Pressurized intraperitoneal aerosol chemotherapy (PIPAC) with cisplatin and doxorubicin in combination with FOLFOX chemotherapy as a first-line treatment for gastric cancer patients with peritoneal metastases: single-arm phase II study.

BACKGROUND: Gastric cancer (GC) remains among the most common and most lethal cancers worldwide. Peritoneum is the most common site for distant dissemination. Standard treatment for GC peritoneal metastases (PM) is a systemic therapy, but treatment outcomes remain very poor, with median overall survival ranging between 3-9 months. Thus, novel treatment methods are necessary. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is the most novel technique for intraperitoneal chemotherapy. Some preliminary data suggest PIPAC can achieve improved long-term outcomes in patients with GC PM, especially when used in combination with systemic chemotherapy. However, there is a lack of data from well-design prospective studies that would confirm the efficacy of PIPAC and systemic therapy combination for first-line treatment. METHODS: This study is an investigator-initiated single-arm, phase II trial to investigate the efficacy of PIPAC combined with systemic FOLFOX (5-fluorouracil, oxaliplatin, leucovorin) as a first-line treatment for GC PM. The study is conducted in 2 specialized GC treatment centers in Lithuania. It enrolls GC patients with histologically confirmed PM without prior treatment. The treatment protocol consists of PIPAC with cisplatin (10.5 mg/m2 body surface in 150 mL NaCl 0.9%) and doxorubicin (2.1 mg/m2 in 50 mL NaCl 0.9%) followed by 2 cycles of FOLFOX every 6-7 weeks. In total 3 PIPACs and 6 cycles of FOLFOX will be utilized. The primary outcome of the study is the objective response rate (ORR) according to RECIST v. 1.1 criteria (Eisenhauer et al., Eur J Cancer 45:228-47) in a CT scan performed 7 days after the 4th cycle of FOLFOX. Secondary outcomes include ORR after all experimental treatment, PIPAC characteristics, postoperative morbidity, histological and biochemical response, ascites volume, quality of life, overall survival, and toxicity. DISCUSSION: This study aims to assess PIPAC and FOLFOX combination efficacy for previously untreated GC patients with PM. TRIAL REGISTRATION: NCT05644249. Registered on December 9, 2022.

Prognostic value of circulating T-lymphocyte subsets in advanced pancreatic cancer patients treated with mFOLFIRINOX or gemcitabine.

Advanced pancreatic ductal adenocarcinoma (PDAC) is commonly treated with a chemotherapy combination of mFOLFIRINOX or gemcitabine. However, predictive and prognostic factors for choosing a more appropriate treatment strategy are still lacking. This study aimed to evaluate how chemotherapy changes immune system parameters and whether these changes influence survival outcomes. We sought to identify an easily accessible marker to help choose the appropriate treatment. Patients with PDAC who were suitable for systemic chemotherapy were eligible for the study. Peripheral blood samples were obtained at baseline and after two months of treatment. Lymphocyte subsets were measured using flow cytometry. Correlation with clinical features and survival analyses were performed. In total, 124 patients were enrolled in this study. Seventy patients were treated with mFOLFIRINOX and 50 with gemcitabine monotherapy. Four patients could not be treated because of rapid deterioration. During overall survival analysis (OS), significant factors included age, Eastern Cooperative Oncology Group (ECOG) performance status, differentiation grade G3, carcinoma antigen (CA) 19-9 more than 100 kU/L, absolute white blood cell count, CD3 + CD8+, and CD8 + CD57-T lymphocytes. Natural killer CD3-CD56 + CD16 + and CD3-CD56 + CD16- and T regulatory CD4 + FOXP3 + and CD3 + CD56 + cells differed during treatment, but these differences did not influence the survival results. At baseline, CD8 + CD57- T lymphocyte count demonstrated a clear independent impact on progression-free survival and OS. Gemcitabine showed better survival in patients with extremely low baseline CD8 + CD57- levels. Therefore, circulating CD3 + CD8 + and CD8 + CD57- cells measured before treatment in PDAC may be considered prognostic and predictive biomarkers.

Sequential treatment of metastatic renal cell carcinoma patients after first-line vascular endothelial growth factor targeted therapy in a real-world setting: epidemiologic, noninterventional, retrospective-prospective cohort multicentre study.

PURPOSE: The purpose of our study was to determine whether data on the clinical effectiveness of second-line therapy collected in a real-world setting provide additional valuable information on the optimal sequence of metastatic renal cell carcinoma (mRCC) treatment. METHODS: Patients diagnosed with mRCC who were treated with at least one dose of first-line vascular endothelial growth factor (VEGF)-targeted therapy with either sunitinib or pazopanib and with at least one dose of second-line everolimus, axitinib, nivolumab, or cabozantinib were included. The efficacy of different treatment sequences was analyzed based on the time to the second objective disease progression (PFS2) and the time to the first objective disease progression (PFS). RESULTS: Data from 172 subjects were available for analysis. PFS2 was 23.29 months. The 1-year PFS2 rate was 85.3%, and the 3-year PFS2 rate was 25.9%. The 1-year overall survival rate was 97.0%, and the 3-year overall survival rate was 78.6%. Patients with a lower IMDC prognostic risk group had a significantly (p < 0.001) longer PFS2. Patients with metastases in the liver had a shorter PFS2 than patients with metastases in the other sites (p = 0.024). Patients with metastases in the lungs and lymph nodes (p = 0.045) and patients with metastases in the liver and bones (p = 0.030) had lower PFS2 rates than patients with metastases in other sites. CONCLUSIONS: Patients with a better IMDC prognosis have a longer PFS2. Metastases in the liver lead to a shorter PFS2 than metastases in other sites. One metastasis site means a longer PFS2 than 3 or more metastasis sites. Nephrectomy performed in an earlier stage of disease or metastatic setting means higher PFS and higher PFS2. No PFS2 difference was found between different treatment sequences of TKI-TKI or TKI-immune therapy.

The Effects of Treatment on Peripheral Blood Immune Cell Profile in Pancreatic Ductal Adenocarcinoma (PDAC).

BACKGROUND/AIM: This study evaluated whether circulating lymphocytes, assessed by flow cytometry, is a prognostic biomarker in pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: We studied T cell subsets in blood samples from a cohort of 41 patients diagnosed with PDAC. Patients underwent surgery of the primary site and adjuvant chemotherapy or were treated with 1st line chemotherapy (mFOLFIRINOX regimen or gemcitabine alone). The changes in T cell subpopulations during treatment were evaluated at the initial diagnosis before surgery, and after 2 and 4 months. Friedman test was used for statistical analysis. RESULTS: A decline in CD19+ B lymphocytes, natural killer (NK) cells CD3-CD56+CD16+, and T regulatory cells CD4+FOXP3+ during treatment was observed. NKT-like cells CD3+CD56+ and cytotoxic T cells CD3+CD8+ tended to increase after two months and decrease after that. CONCLUSION: Statistically significant changes in lymphocyte counts in peripheral blood were detected in patients with PDAC during treatment.

A Retrospective Analysis of Dabrafenib and/or Dabrafenib Plus Trametinib Combination in Patients with Metastatic Melanoma to Characterize Patients with Long-Term Benefit in the Individual Patient Program (DESCRIBE III).

The dabrafenib plus trametinib (dab + tram) combination has demonstrated durable long-term efficacy in patients with BRAF V600-mutant metastatic melanoma. However, real-world data characterizing patients with long-term benefit are limited. DESCRIBE III was a global, observational, retrospective, chart review study in patients with unresectable or metastatic melanoma treated with dab monotherapy and/or dab + tram combination therapy as part of the Named Patient Program or Individual Patient Program. Overall, 509 patients were enrolled. Patients were categorized into three groups based on their observed treatment duration: long-term (on therapy ≥12 months), intermediate (on therapy ≥6 months and <12 months), and short-term (on therapy <6 months) duration of benefit. More patients in the short-term duration of benefit group had baseline characteristics associated with poor prognosis compared with the other two groups. Median lactate dehydrogenase (LDH) levels (368 U/L) at baseline were also higher in the short-term duration of benefit group. No new safety signals were identified. DESCRIBE III identified baseline characteristics associated with long-term benefit of dab + tram. Lower LDH level and <3 metastatic sites at baseline were associated with a longer duration of benefit, confirming that the findings from COMBI-d and COMBI-v are relevant to patients treated in a real-world setting.

Dabrafenib plus trametinib is effective in the treatment of BRAF V600-mutated metastatic melanoma patients: analysis of patients from the dabrafenib plus trametinib Named Patient Program (DESCRIBE II).

In clinical trials, dabrafenib plus trametinib improved overall survival (OS) compared with single-agent BRAF inhibitors (BRAFi) in patients with BRAF V600-mutant unresectable or metastatic melanoma. We investigated dabrafenib plus trametinib therapy in a compassionate-use setting [Named Patient Program (NPP); DESCRIBE II]. A retrospective chart review of patients with BRAF V600-mutated unresectable stage III/IV melanoma receiving dabrafenib plus trametinib as compassionate use was conducted. Treatment patterns and duration, clinical outcomes, and tolerability were evaluated. Of 271 patients, 92.6% had stage IV melanoma, including 36.5% with brain metastases. Overall, 162 patients (59.8%) were BRAFi naive and 171 (63.1%) received first-line dabrafenib plus trametinib. Among BRAFi-naive patients, the overall response rate (ORR) was 67.3%, median OS (mOS) was 20.0 months, and median progression-free survival (mPFS) was 7.5 months. In BRAFi-naive patients with known brain metastases (n = 62), ORR was 61.3%, mOS was 15.5 months, and mPFS was 6.2 months. Eighty-four patients received BRAFi monotherapy for >30 days and switched to dabrafenib plus trametinib prior to progression. Of these 84 patients, 63 had known disease status at the time of switch, and 22 improved with the combination therapy. No new safety signals were identified, and dabrafenib plus trametinib was well tolerated. Dabrafenib plus trametinib showed substantial clinical activity in NPP patients with BRAF V600-mutated unresectable or metastatic melanoma. Analysis of treatment patterns demonstrated the effectiveness of the combination in patients with brain metastases and across lines of therapy with a well tolerated and manageable safety profile.