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Dose escalation and dose limiting toxicity. Flow diagram of the number of patients per dose level, and the choice for subsequent dose levels based on the occurrence of DLTs and toxicity. DLT: dose-limiting toxicity; MTD: maximum tolerated dose; RP2D: recommended phase II dose.
Source publication
First-line triplet chemotherapy including a taxane may prolong survival in patients with metastatic esophagogastric cancer. The added toxicity of the taxane might be minimized by using nab-paclitaxel. The aim of this phase I study was to determine the feasibility of combining nab-paclitaxel with the standard of care in the Netherlands, capecitabine...
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A retrospective study investigating whether the use of capecitabine in colorectal cancer is related to drug-induced liver injury or not.
Citations
... The ORR in the treatment of gastric cancer 22,23 is 34-50%, and that of colorectal cancer 24 is 58.6%, with no serious adverse events. Sandor Schokker et al. 25 combined nab-paclitaxel and capecitabine for EC, with an ORR of 54%, median PFS and OS of 8 and 12.8 months, respectively, and tolerable adverse events. We therefore selected camrelizumab combined with nabpaclitaxel and capecitabine as the neoadjuvant regimen in this study to reduce the toxicity of neoadjuvant therapy. ...
Background:
Immune checkpoint inhibitor (ICI) monotherapy and neoadjuvant immunochemotherapy have shown promising results in esophageal carcinoma. However, it is still unclear whether more courses of immunochemotherapy are therapeutically better. We aimed to investigate the safety and efficacy of three courses of neoadjuvant treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC).
Methods:
Patients with locally advanced ESCC received three courses of camrelizumab plus nab-paclitaxel and capecitabine before undergoing surgery. Additionally, patients received safety, computed tomography (CT), and endoscopy (with endoscopic ultrasonography and mucosal biopsy) assessments before and in the second and third courses of treatment. We used the CT and endoscopic assessment results from the second and third courses for comparison.
Results:
From May 2020 to December 2021, 47 patients were enrolled at Sun Yat-sen University Cancer Center. In our study, 43 patients completed three courses of preoperative chemotherapy combined with anti-Programmed cell death-1 (PD-1) therapy and radical surgical resection. The toxicity of the third course of immunochemotherapy was mild and well tolerated without increased treatment-related adverse events (TRAEs) and mortality compared with that of the second course of treatment. In terms of efficacy, an additional course of treatment after the second course of treatment was effective, with increased CT and endoscopy T (clinical T stage) downstaging rates by 16.3% and 25.9%, N (clincial N stage) downstaging rates by 7.0% and 11.1%, and objective response rates (ORRs) by 13.6% and 22.0%, respectively.
Conclusions:
Regardless of downstaging or ORR, three courses of immunochemotherapy appear to be superior to two courses of treatment without increasing TRAEs.
... Baseline CT scans were used to measure three dimensional tumor volume as previously described [24]. In short semiautomated software (MM oncology, Syngo Via, Siemens Healthineers, Forchheim, Germany) was used for volume calculations (in milliliters) under the supervision of an experienced radiologist blinded for outcome. ...
... Palliative treatment consisted of capecitabine and oxaliplatin (CAPOX) in 67% of patients. Nab-paclitaxel was added to CAPOX in 22% of patients who participated in a phase II clinical trial (ACTION) [24]. Of the remaining patients, 8% received trastuzumab in addition to chemotherapy and 3% of patients did not start palliative systemic treatment. ...
Background
Circulating tumor DNA (ctDNA) has predictive and prognostic value in localized and metastatic cancer. This study analyzed the prognostic value of baseline and on-treatment ctDNA in metastatic gastroesophageal cancer (mGEC) using a region-specific next generation sequencing (NGS) panel.
Methods
Cell free DNA was isolated from plasma of patients before start of first-line palliative systemic treatment and after 9 and 18 weeks. Two NGS panels were designed comprising the most frequently mutated genes and targetable mutations in GEC. Tumor-derived mutations in matched metastatic biopsies were used to validate that the sequencing panels assessed true tumor-derived variants. Tumor volumes were calculated from baseline CT scans and correlated to variant allele frequency (VAF). Survival analyses were performed using univariable and multivariable Cox-regression analyses.
Results
ctDNA was detected in pretreatment plasma in 75% of 72 patients and correlated well with mutations in metastatic biopsies (86% accordance). The VAF correlated with baseline tumor volume (Pearson’s R 0.53, p < 0.0001). Detection of multiple gene mutations at baseline in plasma was associated with worse overall survival (OS, HR 2.16, 95% CI 1.10–4.28; p = 0.027) and progression free survival (PFS, HR 2.71, 95% CI 1.28–5.73; p = 0.009). OS and PFS were inferior in patients with residual detectable ctDNA after 9 weeks of treatment (OS: HR 4.95, 95% CI 1.53–16.04; p = 0.008; PFS: HR 4.08, 95% CI 1.31–12.75; p = 0.016).
Conclusion
Based on our NGS panel, the number of ctDNA mutations before start of first-line chemotherapy has prognostic value. Moreover, residual ctDNA after three cycles of systemic treatment is associated with inferior survival.
... ADAM12 levels were measured by ELISA in all available serum samples from the CAIRO2 cohort (n = 235 (31%)). ADAM12 levels were high with a median of 603 (IQR 1351) pg/mL, compared to previously published healthy controls (median 153 (IQR 169) pg/mL [21]), and higher compared to metastatic esophagogastric adenocarcinoma (median 242.5 pg/mL) [43] and esophageal adenocarcinoma (median 108.7 pg/mL) [44], but lower than metastatic pancreatic ductal adenocarcinoma patients (median 2293 pg/mL) [21]. ...
... CMS4 tumors harbor more stroma, explaining the association in bulk tumor measurements. We take this to imply that ADAM12 is a purely stromal activation marker, as also shown for pancreatic and esophageal cancer [21,43,44]. There was however a clear prognostic signal for ADAM12 within the mesenchymal subtype. ...
Background
Recently it has been recognized that stromal markers could be used as a clinically relevant biomarker for therapy response and prognosis. Here, we report on a serum marker for stromal activation, A Disintegrin and Metalloprotease 12 (ADAM12) in colorectal cancer (CRC).
Methods
Using gene expression databases we investigated ADAM12 expression in CRC and delineated the source of ADAM12 expression. The clinical value of ADAM12 was retrospectively assessed in the CAIRO2 trial in metastatic CRC with 235 patients (31% of total cohort), and an independent rectal cancer cohort ( n = 20).
Results
ADAM12 is expressed by activated CRC associated fibroblasts. In the CAIRO2 trial cohort, ADAM12 serum levels were prognostic (ADAM12 low versus ADAM12 high; median OS 25.3 vs. 17.1 months, HR 1.48 [95% CI 1.11–1.96], P = 0.007). The prognostic potential was specifically high for metastatic rectal cancer (HR 1.78 [95% CI 1.06–3.00], P = 0.030) and mesenchymal subtype tumors (HR 2.12 [95% CI 1.25–3.60], P = 0.004). ADAM12 also showed potential for predicting recurrence in an exploratory analysis of non-metastatic rectal cancers.
Conclusions
Here we describe a non-invasive marker for activated stroma in CRC which associates with poor outcome, especially for primary cancers located in the rectum.
... 3 In subsequent studies, serum ADAM12 levels showed prognostic value in patients with gastrointestinal adenocarcinomas. 4 In metastatic PDAC, it was shown that only patients with low circulating ADAM12 levels benefited from the addition of nab-paclitaxel to the standard of care gemcitabine. 3 This could possibly be explained by the mechanical barrier function of stroma preventing delivery of nabpaclitaxel, but needs to be explored further. ...
... Serum is stored at −80 C. ADAM12 levels were determined in mono in 80 ml of serum, using a commercially available ADAM12 DuoSet ELISA kit (R&D Systems, Minneapolis, MN), according to the manufacturer's instructions and as previously described. 4 The analyses were performed by a technician, blinded for outcomes. Carbohydrate antigen (CA) 19-9 and bilirubin levels were measured in 50 ml serum using an immunochemical assay on the Roche e602 (Roche Diagnostics, Almere, The Netherlands) integrated in a Cobas c8000 system (Roche Diagnostics). ...
Background
We evaluated the stroma marker A Disintegrin And Metalloprotease 12 (ADAM12) as a preoperative prognostic and treatment-predictive marker for overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) and periampullary cancers.
Methods
Materials were derived from the prospective nationwide Dutch Pancreas Biobank (2015-2017). We included patients who underwent resection because of PDAC/periampullary cancer or non-invasive IPMN (control group) and had a preoperative serum sample available. ADAM12 levels were dichotomized using a pre-defined cut-off (316 pg/mL). Univariable and multivariable Cox regression analyses (backward selection) were performed.
Results
Median ADAM12 levels were 161 (IQR 79-352) pg/mL in 215 PDAC and periampullary adenocarcinomas. High ADAM12 levels (>316 pg/mL) predicted poor OS in the total group of pancreatic and periampullary adenocarcinomas (P=0.04), but not after adjustment. In distal cholangiocarcinoma (n=33), high ADAM12 levels predicted poor OS in univariable analysis (P=0.02), but not in PDAC (P=0.63). PDAC patients (n=135) with high ADAM12 levels benefited from adjuvant treatment (median OS 27 vs 14 months, P=0.02), whereas those with low levels did not (21 vs 21 months, P=0.87).
Discussion
High circulating ADAM12 levels, as a proxy for activated stroma, predict survival benefit from adjuvant chemotherapy in PDAC, requiring validation in future studies.
... As the third-generation platinum-derived chemotherapeutic drug, oxaliplatin (OXA) displays its anti-cancer activity to treat hepatocellular carcinoma (HCC) patients in numerous studies [9][10][11]; however, the pooled response rates of OXA are not more than 20% for patients with advanced HCC [10]. The low response rates partly attribute to chemotherapy resistance, which negatively influences on the recovery rate of OXA-treatment patients [12]. ...
Recent studies suggest that up-regulated HSF1 possesses metabolic phenotypes switch and chemoresistance in cancer cells. However, the mechanism in which these characteristics are still ambiguous. Our study aims to identify how HSF1 confers chemoresistance through regulating metabolic pathway in hepatocellular carcinoma (HCC). Oxaliplatin (OXA)-resistant HCC cells (HCC-OXR) in both of abundant glucose (AG; 25 mM) and low glucose (LG; 5.5 mM) conditions were constructed; then glucose consumption, lactate production, intracellular ATP level and oxygen consumption of parental and OXA-resistant cells were determined by using the associated detected kits. Moreover, HSF1 was knocked down to analyze its effects on metabolic phenotypes alteration and chemoresistance formation in HCC cells. Compared to cells in AG condition, HCC cells delayed to form chemoresistance to OXA in LG condition; and OXA-resistant cells underwent a metabolic switch from glycolysis to oxidative phosphorylation (OXPHOS), which presented decreased glucose uptake and lactate production with increased levels of oxygen consumption and intercellular ATP; interestingly, this energy-producing pathway was blocked in HSF1-knockdown OXA-resistant cells, especially in LG condition. Analysis on previous data revealed that AMPK pathway was a critical regulator in the metabolism of OXA-resistance HCC cells. Furthermore, AMPKα2 was identified as an important factor regulated by HSF1 to achieve metabolic phenotype switch in OXA-resistance HCC cells. Consequently, these results suggest that combining restrictive glucose uptake and targeting HSF1/AMPKα2 is an attractive strategy to prevent chemoresistance to OXA in HCC patients.
While immune checkpoint inhibitors have revolutionized cancer treatment, in esophageal cancer, response rates are only modest. One potential explanation can be found in the composition of the tumor immune microenvironment, which is characterized by immune cell exclusion, infiltration of immune suppressive macrophages, epithelial-to-mesenchymal transition, and stromal factors that suppress local immunity. Improving success of immune checkpoint inhibitor will likely need targeting of these factors as well. Furthermore, determining the best timing of immunotherapy relative to conventional therapies such as chemotherapy and radiotherapy needs to be studied in more detail and likely influences it success. Based on this knowledge alternative immunomodulatory strategies can be developed using a precision oncology approach.
