The involvement of the hepatic artery is a risk factor for unresectability after neoadjuvant treatment in borderline pancreatic adenocarcinoma.

INTRODUCTION: Borderline Resectable Pancreatic Ductal Adenocarcinoma (BR-PDAC) benefits from neoadjuvant treatment (NAT) with the intent of surgical salvage in the absence of disease progression during chemotherapy (CT) or chemoradiotherapy (CRT). Scarce literature exists about prognostic factors of resectability at the time of diagnosis or during neoadjuvant treatment, especially regarding vascular relationships. MATERIALS: We reviewed our prospective BR-PDAC cohort to determine resectability predictors. We collected data about clinical baseline characteristics, vessels' involvement, type of NAT, CA19-9 evolution, and radiological outcome. We performed a descriptive analysis and a logistic regression model to define resectability predictors; we finally compared overall survival (OS) and progression-free survival (PFS) for those predictors. RESULTS: One hundred patients started NAT, with a resection rate of 44 % (40 pancreaticoduodenectomies, 4 distal pancreatectomies). The most frequent vessel relationship was the abutment of the superior mesenteric artery (44 %), and 26 patients had ≥2 vessels involved. Prognostic factors of resectability were CA19-9 response >10 % (OR 3.07, p = 0.016) and Hepatic Artery involvement (OR 0.21, p = 0.026). Median overall survival was better for CA19-9 responders than for non-responders (20.9 months and 11.8 months respectively, p < 0.001), and similar to normalized CA19-9 (25.0 months, p = 0.48). There were no differences in terms of OS or PFS with the involvement of the HA (17.7 vs 17.1 months, p = 0.367; and 8.7 vs 12.0 months, p = 0.267). CONCLUSION: The involvement of the Hepatic Artery seems to confer a worse prognosis regarding resectability. A decrease of only >10 % of CA19-9 is a predictive factor for resectability and better overall and progression-free survival.

Predictive value of baseline serum carbohydrate antigen 19-9 level on treatment effect of neoadjuvant chemoradiotherapy in patients with resectable and borderline resectable pancreatic cancer in two randomized trials.

BACKGROUND: Guidelines suggest that the serum carbohydrate antigen (CA19-9) level should be used when deciding on neoadjuvant treatment in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer). In patients with resectable pancreatic cancer, neoadjuvant therapy is advised when the CA19-9 level is 'markedly elevated'. This study investigated the impact of baseline CA19-9 concentration on the treatment effect of neoadjuvant chemoradiotherapy (CRT) in patients with resectable and borderline resectable pancreatic cancers. METHODS: In this post hoc analysis, data were obtained from two RCTs that compared neoadjuvant CRT with upfront surgery in patients with resectable and borderline resectable pancreatic cancers. The effect of neoadjuvant treatment on overall survival was compared between patients with a serum CA19-9 level above or below 500 units/ml using the interaction test. RESULTS: Of 296 patients, 179 were eligible for analysis, 90 in the neoadjuvant CRT group and 89 in the upfront surgery group. Neoadjuvant CRT was associated with superior overall survival (HR 0.67, 95 per cent c.i. 0.48 to 0.94; P = 0.019). Among 127 patients (70, 9 per cent) with a low CA19-9 level, median overall survival was 23.5 months with neoadjuvant CRT and 16.3 months with upfront surgery (HR 0.63, 0.42 to 0.93). For 52 patients (29 per cent) with a high CA19-9 level, median overall survival was 15.5 months with neoadjuvant CRT and 12.9 months with upfront surgery (HR 0.82, 0.45 to 1.49). The interaction test for CA19-9 level exceeding 500 units/ml on the treatment effect of neoadjuvant CRT was not significant (P = 0.501). CONCLUSION: Baseline serum CA19-9 level defined as either high or low has prognostic value, but was not associated with the treatment effect of neoadjuvant CRT in patients with resectable and borderline resectable pancreatic cancers, in contrast with current guideline advice.

The importance of CA 72-4 and CA 19-9 dosing in gastric cancer.

Serological analysis of tumor markers has emerged as a non-invasive method for monitoring cancer patients, including tumor recurrence and response to treatment. Tumor markers have the potential to aid in both the diagnosis and prognosis of cancer, but their most important role currently lies in the monitoring of tumor progression. Tumor markers can also provide valuable information on treatment effectiveness, with changes in plasma values indicating tumor regression or progression. This research aimed to investigate the correlation between the serum detection values of three tumor markers - CEA, CA 19-9, and CA 72-4 - and their utility in the diagnosis and prognosis of patients with gastric cancer. The study seeks to uncover the relationship between these tumor markers and the evolution of gastric cancer, providing insights into their potential use in clinical practice.

Added value of digital FDG-PET/CT in disease staging and restaging in patients with resectable or borderline resectable pancreatic cancer.

BACKGROUND: We studied the added value of digital FDG-PET/CT in disease staging and restaging compared to the standard work-up with contrast enhanced CT (ceCT) and CA19-9 in patients with resectable or borderline resectable pancreatic cancer who received neo-adjuvant therapy. Primary endpoints were tumor response compared to ceCT and CA19.9 as well as the ability to detect distant metastatic disease. METHODS: 35 patients were included in this dual-center prospective study. FDG-PET using digital photon counting technology combined with CT scans were acquired before (T1) and after neo-adjuvant therapy (T2). Patients were staged and restaged based on standard protocol with ceCT and CA 19.9, while all PET/CT scans were stored securely and not included in clinical decision making. After the pancreatic resection, an expert team retrospectively assessed the CT tumor diameter, CA19-9, tumor FDG-uptake, and appearance of metastatic disease of all patients for both time points. RESULTS: CA19-9 levels, CT tumor diameter, and tumor FDG-uptake on PET significantly decreased from T1 to T2 (p = 0.017, p = 0.001, and p < 0.0001). The change in FDG-uptake values showed a strong positive correlation with the change in CT tumor diameter and change in CA19-9 (R = 0.75 and R = 0.73, respectively). In addition, small-volume liver lesions were detected on digital PET/CT in 5/35 patients (14%), 4 of which were pathology confirmed at laparotomy. Only one of these five cases was detected on baseline staging ceCT (3%). CONCLUSION: We found that adding digital PET/CT strengthens restaging after neo-adjuvant therapy based on the observed strong correlation with ceCT tumor diameter and Ca19.9. Also, digital PET/CT was found to detect occult metastatic disease not visualized on ceCT, that would have resulted in altered disease staging and therapeutic strategy in a substantial proportion of patients.

Measuring response to neoadjuvant therapy using biomarkers in pancreatic cancer: a narrative review.

BACKGROUND AND OBJECTIVE: Pancreatic cancer is the 4th leading cause of cancer death in the US, with incidence increasing over the last 20 years. Recently neoadjuvant therapy (NAT) has emerged as an important tool in improving resectability and overall survival. The objective is to describe and discuss the current literature on the use of biomarkers in measuring response to NAT in pancreatic adenocarcinoma. METHODS: An electronic review of PubMed, Google Scholar and Cochrane was performed to obtain key literature on serum, imaging, clinical, and histologic biomarkers utilized to measure response to NAT in pancreatic cancer. This literature review included publications in English written between January 1, 2011 to March 31, 2022. KEY CONTENT AND FINDINGS: An overview of four categories of biomarkers was evaluated for their utility in assessing both pathologic response and overall survival following NAT in pancreatic adenocarcinoma. Serum CA19-9 as well as CT radiomic features, FDG PET response and development of histologic grading system all show promise as markers of response to NAT. CONCLUSIONS: While multiple promising modalities exist, all require some form of standardization in terms of predicting response to NAT. Further investigation and large-scale studies to evaluate the efficacy of various imaging modalities are necessary. Additionally, there needs to be standardization of histologic grading system post NAT, and consensus on CA19-9 cutoff values in determining NAT response.

Prognostic and predictive value of CA 19-9 in locally advanced pancreatic cancer treated with multiagent induction chemotherapy: results from a prospective, multicenter phase II trial (NEOLAP-AIO-PAK-0113).

BACKGROUND: The prognostic and predictive value of carbohydrate antigen 19-9 (CA 19-9) in locally advanced pancreatic cancer (LAPC) has not yet been defined from prospective randomized controlled trials (RCTs). PATIENTS AND METHODS: A total of 165 LAPC patients were treated within the NEOLAP RCT for 16 weeks with multiagent induction chemotherapy [ICT; either nab-paclitaxel/gemcitabine alone or nab-paclitaxel/gemcitabine followed by FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin)] followed by surgical exploration of all patients without evidence of disease progression. CA 19-9 was determined at baseline and after ICT and correlated with overall survival (OS) and secondary R0 resection rate. RESULTS: From the NEOLAP study population (N = 165) 133 patients (81%) were evaluable for CA 19-9 at baseline and 81/88 patients (92%) for post-ICT CA 19-9 response. Median OS (mOS) in the CA 19-9 cohort (n = 133) was 16.2 months [95% confidence interval (CI) 13.0-19.4] and R0 resection (n = 31; 23%) was associated with a significant survival benefit [40.8 months (95% CI 21.7-59.8)], while R1 resected patients (n = 14; 11%) had no survival benefit [14.0 (95% CI 11.7-16.3) months, hazard ratio (HR) 0.27; P = 0.001]. After ICT most patients showed a CA 19-9 response (median change from baseline: -82%; relative decrease ≥55%: 83%; absolute decrease to ≤50 U/ml: 43%). Robust CA 19-9 response (decrease to ≤50U/ml) was significantly associated with mOS [27.8 (95% CI 18.4-37.2) versus 16.5 (95% CI 11.7-21.2) months, HR 0.49; P = 0.013], whereas CA 19-9 baseline levels were not prognostic for OS. Multivariate analysis demonstrated that a robust CA 19-9 response was an independent predictive factor for R0 resection. Using a CA 19-9 decrease to ≤61 U/ml as optimal cut-off (by receiver operating characteristic analysis) yielded 72% sensitivity and 62% specificity for successful R0 resection, whereas CA 19-9 nonresponders (<20% decrease or increase) had no chance for successful R0 resection. CONCLUSIONS: CA 19-9 response after multiagent ICT provides relevant prognostic and predictive information and is useful in selecting LAPC patients for explorative surgery. CLINICAL TRIAL NUMBER: ClinicalTrials.govNCT02125136; https://clinicaltrials.gov/ct2/show/NCT02125136; EudraCT 2013-004796-12; https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004796-12/results.

Adaptive Dynamic Therapy and Survivorship for Operable Pancreatic Cancer.

Importance: Neoadjuvant therapy is increasingly used in localized pancreatic carcinoma, and survival is correlated with carbohydrate antigen 19-9 (CA19-9) levels and histopathologic response following neoadjuvant therapy. With several regimens now available, the choice of chemotherapy could be best dictated by response to neoadjuvant therapy (as measured by CA19-9 levels and/or pathologic response), a strategy defined herein as adaptive dynamic therapy. Objective: To evaluate the association of adaptive dynamic therapy with oncologic outcomes in patients with surgically resected pancreatic cancer. Design, Setting, and Participants: This retrospective cohort study included patients with localized pancreatic cancer who were treated with either gemcitabine/nab-paclitaxel or fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) preoperatively between 2010 and 2019 at a high-volume tertiary care academic center. Participants were identified from a prospectively maintained database and had a median follow-up of 49 months. Data were analyzed from October 17 to November 24, 2020. Exposures: The adaptive dynamic therapy group included 219 patients who remained on or switched to an alternative regimen as dictated by CA19-9 response and for whom the adjuvant regimen was selected based on CA19-9 and/or pathologic response. The nonadaptive dynamic therapy group included 103 patients who had their chemotherapeutic regimen selected independent of CA19-9 and/or tumoral response. Main Outcomes and Measures: Prognostic implications of dynamic perioperative therapy assessed through Kaplan-Meier analysis, Cox regression, and inverse probability weighted estimators. Results: A total of 322 consecutive patients (mean [SD] age, 65.1 [9] years; 162 [50%] women) were identified. The adaptive dynamic therapy group, compared with the nonadaptive dynamic therapy group, had a more pronounced median (IQR) decrease in CA19-9 levels (-80% [-92% to -56%] vs -45% [-81% to -13%]; P < .001), higher incidence of complete or near-complete tumoral response (25 [12%] vs 2 [2%]; P = .007), and lower median (IQR) number of lymph node metastasis (1 [0 to 4] vs 2 [0 to 4]; P = .046). Overall survival was significantly improved in the dynamic group compared with the nondynamic group (38.7 months [95% CI, 34.0 to 46.7 months] vs 26.5 months [95% CI, 23.5 to 32.9 months]; P = .03), and on adjusted analysis, dynamic therapy was independently associated with improved survival (hazard ratio, 0.73; 95% CI, 0.53 to 0.99; P = .04). On inverse probability weighted analysis of 320 matched patients, the average treatment effect of dynamic therapy was to increase overall survival by 11.1 months (95% CI, 1.5 to 20.7 months; P = .02). Conclusions and Relevance: In this cohort study that sought to evaluate the role of adaptive dynamic therapy in localized pancreatic cancer, selecting a chemotherapeutic regimen based on response to preoperative therapy was associated with improved survival. These findings support an individualized and in vivo assessment of response to perioperative therapy in pancreatic cancer.

Cell-free DNA Predicts Prolonged Response to Multi-agent Chemotherapy in Pancreatic Ductal Adenocarcinoma.

The treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) is frequently characterized by significant toxicity and rapid development of resistance to current approved therapies. More reliable biomarkers of response are needed to guide clinical decision making. We evaluated cell-free DNA (cfDNA) using a tumor-agnostic platform and traditional biomarkers (CEA and CA19-9) levels in 12 patients treated at Johns Hopkins University on NCT02324543 "Study of Gemcitabine/Nab-Paclitaxel/Xeloda (GAX) in Combination With Cisplatin and Irinotecan in Subjects With Metastatic Pancreatic Cancer." The pretreatment values, levels after 2 months of treatment, and change in biomarker levels with treatment were compared with clinical outcomes to determine their predictive value. The variant allele frequency (VAF) of KRAS and TP53 mutations in cfDNA after 2 months of treatment was predictive of progression-free survival (PFS) and overall survival (OS). In particular, patients with a lower-than-average KRAS VAF after 2 months of treatment had a substantially longer PFS than patients with higher posttreatment KRAS VAF (20.96 vs. 4.39 months). Changes in CEA and CA19-9 after 2 months of treatment were also good predictors of PFS. Comparison via concordance index demonstrated KRAS or TP53 VAF after 2 months of treatment to be better predictors of PFS and OS than CA19-9 or CEA. This pilot study requires validation but suggests cfDNA measurement is a useful adjunct to traditional protein biomarkers and imaging evaluation and could distinguish between patients who are likely to achieve prolonged responses versus those that will have early progression and may benefit from a change in treatment approach. Significance: We report on the association of cfDNA with response durability for patients undergoing treatment with a novel metronomic chemotherapy regimen (gemcitabine, nab-paclitaxel, capecitabine, cisplatin, irinotecan; GAX-CI) for metastatic PDAC. This investigation offers encouraging evidence that cfDNA may prove to be a valuable diagnostic tool to guide clinical management.

On a new strategy of preventive oncology.

The etiology of cancer is much wider than separately taken causal agent and rests against the most complicated interrelation and mutuality of many external and internal influences. Our researches with use of fluorescing antibodies to AFP, CEA and Ca-19-9 have shown that they are intensively besieged on a surface of cultivated malignant cells. It is the basic mechanism of tolerance and immunological escape, which is similar to pregnancy when "the maximal immunological most favored status" to developing fetus (semiallogenic transplant) is provided. The earliest revealing of first cancer cells, before steady community of cells and tumor angiogenesis were formed, has particular importance in the fight against cancer. The necessity of the specific completion of the weakened antineoplastic resistibility of people from high oncological risk groups is substantiated. The activity in this direction brought forth the design of embryonic anti-tumor modulator (EATM). EATM is composed of a wide pool of fetal proteins and proteoglycans isolated exceptionally from normal embryonic substances.

Resistance of pancreatic carcinoma cells is reversed by coculturing NK-like T cells with dendritic cells pulsed with tumor-derived RNA and CA 19-9.

Immunization with defined tumor antigens is limited to the small number of cancers in which specific tumor antigens have been defined but insufficient tumor material is available to produce an antitumor vaccine. In this study, we investigated whether pulsing dendritic cells (DC) using a liposomal transfer technique with a pancreatic tumor cell line-derived RNA can effectively activate NK-like T cells and tumor immunity. Pulsed DC were cocultured with NK-like T cells, i.e., CD3+CD56+ cells, as immunologic effector cells. Target cells resistant to NK-like T-cell-mediated lysis were used. Total tumor-derived RNA transfected into DC was found to completely reverse tumor cell resistance. Total tumor RNA transfection (30 microg) was found to be superior to poly(A)(+) RNA transfection (5 microg) in inducing NK-like T lymphocytes. Interestingly, additional pulsing of DC with the CA 19-9 peptide in a CA 19-9-positive cell line further increased the sensitivity of pancreas carcinoma cells to NK-like T cells. Treatment of tumor RNA with RNase completely blocked the effect of RNA-transfected DC on NK-like T cells, suggesting that intact tumor-derived RNA is needed for reversal of tumor cell resistance. In conclusion, coculture of NK-like T cells with DC transfected with pancreatic tumor cell line-derived RNA reverses pancreatic tumor cell resistance by directly triggering NK-like T lymphocytes.