techniques can be combined. In total 272 patients will be enrolled and will be randomized 1:1. The primary endpoint is overall survival, secondary endpoints are progression free survival, procedure related complications and mortality, quality of life, quality-adjusted time without symptoms and toxicity. METAPANC is accompanied by an exploratory biomarker analysis program of collecting biological and imaging samples to subsequently identify and evaluate molecular-based patient subgroups and biomarkers for identification of a potential target population which may benefit from the intensified multimodal treatment strategy. 22 German participating sites are selected. Further international sites are planned in the Netherlands, Norway, Finland and Sweden. Clinical trial information: 2023-503558-10-00.

Adjuvant chemotherapy following concurrent chemoradiation (CRT) in patients with high-risk early-stage cervical carcinoma following radical hysterectomy: Results of NRG oncology/RTOG 0724/GOG-0724.

5504 Background: To assess the efficacy of adjuvant systemic chemotherapy following CRT for patients (pts) with high-risk early-stage cervical carcinoma. Methods: Pts with clinical stage IA2, IB, or IIA cervical carcinoma with at least one of the following high-risk features after radical hysterectomy: positive pelvic nodes, positive parametrium, and/or positive para-aortic nodes were stratified by intention to use brachy (yes v no), RT (Standard v IMRT); and RT dose (45 v 50.4 Gy) then randomized 1:1 to CRT or CRT and 4 cycles of adjuvant chemotherapy with paclitaxel and carboplatin (CRT + chemo). Primary endpoint was disease-free survival (DFS: death, local or regional failure, or distant mets). Reported secondary endpoints are OS (death due to any cause) and AEs (CTCAEv4). Sample size was 235 pts (50 DFS events, HR=0.47, corresponding to an increase in 4-year DFS from 80% to 90% for the CRT + chemo arm, 80% power, 1-sided log-rank α=0.05). Multivariable analysis (MVA) used Cox regression models. Results: From 9/16/2009 to 3/2/2022, this phase III international trial enrolled 236 pts, with 212 eligible/analyzed (109 CRT and 103 CRT + chemo). Median age was 46 yrs (min-max: 25-77) and median follow-up for all pts was 4.5 yrs (min-max: 0.02-12.8). Fifty-one percent of pts identified as white, 39% as Asian, and 6% Black. Most pts had squamous cell carcinoma (76%), with 18% adenocarcinoma and 5% adenosquamous. 56% of pts had open radical hysterectomy, 23% laparoscopic, and 22% robotic. Most pts had stage IB (87%) and 74% had positive pelvic nodes. Four (4%) pts on the CRT arm and 1 (1%) patient on CRT + chemo did not receive RT. The median (min-max) RT dose delivered was 50.4 Gy (7.2-60.4). Four pts (2 on each arm) did not receive concurrent cisplatin and 27 (26%) pts did not receive adjuvant carboplatin and paclitaxel on the CRT + chemo arm. Grade 3 and 4 events occurred in 36% and 7% of CRT pts; 44% and 21% in the CRT + chemo arm. There were 50 failures, 26 and 24 on the CRT and CRT + chemo arms, respectively, with 4-yr DFS estimates of 76% (90% CI: 69%, 83%) and 77% (90% CI: 70%, 84%) for the CRT and CRT + chemo arms, respectively (HR=1.05 [90% CI: 0.65, 1.68], p=0.56). Thirty-seven of 50 first failures were distant [74%], 20 (40%) and 17 (34%) in CRT and CRT + chemo arms, respectively. On MVA, factors that were statistically significant for worse DFS were receiving vaginal brachy (p&lt;0.0001), RT dose ≥50 Gy (p=0.0021), and adenocarcinoma histology (p=0.03). Pts receiving brachy had close or positive margins. The estimated 4-yrs OS is 87% (90% CI: 82%, 93%) and 89% (90% CI: 84%, 94%) for the CRT and CRT +chemo arms, respectively (HR=0.91 [90% CI: 0.49 to 1.69]; 1-sided log-rank p=0.40). Conclusions: The addition of systemic chemotherapy following CRT didn't improve DFS or OS in cervical cancer patients with high-risk factors after radical hysterectomy. Clinical trial information: NRG Oncology/RTOG 0724/GOG-0724.

Exploring the prognostic impact of differences in treatment strategies for SCLC with different histologies and prognostic factors for C-SCLC: A SEER population-based study

BackgroundCombined small cell lung cancer (C-SCLC) is a rare type of small cell lung cancer (SCLC), and it is controversial whether to choose the same treatment regimen as SCLC due to its multiple histologic components. Study methods and resultsRecords of patients with small cell lung cancer diagnosed between 2010 and 2020 were extracted using the SEER database. The OS of patients with different histological types under the same staging and treatment regimen was analyzed. It was found that early-stage (stage IA-IIA) surgical treatment, systemic chemotherapy alone, and chemoradiotherapy were more efficacious than C-SCLC and P-SCLC in patients with limited-stage (P = 0.054, P = 0.001, P = 0.019). In patients with extensive staging, the OS of patients with systemic chemotherapy regimens differed (P = 0.045) and was better in C-SCLC than in P-SCLC. We further explored the treatment strategy for patients with C-SCLC, which was shown by a COX regression model based on prognostic factors screened by Random Forest and LASSO regression models. Surgery, radiotherapy, and chemotherapy would be beneficial for survival. In a subgroup analysis based on stage and treatment regimen, it was shown that patients with early staging (stage IA-IIA) had a better prognosis with surgery (P < 0.001); in patients with extensive staging, chemoradiotherapy was favorable to the patient's prognosis (P = 0.022). ConclusionBoth limited-stage and extensive-stage C-SCLC patients are more sensitive to chemotherapy than P-SCLC patients. Patients with C-SCLC who have access to surgery should undergo surgery as early as possible, while chemoradiotherapy is recommended for patients with extensive staging. Patient age, gender, tumor size, surgery, chemotherapy, radiotherapy, and metastasis may individually affect patient prognosis.

Analysis of long-lasting tumor-specific antibodies from murine tumors treated with Aliya pulsed electric fields.

e14543 Background: Pulsed electric field (PEF) tissue destruction has demonstrated meaningful systemic immune responses in mice that are superior to thermal ablation, and synergize effectively with systemic chemotherapy and checkpoint blockade (CPB) immunotherapy. Immune cell populations are increased by PEF, including tumor specific activated CD8 T-cells and plasma B-cells. Antitumor immunity can include the presence of circulating anti-cancer antibodies. However, the presence and role of circulating tumor specific antibodies induced by PEF have not been explored. Serological antibodies are often detected with the ELISA assay, where tumor-associated antigens are coated to a microtiter plate to attract the corresponding serum antibodies. Here, we quantify IgG tumor specific antibodies after PEF using an in-house ELISA. Methods: Mice bearing immune-warm (EMT6) and immune-cold (4T1) orthotopic murine breast tumors were treated with a biphasic PEF dose comparable to Aliya titrated for mouse tumors. To detect tumor specific circulating IgG1 immunoglobulin in serum, an ELISA plate was coated with EMT6 and 4T1 protein lysate, as well as with a known 4T1-expressed tumor-specific antigen (gp70). Serum draws from the treated, untreated, and naïve mice were exposed to the coated wells for 1 hour. Bound IgG were detected by anti-mouse IgG (HRP tagged) antibody added to the wells and incubated 1 hour. A TMB substrate was added and color development was allowed for 15 minutes. The optical density was quantified using a microtiter plate reader. Results: ELISA quantification of serum IgG at multiple timepoints show that 4T1 tumor-specific IgG antibodies were increased 14.3- and 2.6-fold by day 20 in the PEF-treated and untreated group survivors relative to Naïve mice, respectively, (OD=0.86 and 0.15 v. 0.06). Furthermore, IgG antibodies specific to the gp70 antigen of the 4T1 cell line were increased by 44.9- and 2.7-fold in the PEF-treated and untreated groups relative to naïve mice (OD=3.14 and 0.19 v. 0.07). In the EMT6 model, at 3 months post-treatment, only the PEF-ablated group mice survived, and showed 15.5-fold higher antibodies against EMT6 tumor antigens compared to naive mice (OD=0.62 v. 0.04). Conclusions: The specific form of PEF in this study generated tumor-specific IgG long-lived antibodies in mice for immune-warm and immune-cold tumor models, corroborating previous findings of increased murine B-cell and plasma cell populations. This effect has not been well-reported for other ablation technologies. Increases were evident by Day 20 post-PEF and persisted at least 3 months. These murine data suggest the PEF used may invoke potent, long-lived immune responses and anti-tumor immune surveillance, offering a potential approach for in situ tumor vaccination to improve metastatic disease outcomes. Future studies should determine response durability and its role in attaining distant tumor clearance.