BACKGROUND:Carcinomas of the stomach and esophagogastric junction (EGJ) are the fifth leading cause of cancer-related deaths worldwide. In Germany, gastric cancer ranks tenth in incidence across both sexes. The new German national guideline aims to provide the most relevant evidence-based recommendations on diagnosis and treatment of gastric and EGJ adenocarcinomas and has been comprehensively updated by an interdisciplinary panel of experts from national medical societies. SUMMARY:The updated S3 guideline reflects the latest advances in diagnostics, improved palliative therapies, and supportive care. The objectives are to improve the quality of individual and broad care and to ensure consistent, evidence-based treatment strategies. KEY MESSAGES:New recommendations introduce preventive strategies, including management of familial risk due to microsatellite instability (MSI) and H. pylori eradication. The biomarkers HER2, PD-L1, MSI, and Claudin 18.2 enable the use of targeted therapies that improve long-term outcomes in advanced disease. Combinations of chemotherapy with immunotherapy nivolumab, pembrolizumab, or tislelizumab significantly prolong survival compared with chemotherapy alone (e.g., nivolumab 14.4 vs. 11.1 months, HR 0.71; pembrolizumab 13.0 vs. 11.4 months, HR 0.75; tislelizumab 17.2 vs. 12.6 months, HR 0.74) with 5-year survival rates up to 16%. In patients with high Claudin 18.2 expression, zolbetuximab plus chemotherapy improved median survival to 16.4 vs. 13.4 months (HR 0.77). For patients in good general condition, subsequent lines of therapy including biomarker-driven approaches (trastuzumab deruxtecan, pembrolizumab) or third-line therapies (e.g., trifluridine tipiracil) and advanced molecular diagnostics are recommended after treatment failure.

Background: Gastric carcinoma ranks tenth in incidence among all cancers in men and women in Germany. 5565 women and 9027 men received a diagnosis of gastric carcinoma in Germany in 2022. Methods: The German clinical practice guideline was comprehensively revised with the interdisciplinary participation of German specialty societies under the leadership of the German Society for Gastroenterology, Digestive and Metabolic Disorders, according to the methodological specifications of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). Results: The new recommendations promote preventive measures in the presence of risk factors such as hereditary diseases or infection with Helicobacter pylori. Combinations of chemotherapy with immunotherapy, such as nivolumab, pembrolizumab, and tislelizumab, prolong median overall survival compared to chemotherapy alone (e.g., nivolumab plus chemotherapy, 14.4 vs. 11.1 months, HR 0.71) and markedly prolong 5-year survival to 16%. In patients with high claudin18.2 expression, the antibody zolbetuximab, combined with chemotherapy, prolongs median survival to 16.4 vs. 13.4 months (HR 0.77). For patients in good general health, further chemotherapy or biomarker-defined approved second-line (trastuzumab deruxtecan, pembolizumab) or third-line treatment (e.g., trif luridine tipirazole) and advanced molecular-pathological diagnostic testing should be offered at centers for personalized oncology in case of treatment failure. The biomarkers HER2, PD-L1, MSI, and claudin18.2 enable new targeted therapies in palliative situations with long-term improvement in outcome. Conclusion: The diagnostic evaluation of gastric carcinoma should include high-resolution video endoscopy, and its treatment should be stage-adapted and interdisciplinary. Monoclonal antibodies and immune checkpoint inhibitors are increasingly being used for palliative treatment. The new modifications to the clinical practice guideline will promote the use of uniform strategies for perioperative and palliative treatment and supportive measures.

Introduction Immunotherapy recently approved with first-line (1L) chemotherapy for advanced biliary tract cancer (aBTC). Translational research is warranted to identify biomarkers for efficacy. Methods This prospective multicenter non-randomised phase-II study recruited 50 treatment-naïve proven aBTC patients for cisplatin and gemcitabine with pembrolizumab until disease progression or unacceptable toxicity. Primary endpoint was progression-free survival at 6 months (6mPFS, RECIST v.1.1). Secondary endpoints were overall survival (OS), radiological responses and safety. Exploratory translational research was to identify predictive biomarkers. Tumour tissue and blood were collected for MMR, PD-1/PD-L1 in T-cells, monocytes and myeloid derived suppressor cells (MDSCs). Results Fifty patients were 38% male, aged 63 (35–84) years. 6mPFS was 61.2% (80% CI 51.7–69.5) with mPFS 8.3 months (95% CI 5.6–10.6); ORR 40.8% (95% CI 27.0–55.8). Med. OS was 13.4 months (95% CI 8.3–20.5) with 24-months-OS 28.4% (95% CI 16.6–41.4). Higher PD-L1 expression correlated with improved PFS (HR=0.59; 95% CI: 0.26–1.37) and OS (HR=0.68; 95% CI: 0.28–1.64). Responders showed higher CD8/Treg ratio than non-responders (26.2% vs 21.2%) and lower CD4/PD1+ and CD8/PD1+ T-cells (33.5% vs 41.5% and 26.4% vs 44.7%) respectively. During treatment, profiling decreased in CD4/PD1+ and CD8/PD1+ Tcells (36.0% vs 22.2% and 41.6% vs 21.0%) respectively. MDSCs increased in non-responders. Responders, CPS-positive and low-stage patients showed normal Neutrophil-Lymphocyte-Ratios. Conclusion Pembrolizumab plus CisGem showed consistent efficacy to prior phase-III trials. Biomarkers suggest baseline immune landscape influences responses, T-cell exhaustion and immunosuppressive myeloid expansion. Immune phenotyping supports patient selection and further biomarker-driven trials in BTC.

Abstract Purpose The aim of this study was to evaluate the visibility of colorectal liver metastases (CRLM) using photon-counting detector computed tomography (PCD-CT) and to determine the optimal virtual monoenergetic image (VMI) and iodine map reconstructions for improved contrast detection between metastases and surrounding liver parenchyma. Materials and methods A total of 117 patients with 227 CRLM (up to three measurements per patient) who underwent abdominal PCD-CT for staging between 09/2022 and 08/2024 were retrospectively included. VMI were reconstructed at energy levels between 40 and 90 keV (in 10 keV increments), and scanner-generated iodine maps were additionally analysed. To quantify contrast between CRLM and liver parenchyma, the parenchyma-to-lesion ratio (PLR) was calculated for each VMI and iodine map. The contrast-to-noise ratio (CNR) was determined based on attenuation values of the metastases and the bilateral musculus erector spinae, as well as its standard deviation. For the iodine map, lesion and parenchyma iodine concentrations were used analogously. Subjective assessment of metastases visibility on the three best VMIs in PLR and CNR (40–60 keV) and iodine maps were independently performed by three radiologists. Results Lesion and liver attenuation decreased steadily with higher keV levels. Iodine maps showed markedly higher iodine concentration in liver parenchyma than in metastases. The PLR was highest on the iodine map (3.29 ± 2.01), followed by 40 keV (2.19 ± 0.73). Regarding CNR, the 40 keV VMI showed the highest value (1.49 ± 1.70), followed by the iodine map (1.09 ± 0.99). CNR values decreased further at higher energies and significantly reduced at 70–90 keV. Paired superiority testing confirmed 40 keV as the best-performing VMI, showing significantly higher CNR than the iodine map, whereas PLR remained superior on the iodine map. Subjective ratings indicated that the 50 keV VMI provided the best visibility of CRLM. The iodine map consistently received lower subjective ratings across all criteria. Conclusion Both iodine maps and low-keV VMIs, particularly at 40 keV, demonstrated high PLR and CNR values, contributing to improved depiction of CRLM in PCD-CT. The complementary use of these reconstructions may enhance lesion detection and overall diagnostic confidence.

This article presents new relevant aspects of the recently updated German, Swiss, Austrian Onkopedia guideline for the treatment of esophageal cancer. The full guideline can be accessed at https://www.onkopedia-guidelines.info/en/onkopedia/guidelines/esophageal-cancer/@@guideline/html/index.html. All rights for the use of text sections and figures have been obtained. The most important aspects in the perioperative treatment of resectable esophageal adenocarcinoma include the recommendation for the use of perioperative chemotherapy with FLOT as it was shown superior to preoperative chemoradiotherapy analogous CROSS in the ESOPEC trial. Furthermore, there is increasing evidence for the effectivity of targeting therapy and immune checkpoint inhibition in certain molecular defined subgroups. Immune checkpoint inhibition is recommended in combination with perioperative chemotherapy (FLOT) for MSI-H tumors, whereby the treatment should preferably take place in studies. In the metastatic setting, the approval for the PD-1 inhibitor tislelizumab was extended to the first-line treatment of both squamous cell carcinoma and adenocarcinoma of the esophagus (TAP score (≥5%) and for second line for squamous-cell cancer only (independent of PD-L1 expression). Moreover, for gastroesophageal junction (GEJ) tumors, pembrolizumab is available upon PD-L1 expression (CPS ≥1) according to the data of the KEYNOTE-859 trial. In addition to the established biomarkers HER2 und PD-L1, Claudin 18.2 represents now a new targetable option. First-line chemotherapy is to be combined with zolbetuximab in Claudin 18.2 positive GEJ tumors. For biomarker-negative adenocarcinomas of the esophagus and GEJ, a modified triplet regimen (TFOX) is a newly presented treatment option. Because of high toxicity rates and yet unclear survival benefit this option is only recommended for docetaxel-naïve patients with high remission pressure.

365 Background: The relationship between patient-reported outcome (PRO)-based symptom scores, recurrent PRO-based symptomatic deterioration events (RDEs), and terminal events such as progression-free survival (PFS) are rarely examined in the oncology therapeutic domain. Thus, we applied a 3-component joint model (JM) framework aiming to illuminate more clinically interpretable associations between PRO-based treatment effects, RDEs, and PFS among subgroups of patients with programmed death-ligand 1 (PD-L1) expression of ≥1%, ≥5%, and ≥10%. Methods: The final analytic sample included 378 patients in the tislelizumab + chemotherapy arm (T+C) vs 401 in the placebo + chemotherapy arm (P+C) for the PD-L1 ≥1% subgroup, 238 in the T+C arm vs 237 in the P+C for the PD-L1 ≥5% subgroup, and 118 in the T+C arm vs 125 in the P+C arm for the PD-L1 ≥10% subgroup. Symptom domain scores from the EORTC QLQ-C30 and QLQ-STO22 symptom were modeled. Change from baseline (CFBL) in each domain was analyzed every cycle up to cycle 6, then every other cycle thereafter (up to cycle 25). The joint model was applied to all PD-L1 subgroups and comprised three components: 1) linear mixed model (LMM) predicting CFBL symptom scores, 2) Cox proportional hazard (CPH) model for disease progression (PFS as terminal event), and 3) frailty (random effects for RDEs) CPH model for time to PRO-based RDEs. Osoba’s 10-point threshold was used to define RDEs. Results: In the LMM, significant treatment efficacy for the T+C arm compared with the P+C arm was observed for the GHS/QoL ( P =0.0080) and dietary restriction scores ( P =0.0475) in the PD-L1 ≥5% subgroup. In the PD-L1 ≥1% subgroup, compared with the P+C arm, the T+C arm was associated with less worsening in pain/discomfort ( P =0.0376), upper gastrointestinal symptoms ( P =0.0088), and dietary restrictions ( P =0.0352). In the CPH model, the average hazard ratio indicated that compared with the P+C arm, the T+C arm was associated with a reduction in risk of disease progression across all PRO domains and PD-L1 subgroups. Lastly, the PRO-based RDE frailty predictions were strongly associated with PFS risk in the PD-L1 ≥1% and ≥5% subgroups for GHS/QoL, and in the PD-L1 ≥1% subgroup for physical functioning, fatigue, dysphagia-odynophagia, pain/discomfort, and dietary restrictions, as well as for pain/discomfort and dietary restrictions in the PD-L1 ≥5% subgroup. Conclusions: Through the 3-component JM, PRO-based effects were detected and demonstrated strong associations between PRO-based RDEs, and investigator-assessed PFS among varying PD-L1 expression levels. This framework may be a promising alternative for analyzing and interpreting PRO data in the context of PFS.

BACKGROUND:Clinical trials in metastatic colorectal cancer (mCRC) are usually conducted irrespectively of sex. However, differences relating to safety and efficacy in the treatment of mCRC between male and female patients are of growing interest. METHODS:The randomized FIRE-3 study compared first-line treatment with folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) plus cetuximab to FOLFIRI plus bevacizumab in patients with RAS wildtype (RAS WT) mCRC. The present analysis focusses on the impact of sex and primary tumor (PT) sidedness on outcome parameters. RESULTS:Of 352 patients with RAS WT tumors, 249 (71 %) were male and 103 (29 %) female. In male patients with left-sided RAS/BRAF WT tumors, a significant benefit from cetuximab was noted with regard to ORR (OR 1.15; P = 0.035) and OS (0.66; P = 0.010), while in right-sided patients cetuximab improved ORR (OR 2.92) and had no significant effect on PFS or OS. In female patients with left-sided, RAS/BRAF WT PT, a comparable effect of cetuximab versus bevacizumab was observed with regard to ORR (OR 1.05; P > 0.999), while a numerical OS benefit was noted in the cetuximab-arm (HR 0.78; P = 0.385). By contrast, in female patients with right-sided PT, a clearly detrimental effect of cetuximab-based therapy was observed for ORR (OR 0.44; P = 0.617), PFS (HR 4.95; P = 0.005), and OS (HR 2.58; P = 0.080). In the bevacizumab arm, neutropenia grade ≥ 3 was more frequent in female versus male patients (30.6 % versus 18.3 %; P = 0.063). Otherwise, there was no significant difference of grade ≥ 3 adverse events between male and female patients. CONCLUSIONS:The exploratory analysis of FIRE-3 suggests that the efficacy of cetuximab combined with FOLFIRI in RAS wild-type mCRC is related to sex and primary tumor sidedness. The results support the inclusion of patient sex into the design of future trials.

398 Background: At 4-y follow-up, 1L NIVO + chemo continued to demonstrate clinically meaningful overall survival (OS) and progression-free survival (PFS) benefit vs chemo with acceptable safety in patients (pts) with advanced non-HER2+ GC/GEJC/EAC from CheckMate 649. We report efficacy and safety results of NIVO + chemo vs chemo at 5-y follow-up. Methods: Adults with previously untreated, unresectable, advanced or metastatic, non-HER2+ GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. Pts were randomized to NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: Pts were randomized to NIVO + chemo (n = 789) or chemo (n = 792). NIVO + chemo continued to show OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts at 60-month (mo) minimum follow-up (Table). OS rates at 60-mo were higher with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts (Table), and OS benefit with NIVO + chemo continued to be observed in most prespecified subgroups. Objective response rates (ORRs) were higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts (Table). No new safety signals were identified. Conclusions: These results represent the first report of 5-y follow-up for anti–PD-1 + chemo combination therapy in GC/GEJC/EAC to our knowledge. NIVO + chemo continued to provide sustained long-term survival vs chemo with an acceptable safety profile after 5 y of follow-up. These data continue to support the use of NIVO + chemo as a standard 1L treatment for advanced GC/GEJC/EAC. Clinical trial information: NCT02872116 . Efficacy PD-L1 CPS ≥ 5 PD-L1 CPS ≥ 1 All randomized NIVO + chemo(n = 473) Chemo (n = 482) NIVO + chemo (n = 641) Chemo (n = 656) NIVO + chemo (n = 789) Chemo (n = 792) mOS (95% CI), mo 14.4 (13.1–16.2) 11.1 (10.1–12.1) 13.8 (12.4–14.8) 11.4 (10.7–12.3) 13.7 (12.4–14.5) 11.6 (10.9–12.5) HR (95% CI) 0.71 (0.61–0.81) 0.76 (0.67–0.85) 0.79 (0.71–0.88) 60-mo OS rate (95% CI), % 16 (12–19) 6 (4–9) 13 (11–16) 5 (4–7) 12 (10–14) 6 (4–8) mPFS a (95% CI), mo 8.3 (7.0–9.4) 6.1 (5.6–6.9) 7.5 (7.0–8.5) 6.9 (6.2–7.1) 7.8 (7.1–8.6) 6.9 (6.7–7.2) HR (95% CI) 0.71 (0.61–0.82) 0.77 (0.68–0.87) 0.79 (0.71–0.89) ORR a,b (95% CI), % 60 (55–65) 45 (40–50) 60 (55–64) 46 (42–51) 58 (54–62) 46 (42–50) mDOR a,c (95% CI), mo 9.6 (8.3–12.4) 7.0 (5.7–8.0) 8.6 (7.9–10.5) 6.9 (5.8–7.6) 8.5 (7.7–9.9) 6.9 (5.9–7.6) a Per BICR. b In pts with measurable target lesions at baseline. c In all measurable responders. DOR, duration of response; m, median.

INTRODUCTION:The role of systemic chemotherapy for patients with resectable or resected colorectal cancer liver metastases (CRCLM) is debated. MATERIAL AND METHODS:After a systematic search in PubMed and EMBASE databases, we conducted a meta-analysis of individual patient data from randomised phase III trials comparing surgery plus systemic chemotherapy with surgery alone in patients with CRCLM. Analyses were performed in the overall intention-to-treat (ITT) population, in patients who had curative-intent surgery (resected population), and in those who received post-operative chemotherapy only. The primary endpoint was progression-free survival (PFS). RESULTS:821 patients (411 surgery alone, 410 surgery plus systemic chemotherapy) from four trials (EORTC 40983/EPOC, FFCD-ACHBTH-AURC 9002, ENG, and UMIN C000000013) were included. Systemic chemotherapy improved PFS in the overall ITT (HR 0.79; 95 %CI: 0.67-0.93, p = 0.004), in the resected (HR 0.77; 95 %CI: 0.65-0.91, p = 0.003) and in the post-operative chemotherapy only (HR 0.76; 95 %CI: 0.61-0.95, p = 0.016) populations. Systemic chemotherapy also improved overall survival (OS) in the overall ITT (HR 0.82; 95 %CI: 0.68-1.0, p = 0.048) and in the resected (HR 0.81; 95 %CI: 0.66-1.00, p = 0.046) populations. After adjusting for prognostic factors in multivariable analyses, the effect of systemic chemotherapy remained significant for PFS in the overall ITT (p < 0.001) and in the post-operative chemotherapy only (p = 0.003) populations. An interaction between systemic chemotherapy and time to diagnosis of liver metastases for PFS was found in the overall ITT (p = 0.027) and in the resected (p = 0.024) populations. CONCLUSIONS:Systemic chemotherapy improves PFS of patients with resectable or resected CRCLM. This effect is stronger for patients with synchronous metastases.

Tumor Area Positivity (TAP) score is an emerging score measuring programmed death-ligand 1 (PD-L1) expression in tumors. However, the availability of concordance data between TAP score and other immunohistochemistry scoring methods is limited. We investigated concordance between TAP score and combined positive score (CPS) and the relationship between PD-L1 status and clinical outcomes using gastric/gastroesophageal junction adenocarcinoma (GC/GEJC) and esophageal squamous cell carcinoma (ESCC) samples from patients subsequently treated with tislelizumab. Baseline tissue samples from RATIONALE-305 (GC/GEJC; NCT03777657), RATIONALE-302 (ESCC; NCT03430843), and RATIONALE-306 (ESCC; NCT03783442) were assessed for PD-L1 expression using an investigational use-only version of the VENTANA PD-L1 (SP263) CDx Assay. PD-L1 status was scored by TAP score and CPS. Concordance and correlation of both scores with clinical and safety outcomes were analyzed. Across all trials, agreement between TAP score and CPS was significant at PD-L1 cutoffs of ≥1%/≥1, ≥5%/≥5, and ≥10%/≥10 (Cohen's κ, 0.64-0.85). Similar outcomes for overall survival (OS), progression-free survival, objective response rate, and duration of response were observed between TAP score- and CPS-defined PD-L1-positive subgroups at analogous PD-L1 cutoffs. OS hazard ratios in the PD-L1-high subgroups were similar between protocol-defined TAP score and the same numeric CPS value (OS hazard ratio [95% CI]: RATIONALE-305, 0.72 [0.59-0.88] and 0.73 [0.60-0.89]; RATIONALE-302, 0.52 [0.35-0.76] and 0.54 [0.37-0.78]; and RATIONALE-306, 0.63 [0.45-0.89] and 0.58 [0.42-0.81], respectively). Safety outcomes were generally comparable between all PD-L1 subgroups. In conclusion, TAP score and CPS are clinically comparable immunohistochemistry measures of tumor PD-L1 expression in tislelizumab-treated patients with GC/GEJC or ESCC.

BACKGROUND:The appropriate distance to the resection margin in gastric cancer surgery remains debated and is often based on limited or outdated evidence. With evolving perioperative strategies, this study aimed to assess current resection margin practices across European centers. METHOD:A web-based survey consisting of 45 questions was developed by a panel of 13 international experts including surgeons, pathologists, and oncologists. It covered center demographics, resection margin strategies, and postoperative care. Distributed from January to June 2022, the survey targeted Upper Gastrointestinal (UGI) surgeons via mailing lists and social media platforms of various UGI and visceral surgical societies. RESULTS:Responses were received from 172 surgeons at 154 centers across 19 countries. Of these respondents, 54% were from university hospitals, 39% from general hospitals, and 8% from private hospitals. Surgeons had on average 20.8 (SD ± 9.4) years of surgical experience and managed an average of 23.2 (SD ± 21.8) cases per year. For intestinal-type tumors, 77% of surgeons reported using a proximal margin of at least 5 cm, with 64% selecting exactly 5 cm. For diffuse type gastric cancer, 63% of surgeons recommended a minimum of 8 cm. There was no difference with respect to the recommended distance to the resection margin between low, medium and high-volume surgeons or between university, general and private hospitals. Routine macroscopic inspection of the specimen was performed by 64% of respondents. CONCLUSION:This survey reveals a heterogeneity in applying the current guidelines for resection margin lengths across European centers. Further prospective studies are essential to evaluate the feasibility and oncological safety of future organ-sparing strategies.

Background: Primary tumor sidedness (PTS) with discrimination of left-sided (LC) and right-sided tumors (RC) guides patient selection for targeted first-line therapy in RAS wild-type (RAS-WT) metastatic colorectal cancer (mCRC). This study assessed the hypothesis whether considering PTS with additional clinical parameters better predicts the treatment benefit of targeted first-line treatment. Methods: In FIRE-3, first-line treatment with folinic acid, fluorouracil and irinotecan (FOLFIRI) plus cetuximab (FOLFIRI/Cet) was compared to FOLFIRI plus bevacizumab (FOLFIRI/Bev) in patients with RAS-WT mCRC and unresectable metastasis. We evaluated whether combining PTS with number of metastatic sites (NOM), liver-limited disease status (LLD), age, sex, or carcinoembryonic antigen level (CEA) better predicts treatment benefit regarding overall survival (OS). Here, Cox regression models with second-order interactions were applied. Further, the results were validated by policy learning and Lasso regression analysis. Findings: Among 400 RAS-WT mCRC patients, combining PTS with LLD status in a Cox regression model outperformed PTS alone for predicted treatment benefit (P = 0.005; c-index=0.603). Significant OS benefit from FOLFIRI/Cet over FOLFIRI/Bev was observed in LC/non-LLD patients (HR=0.62; 95 %-confidence interval [CI]= 0.46-0.82; P = 0.002), but mitigated in LC/LLD patients (HR=0.83; 95 %-CI=0.53-1.29; P = 0.400). In RC/nonLLD patients, FOLFIRI/Bev demonstrated a significant OS advantage over FOLFIRI/Cet (HR=2.09; 95 %-CI=1.20-3.63; P = 0.010). However, RC/LLD patients showed potential benefit from FOLFIRI/Cet, though not statistically significant (HR=0.59; 95 %-CI=0.25-1.39; P = 0.218). Interpretation: Incorporating PTS and LLD status might improve selection of targeted first-line treatment in RAS-WT mCRC patients. FOLFIRI/Cet appears to be particularly beneficial for LC/non-LLD patients with mitigated benefit in patients with LC/LLD. In contrast, FOLFIRI/Bev is significantly favoured over FOLFIRI/Cet in patients with RC/non-LLD. Notably, RC/LLD patients may still benefit from anti-EGFR therapy despite right-sided primary tumor. These results are hypothesis-generating and warrant further validation.

This article presents new relevant aspects of the recently updated German, Swiss, Austrian Onkopedia guideline for the treatment of esophageal cancer. The full guideline can be accessed at https://www.onkopedia-guidelines.info/en/onkopedia/guidelines/esophageal-cancer/@@guideline/html/index.html. All rights for the use of text sections and Figures have been obtained. The most important aspects in the perioperative treatment of resectable esophageal adenocarcinoma include the recommendation for the use of perioperative chemotherapy with FLOT as it was shown superior to preoperative chemoradiotherapy analogous CROSS in the ESOPEC trial. Furthermore, there is increasing evidence for the effectivity of targeting therapy and immune checkpoint inhibition in certain molecular defined subgroups. Immune checkpoint inhibition is recommended in combination with perioperative chemotherapy (FLOT) for MSI-H tumors, whereby the treatment should preferably take place in studies. In the metastatic setting, the approval for the PD-1 inhibitor tislelizumab was extended to the first-line treatment of both, squamous cell- and adenocarcinoma of the esophagus (TAP score (≥ 5%) and for second line for squamous-cell cancer only (independent of PD-L1 expression). Moreover, for gastroesophageal junction (GEJ) tumors, pembrolizumab is available upon PD-L1 expression (CPS ≥ 1) according to the data of the KEYNOTE-859 trial. In addition to the established biomarkers HER2 und PD-L1, Claudin 18.2 represents now a new targetable option. First-line chemotherapy is to be combined with zolbetuximab in Claudin 18.2 positive GEJ tumors. For biomarker-negative adenocarcinomas of the esophagus and esophago-gastric junction (GEJ), a modified triplet regimen (TFOX) is a newly presented treatment option. Because of high toxicity rates and yet unclear survival benefit this option is only recommended for docetaxel-naïve patients with high remission pressure.

Multimodal care, including nutritional support, physical exercise, and pain management, is essential to address complex therapeutic challenges in advanced pancreatic cancer. There is an increasing prevalence worldwide in pancreatic cancer and the disease is often diagnosed late leading to limited treatment options and poor prognosis. Advanced pancreatic cancer patients experience a wide range of adverse symptoms that affect their quality of life and require comprehensive and interdisciplinary patient care early in treatment. Integrating digital health, particularly through remote monitoring, plays a vital role in addressing the therapeutic challenges and improving data-driven clinical decision-making. Therefore, the European project RELEVIUM examines the effect of a personalized, digitally assisted multimodal supportive care intervention on health-related quality of life in patients with pancreatic cancer aiming to improve early access to multidisciplinary, cost-effective palliative care. In cancer centers in Estonia, Israel, and Germany, 132 patients will be randomly assigned in the prospective randomized controlled trial RELEVIUM-RCT into two groups. Both groups receive standard chemotherapy. The control group follows usual care, while the intervention group receives personalized, digitally assisted multimodal support integrated into usual care. The intervention includes guidance and monitoring on pain, nutrition, fatigue, sarcopenia, and physical activity. Patients track their physical activities, nutritional behavior and rate pain and fatigue daily via a smartwatch and mobile app. The physician analyses these longitudinal data on a dashboard and counsels the patients every two weeks during clinical visits, assisted by an interdisciplinary team and digital support system. The primary endpoint of the study is health-related quality of life including factors such as time until a definitive deterioration in selected dimensions (physical functioning and/or appetite loss) assessed at 8 weeks. Secondary endpoints include longitudinal analyses of efficacy related to pain, physical function, nutrition, sarcopenia, and socioeconomic factors. The RELEVIUM-RCT investigates the efficacy of digital health support for individuals with advanced pancreatic cancer in conjunction with conventional treatments in three European countries. Longitudinal data on the interplay of chemotherapy toxicity, fatigue, pain, physical activity, and nutrition will provide valuable extended insights on multimodal pancreatic cancer care. Moreover, this data can help demonstrate the benefits of digital health in clinical decision-making, ultimately contributing to improved quality of care in Europe. Registry: German Clinical Trials Register; Registration number: DRKS00037143; Date of registration: 5th of June 2025.