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

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

Perioperative Chemotherapy for Gastro-Esophageal or Gastric Cancer:Anthracyclin Triplets versus FLOT

Background: The FLOT4-AIO trial (2019) showed improved survival with perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) compared to anthracyclin triplets in gastric cancer treatment. It is unclear whether these results extend to real-world scenarios in the Netherlands. This study aimed to compare outcomes of perioperative FLOT to anthracyclin triplets in a real-world Dutch gastric cancer population. Methods:Patients diagnosed with resectable (cT2-4a/cTxN0-3/NxM0) gastric or gastro-esophageal junction carcinoma between 2015–2021 who received neoadjuvant FLOT or anthracyclin triplets were selected from the Netherlands Cancer Registry. The primary outcome was overall survival (OS), analyzed through multivariable Cox regression. Secondary outcomes included pathological complete response (pCR), neoadjuvant chemotherapy cycle completion, surgical resection rates, and adjuvant therapy. Results: Adjusted OS showed no significant survival benefit (HR = 0.88, 95% CI 0.77–1.01, p = 0.07), even though the median OS was numerically improved by 8 months with FLOT compared to anthracyclin triplets (48.1 vs. 39.9 months, p = 0.16). FLOT patients were more likely to undergo diagnostic staging laparoscopies (74.2% vs. 44.1%, p &lt; 0.001), had higher rates of completing neoadjuvant chemotherapy (OR = 1.35, 95% CI 1.09–1.68, p = 0.007), receiving adjuvant therapy (OR = 1.34, 95% CI 1.08–1.66, p = 0.08), and achieving pCR (OR = 1.52, 95% CI 1.05–2.20, p = 0.03). No significant differences were observed in (radical) resection rates. Conclusion(s): Real-world data showed no significant OS improvement for FLOT-treated patients compared to anthracyclin triplets, despite more staging laparoscopies. However, FLOT patients demonstrated higher rates of neoadjuvant therapy completion, proceeding to adjuvant therapy, and increased pCR rates. Therefore, we recommend the continued use of neoadjuvant FLOT therapy in the current clinical setting.</p

Induction chemotherapy followed by response evaluation and esophagectomy for advanced esophageal cancer

Introduction: Patients with limited metastatic/advanced esophageal cancer not amenable for neoadjuvant therapy plus surgery have a poor prognosis and often receive palliative care. Alternatively, induction chemotherapy with response evaluation can be considered and in some patients surgery with curative intent may become feasible. The aim of this study was to evaluate the outcomes of patients treated with induction chemotherapy and to identify patient and/or tumor characteristics associated with survival. Material and methods: Patients with esophageal or junctional cancer who underwent induction chemotherapy between 2005 and 2021 were identified from an institutional database of a tertiary referral center. Response to therapy was assessed by (18F-FDG PET)/CT. Response to therapy and treatment options, including surgery or palliation, were discussed in the multidisciplinary tumor board. Overall survival (OS) was calculated using the Kaplan Meier method. Uni- and multivariable analyses were performed to identify prognostic factors for survival. Results: 238 patients were identified. The majority had esophageal adenocarcinoma (68.9 %) and were treated with a taxane/platinum-based chemotherapy (79.4 %). Response evaluation was performed in 233 patients and 154 of 238 patients (64.7 %) underwent surgical exploration. Resection was performed in 127 patients (53.4 %) resulting in a median and 5-year OS of 26.3 months (95 % CI 18.8–33.8) and 29.6 %, respectively. Presence of T4b (HR = 2.01, 95 % CI 1.02–3.92) and poorly differentiated tumor (HR = 1.45, 95 % CI 1.02–2.10) was associated with worse survival (p = 0.04). Conclusion: In carefully selected patients with advanced disease not amenable for standard curative treatment, induction chemotherapy followed by esophagectomy may result in a 5-year overall survival of approximately 30 %.</p