Neoadjuvant treatment in esophageal cancer-established treatments and new developments reviewed

As the majority of patients experiences locoregional relapse and/or distant metastasis even after radical resection of esophageal cancer, many efforts have been made and are ongoing to identify the optimal multimodality treatment strategy. The true benefit and harm of neoadjuvant therapy including chemotherapy, radiotherapy or the combination, is still difficult to interpret given the heterogeneity in patient and tumor characteristics. Nonetheless, neoadjuvant chemoradiation with weekly carboplatin and paclitaxel (the CROSS regimen) is considered standard of care for squamous cell carcinoma in Europe. Definitive chemoradiation is considered an equal alternative in the United States. For adenocarcinoma, preoperative chemoradiation with a platinum and 5FU or the CROSS regimen and peri-operative chemotherapy with a platinum and 5FU or the FLOT (fluorouracil, leukovorin, oxaliplatin and docetaxel) regimen are all options. New developments in systemic anti-tumor therapy will most likely involve dual anti-HER2 inhibition or novel anti-HER2 antibody-drug conjugates for adenocarcinoma. Immunotherapy monotherapy in an unselected patient population does not seem to be as effective in esophageal cancer as it is in other cancer types. However, when we can correctly identify the subset of patients which does benefit from this treatment by employing new predictive markers, or find an effective synergistic combination of immunotherapy with chemotherapy and/or radiotherapy, immunotherapy could still improve patient outcome in the future.</p

Circulation Tumor Cells: counts and characteristics

In recent years, many new anti-cancer agents have been developed and introduced into clinical care. While these new agents have led to substantial gains in response rates and life expectancies, they have also increased the need for tools to select those patients benefitting from said therapies. Once patients develop metastatic disease, treatment is aimed at improving quality of life and prolonging life expectancy, but is always a trade-off against the side-effects that are inevitably associated with anti-tumor therapy, underscoring the need to select only those patients who are likely to respond to a particular drug. However, there is still an unmet need for such an array of reliable predictive factors, a need that can be met by designing studies in which patient subgroups are defined and stratified based on rational, biology-driven but feasible tumor characteristics. An increasing number of studies is being designed in which, for example, only patients with a specific gain-of-function mutation are subjected to a monoclonal antibody therapy aimed at the activated pathway this gene is involved in. While substantial progress is being made with this approach, patient selection has thus far been far from perfect. Even a powerful predictor such as a KRAS mutation for EGFR-inhibiting therapy results in a response in just 20% of patients who are deemed sensitive based on their KRAS wild-type status. One of the reasons for the disappointing performance of predictive factors could be the fact that they are most often based on primary tumor characteristics, while at the time of metastatic disease, a patients’ prognosis is determined by their metastatic tumor load and its biological phenotype. Through processes such as clonal selection and the inherent genomic instability of the tumor or as a consequence of therapy pressure, metastatic tumor cells can differ substantially and vitally from primary tumor cells. Analysis of metastatic tissue would thus probably be better indicative of the actual tumor load and its underlying biology, and lead to better response prediction. Unfortunately, repetitive metastatic biopsies are invasive and painful, understandably limiting their use in clinical practice. Circulating tumor cells (CTCs) provide a very promising solution for this problem, as they can be obtained and characterized repetitively and non-invasively through venipunctures, and thus serve as a surrogate ‘liquid biopsy’ of metastases

Diagnostic applications of cell-free and circulating tumor cell-associated miRNAs in cancer patients

Summary: Circulating tumor cells (CTCs) have rapidly developed as important cancer biomarkers after their enumeration proved to be prognostic in metastatic breast, colorectal and prostate cancer, and their rise or decline after the first cycle of therapy showed to predict therapy response. Besides mere counting, CTCs can be isolated and subsequently analyzed using various molecular applications, including miRNA expression analysis. Recently, miRNA expression profiling in primary tumors has yielded promising results. However, establishing miRNA expression in the circulation likely has advantages over determination in primary tumor tissue, further augmenting the potential applications of miRNA determination in oncology. Additionally to CTC-associated miRNAs, free circulating miRNAs have been identified in whole blood, plasma and serum. Since determination of miRNAs in peripheral blood, either cell-free or CTC-associated, is expected to become important in oncology, especially when linked to and interpreted together with epithelial CTCs, this review focuses on measuring miRNAs in the circulation of cancer patients

Intraperitoneal chemotherapy for peritoneal metastases of gastric origin:a systematic review and meta-analysis

Background: Gastric cancer with peritoneal metastases is associated with a dismal prognosis. Normothermic catheter-based intraperitoneal chemotherapy and normothermic pressurized intraperitoneal aerosol chemotherapy (PIPAC) are methods to deliver chemotherapy intraperitoneally leading to higher intraperitoneal concentrations of cytotoxic drugs compared to intravenous administration. We reviewed the effectiveness and safety of different methods of palliative intraperitoneal chemotherapy. Methods: Embase, MEDLINE, Web of Science and Cochrane were searched for articles studying the use of repeated administration of palliative intraperitoneal chemotherapy in patients with gastric cancer and peritoneal metastases, published up to January 2024. The primary outcome was overall survival. Results: Twenty-three studies were included, representing a total of 999 patients. The pooled median overall survival was 14.5 months. The pooled hazard ratio of the two RCTs using intraperitoneal paclitaxel and docetaxel favoured the intraperitoneal chemotherapy arm. The median overall survival of intraperitoneal paclitaxel, intraperitoneal docetaxel and PIPAC with cisplatin and doxorubicin were respectively 18.4 months, 13.2 months and 9.0 months. All treatment methods had a relatively safe toxicity profile. Conversion surgery after completion of intraperitoneal therapy was performed in 16% of the patients.Conclusions: Repeated intraperitoneal chemotherapy, regardless of method of administration, is safe for patients with gastric cancer and peritoneal metastases. Conversion surgery after completion of the intraperitoneal chemotherapy is possible in a subset of patients.</p

¹⁸F-FDG PET/MRI for restaging esophageal cancer after neoadjuvant chemoradiotherapy

PURPOSE: The purpose of this study was to investigate whether 18F-fluorodeoxyglucose ( 18 F-FDG) PET/MRI may potentially improve tumor detection after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer. METHODS: This was a prospective, single-center feasibility study. At 6-12 weeks after nCRT, patients underwent standard 18 F-FDG PET/computed tomography (CT) followed by PET/MRI, and completed a questionnaire to evaluate burden. Two teams of readers either assessed the 18 F-FDG PET/CT or the 18 F-FDG PET/MRI first; the other scan was assessed 1 month later. Maximum standardized uptake value corrected for lean body mass (SUL max ) and mean apparent diffusion coefficient (ADC mean ) were measured at the primary tumor location. Histopathology of the surgical resection specimen served as the reference standard for diagnostic accuracy calculations. When patients had a clinically complete response and continued active surveillance, response evaluations until 9 months after nCRT served as a proxy for ypT and ypN (i.e. 'ycT' and 'ycN'). RESULTS: In the 21 included patients [median age 70 (IQR 62-75), 16 males], disease recurrence was found in the primary tumor in 14 (67%) patients (of whom one ypM+, detected on both scans) and in locoregional lymph nodes in six patients (29%). Accuracy (team 1/team 2) to detect yp/ycT+ with 18 F-FDG PET/MRI vs. 18 F-FDG PET/CT was 38/57% vs. 76/61%. For ypN+, accuracy was 63/53% vs. 63/42%, resp. Neither SUL max (both scans) nor ADC mean were discriminatory for yp/ycT+ . Fourteen of 21 (67%) patients were willing to undergo a similar 18 F-FDG PET/MRI examination in the future. CONCLUSION: 18 F-FDG PET/MRI currently performs comparably to 18 F-FDG PET/CT. Improvements in the scanning protocol, increasing reader experience and performing serial scans might contribute to enhancing the accuracy of tumor detection after nCRT using 18 F-FDG PET/MRI. TRIAL REGISTRATION: Netherlands Trial Register NL9352.</p

¹⁸F-FDG PET/MRI for restaging esophageal cancer after neoadjuvant chemoradiotherapy

PURPOSE: The purpose of this study was to investigate whether 18F-fluorodeoxyglucose ( 18 F-FDG) PET/MRI may potentially improve tumor detection after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer. METHODS: This was a prospective, single-center feasibility study. At 6-12 weeks after nCRT, patients underwent standard 18 F-FDG PET/computed tomography (CT) followed by PET/MRI, and completed a questionnaire to evaluate burden. Two teams of readers either assessed the 18 F-FDG PET/CT or the 18 F-FDG PET/MRI first; the other scan was assessed 1 month later. Maximum standardized uptake value corrected for lean body mass (SUL max ) and mean apparent diffusion coefficient (ADC mean ) were measured at the primary tumor location. Histopathology of the surgical resection specimen served as the reference standard for diagnostic accuracy calculations. When patients had a clinically complete response and continued active surveillance, response evaluations until 9 months after nCRT served as a proxy for ypT and ypN (i.e. 'ycT' and 'ycN'). RESULTS: In the 21 included patients [median age 70 (IQR 62-75), 16 males], disease recurrence was found in the primary tumor in 14 (67%) patients (of whom one ypM+, detected on both scans) and in locoregional lymph nodes in six patients (29%). Accuracy (team 1/team 2) to detect yp/ycT+ with 18 F-FDG PET/MRI vs. 18 F-FDG PET/CT was 38/57% vs. 76/61%. For ypN+, accuracy was 63/53% vs. 63/42%, resp. Neither SUL max (both scans) nor ADC mean were discriminatory for yp/ycT+ . Fourteen of 21 (67%) patients were willing to undergo a similar 18 F-FDG PET/MRI examination in the future. CONCLUSION: 18 F-FDG PET/MRI currently performs comparably to 18 F-FDG PET/CT. Improvements in the scanning protocol, increasing reader experience and performing serial scans might contribute to enhancing the accuracy of tumor detection after nCRT using 18 F-FDG PET/MRI. TRIAL REGISTRATION: Netherlands Trial Register NL9352.</p

mRNA expression profiles in circulating tumor cells of metastatic colorectal cancer patients

The molecular characterization of circulating tumor cells (CTCs) is a promising tool for the repeated and non-invasive evaluation of predictive and prognostic factors. Challenges associated with CTC characterization using the only FDA approved method for CTC enumeration, the CellSearch technique, include the presence of an excess of leukocytes in CTC-enriched blood fractions. Here we aimed to identify colorectal tumor-specific gene expression levels in the blood of patients with and without detectable CTCs according to CellSearch criteria. Materials and methods: Blood of 30 healthy donors (HDs) and 142 metastatic colorectal cancer (mCRC) patients was subjected to CellSearch CTC enumeration and isolation. In all samples, 95 mRNAs were measured by reverse transcriptase quantitative PCR (RT-qPCR). HD blood samples and patient samples with three or more CTCs were compared to identify CTC-specific mRNAs. Patient samples without detectable CTCs were separately analyzed. Results: Thirty-four CTC-specific mRNAs were higher expressed in patients with ≥3 CTCs compared with HDs (Mann-Whitney U-test P<0.05). Among patients without detectable CTCs, a HD-unlike subgroup was identified which could be distinguished from HDs by the expression of epithelial genes such as KRT19, KRT20 and AGR2. Also, in an independent patient set, a similar HD-unlike group could be identified among the patients without detectable CTCs according to the CellSearch system. Conclusion: Extensive molecular characterization of colorectal CTCs is feasible and a subgroup of patients without detectable CTCs according to CellSearch criteria bears circulating tumor load, which may have clinical consequences. This CTC-specific gene panel for mCRC patients may enable the exploration of CTC characterization as a novel means to further individualize cancer treatment