ESMO Gastrointestinal Oncology最新文献

Background

Despite aggressive multimodal treatment for locally advanced esophagogastric cancer (LA-EGC), many patients experience early disease progression/death. We aimed to explore the role of Geriatric Assessment (GA) in optimizing patient care in older patients with LA-EGC.

Materials and methods

A retrospective cohort study was conducted in patients aged ≥60 years with LA-EGC referred to the geriatric oncology clinic at our institute between June 2018 and November 2022, who were planned for curative treatment. We explored the role of GA-guided therapy modifications on survival, identification of factors predicting potential ‘overtreatment’ (arbitrarily defined as patients in whom disease recurrence or death occurred within 6 months of treatment completion), and utility of the GA in identification of this patient subset.

Results

We enrolled 199 patients. The median age was 68 years (interquartile range 64-73 years). There were 131 (65.8%) males and 157 patients (78.9%) had a performance status of 0-1. Based on the GA, 110 (55.3%) patients were deemed fit (≤2 domains affected). Therapy modification (primarily de-intensification) occurred in 72 (36.2%) patients. At a median follow-up of 34.1 months [95% confidence interval (CI) 31.5-36.7 months], median event-free survival with de-intensified treatment was 12.2 months (95% CI 9.1-15.3 months) versus 18.8 months (95% CI 14.7-22.9 months) with standard treatment; P = 0.113. Median overall survival was 15.4 months (95% CI 9.3-21.5 months) with de-intensified treatment versus 21.1 months (95% CI 16.1-26.1 months) with standard treatment, P = 0.116. Six months following treatment completion, 79 (39.7%) patients were potentially overtreated. Initial GA failed to identify patients who were potentially overtreated (P = 0.923).

Conclusion

GA-tailored treatment de-escalation does not impair survival in older patients with LA-EGC but fails to identify the patient cohort at risk for overtreatment.

Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) is the established therapy for refractory metastatic colorectal cancer, but there are concerns regarding the regimen’s complexity and hematotoxic effects, especially for patients with organ dysfunction, comorbidities, or a reduced performance status—groups often excluded from conventional clinical trials. Preliminary studies demonstrated that bi-weekly FTD/TPI + BEV may mitigate these hematotoxic effects compared with the conventional schedule without compromising efficacy. No clinical trials, however, have directly compared these two regimens. Therefore, we initiated the PRABITAS trial, a multicenter, randomized, phase III non-inferiority trial, to evaluate the efficacy and safety of bi-weekly FTD/TPI + BEV compared with conventional FTD/TPI + BEV. This was designed as a pragmatic trial, a novel approach in clinical trials aiming to aid decision-making in daily practice by mimicking real-world clinical settings. The PRABITAS trial incorporates minimal eligibility criteria to include a more representative patient population, allows flexibility in intervention adherence and assessment, and employs streamlined data collection to reduce the burden on both patients and healthcare providers. The primary endpoint is overall survival in the intention-to-treat population. Launched in December 2023, the trial aimed to enroll a total of 890 patients.

Biliary tract cancer (BTC) is a rare but highly lethal malignancy. Despite recent advances in diagnosis and treatment, the overall prognosis remains dismal, with a median survival of <1 year in most cases. This highlights an urgent medical need for better treatment options, especially in the area of systematic treatments.

This review aims to give a concise overview of the current available treatment options for BTC, including a short summary of longstanding therapeutic approaches such as surgery, interventional techniques, radiotherapy, chemotherapy, and chemoradiotherapy. Special emphasis is placed on genetic alterations and treatment advances with immunotherapy in combination with chemotherapy, however, including current trials on new immunotherapeutic drugs. Furthermore, the recent recommendation by international guidelines to use durvalumab plus the combination of gemcitabine and cisplatin as a first-line treatment in the advanced setting is highlighted and the evidence supporting this recommendation is explored. Moreover, this review looks at genetic alterations which can be used as targets for immunotherapy, especially isocitrate dehydrogenase 1/2 (IDH1/2), fibroblast growth factor receptor 2 (FGFR2), and human epidermal growth factor receptor 2 (HER2/neu). Upcoming biomarkers such as microRNAs (miRNAs and especially miR-221) can possibly facilitate the choice of the appropriate treatment regimen in the future.

We conclude that there is a lot of recent development in the area of biomarker-driven targeted therapies and immunotherapies for BTC, which could consequently bring major benefits to patients’ treatment outcomes and quality of life.

Background

Hepatic chemosaturation by isolated percutaneous liver perfusion (CS-PHP) with melphalan controls hepatic tumor growth. However, optimal treatment frequency and the prognostic relevance of extrahepatic tumor manifestation remain unclear. We analyzed response and tolerability of repeated treatment in regular cycles of CS-PHP.

Materials and methods

CS-PHP was administered to patients with primary or secondary liver tumors. Overall survival (OS) and hepatic disease control rate (hDCR) were assessed retrospectively by modified RECIST after at least one response assessment, and toxicity by Common Terminology Criteria for Adverse Events v4.03.

Results

A total of 97 CS-PHP treatments were carried out in 33 patients between 2016 and 2023. Patients had unresectable intrahepatic metastases of uveal melanoma (n = 19), intrahepatic cholangiocarcinoma (n = 8), hepatocellular carcinoma (n = 2), ciliary body melanoma (n = 1), acinar cell carcinoma (n = 1), pancreatic cancer (n = 1) or tonsil cancer (n = 1). CS-PHP was carried out seven times in 1 patient, six times in 5, five times in 3, four times in 2, three times in 4, twice in 7 and once in 11 patients. The median OS was 65 weeks (standard error 13.6, 95% confidence interval 38.2-91.5 weeks). hDCR was 91% (30 of 33 patients) at last observation time point. Extrahepatic tumor manifestations were not associated with OS. CS-PHP was well tolerated. Grade III or IV pancytopenia occurred in two patients.

Conclusion

CS-PHP induced hepatic disease control in the majority of patients. Extrahepatic tumor manifestation had no significant impact on OS. The relevance of CS-PHP as long-term treatment needs to be validated in future studies.

Background

Programmed death-ligand 1 (PD-L1) expression serves as a predictive biomarker for response to immune checkpoint inhibitors (ICIs) in metastatic gastroesophageal adenocarcinoma (mGEA). The peritoneum is one of the most common metastatic sites and is associated with a poor prognosis and apparently lower clinical efficacy of ICIs.

Patients and methods

We investigated the heterogeneity of PD-L1 expression in mGEA by examining its concordance between primary tumors and matched peritoneal metastases (PMs), and before and after systemic treatment. PD-L1 expression was assessed using combined positive score (CPS) by immunohistochemistry with VENTANA PD-L1 (SP263) assays on formalin-fixed paraffin-embedded tumor tissues. Results were reported using CPS cut-offs of 1 and 5.

Results

Twenty-two primary tumor and matched PM specimens from patients with mGEA were analyzed. The concordance of PD-L1 CPS was 54.5% with a CPS cut-off of 1 and 72.7% with a CPS cut-off of 5, highlighting spatial heterogeneity. Notably, none of the PD-L1-positive primary tumor samples tested positive in the matched PM specimens using the CPS ≥5 cut-off. Potential temporal heterogeneity of PD-L1 expression related to chemo(immuno)therapy administration was also observed, with a 55.6% concordance rate using the CPS ≥5 cut-off.

Conclusions

PD-L1 expression in PMs from mGEA is characterized by both spatial and potentially temporal heterogeneity, with the variability being more pronounced at lower CPS cut-off values. This variability complicates its role as a predictive biomarker for ICI outcomes. The high intrapatient discordance rate in PD-L1 CPS expression between positive primary tumor samples and matched PM specimens suggests that peritoneal specimens should not be used as the only source for PD-L1 assessment if representative tissue from other disease sites is available.

Introduction

Triplet chemotherapy + bevacizumab (TripletBev) demonstrated an overall survival (OS) benefit for patients with newly diagnosed metastatic colorectal cancer in randomized trials. We aimed to evaluate the uptake and estimate the effectiveness of TripletBev versus doublet chemotherapy + bevacizumab (DoubletBev) in a real-world population in the United States.

Methods

We carried out a retrospective cohort study of patients initiating first-line treatment of metastatic colorectal cancer between 23 October 2014 and 31 October 2022 using the Flatiron Health nationwide electronic health record (EHR)-derived de-identified database. The data originated from ∼280 cancer clinics (∼800 sites of care) in the USA. The primary analysis compared OS between patients receiving TripletBev or DoubletBev using a Cox proportional hazards model with adjustment for pre-specified covariates using stabilized inverse probability of treatment weighting. This analysis was also carried out within pre-specified and post hoc subgroups. A secondary analysis used Stürmer-trimming of the propensity score distribution to include patients most likely to be eligible to receive either treatment.

Results

Some 391 patients received TripletBev and 9625 received DoubletBev. There was no association between TripletBev and OS in the primary analysis [hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.75-1.13]. TripletBev was associated with lower hazard of death in patients with synchronous metastases (HR 0.79; 95% CI 0.64-0.98; statistically significant) and in the secondary analysis of patients most likely to be eligible to receive either treatment (HR 0.80; 95% CI 0.63-1.02; non-statistically significant).

Conclusion

Uptake of TripletBev remains low and the primary analysis did not demonstrate effectiveness in a real-world population in the United States. Patients with synchronous metastases and those most likely to be eligible to receive either treatment may be most likely to benefit from TripletBev.

Advanced biliary tract cancers (BTCs) have gained notoriety among gastrointestinal tumours for their comparatively high incidence of actionable alterations and their compelling benefit from targeted therapies matched to these alterations. Such successes are exemplified by BTC-specific approvals of fibroblast growth factor receptor (FGFR) inhibitors for tumours with FGFR2 rearrangements, as well as mutant isocitrate dehydrogenase 1 inhibitors. Nevertheless, there is a clear absence of therapeutic benefit in a subset of patients despite their tumours fulfilling the current molecular criteria for treatment with these drugs. This results in inefficient management of patients with otherwise bleak prognosis, as well as considerable financial burden. Even among responders, the duration of response is limited, a clinical observation that could be considered unusual as these inhibitors typically target driver genes hypothesised to be responsible for tumour formation. However, BTCs exhibit oncogenic addiction to signalling networks rather than individual genes, and by extension, therapeutic response is dependent on these signalling networks rather than simply the status of the specific target gene. Primary resistance is mediated by co-occurring genetic (DNA) and non-genetic (transcriptional, translational, post-translational) alterations in members of signalling networks that are upstream, downstream, or in parallel pathways to the target alteration. Refining the molecular criteria to select patients is a necessary next step, by incorporating co-occurrence of resistance biomarkers as individual parameters or into predictors of treatment benefit. Characterising the molecular bases of resistance to targeted therapies will fuel next-generation combination treatments, maximising the catchment of responders and enhancing the duration of response.

Background

Precision oncology is gaining momentum in managing patients with gastrointestinal cancers. This study examines the implementation of personalized medicine technologies in upper gastrointestinal (UGI) oncology across European academic centers.

Material and methods

Forty-five oncology specialists from 41 European institutions completed a survey designed by the Personalized Medicine Task Force of the European Organization of Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Working Group, providing insights into molecular testing, timing, availability of targeted therapies, funding sources, and utilization of molecular tumor boards (MTBs) for patients with UGI cancers. Frequencies and percentages were calculated.

Results

Routine testing for human epidermal growth factor receptor 2 (HER2, 100%), programmed death-ligand 1 (PD-L1, 89%), and DNA mismatch repair (MMR, 91%) is implemented in most centers. Comprehensive gene panels on tumor tissue are frequently utilized, especially in biliary tract cancer, with almost all centers incorporating them into routine practice. Blood-based sequencing is increasingly employed, and half of centers carry out comprehensive gene panels for circulating tumor DNA analyses. MTBs are regularly held in 76% of centers, predominantly utilizing ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)-based recommendations for tissue molecular alterations. The translation of genomic information into prescribed treatments remains limited, however, with the majority of centers reporting ∼25% of molecularly stratified treatment decisions following comprehensive genetic testing.

Conclusion

This survey provides important insights into current personalized medicine practice in European academic clinical centers for UGI oncology. Despite widespread adoption of molecular testing and implementation of MTBs, further efforts are needed to optimize the integration of personalized medicine into clinical practice.

Background

Evaluating multiple biomarkers including human epidermal growth factor receptor 2 (HER2), mismatch repair (MMR) status, programed death-ligand 1 (PD-L1), and claudin 18.2 (CLDN18.2) is essential for selecting appropriate first-line therapy of metastatic gastroesophageal adenocarcinoma (mGEA). However, this can be challenging if tumor tissue amount is limited and may cause delays in the initiation of chemotherapy. Therefore, we assessed the feasibility of multiple biomarkers testing in routine clinical practice.

Materials and methods

We reviewed the medical records of treatment-naïve patients with mGEA who underwent prospective multiple biomarkers testing between April 2022 and October 2023 in our institution. Eight biomarker status including HER2, MMR, PD-L1, CLDN18.2, Epstein–Barr virus, fibroblast growth factor receptor 2, epidermal growth factor receptor and mesenchymal epithelial transition expressions were simultaneously examined using biopsy or surgical specimens.

Results

A total of 203 patients with mGEA were analyzed. Most patients underwent gastroendoscopy and tumor biopsy shortly after referral to our institution. Biomarkers testing was successfully completed on the first attempt in 198 patients (97.5%). With additional steps including additional biopsy or asking remaining tumor samples from the referring hospital, the biomarker results were eventually available in all cases. The median turnaround time from sample collection to reporting results was 7 days. Consequently, 178 patients (87.7%) could receive first-line treatment after obtaining the biomarker status.

Conclusions

Multiple biomarkers testing for patients with mGEA was feasible in clinical practice. Establishment of a testing infrastructure based on the collaboration with multiple departments is essential for implementing biomarker-driven precision treatment.

Background

Immune checkpoint inhibitors (ICIs) have become the standard of care in several solid tumours. Thus the action of ICIs may lead to the development of inflammatory damage in nontumoral tissues, defined as immune-related adverse events (irAEs). Scanty data describe upper gastrointestinal tract toxicity.

Patients and methods

We conducted a monocentric retrospective study, enrolling patients with advanced cancer, who developed histology-proven immune-related oesophago-gastro-duodenitis, treated with at least one cycle of ICI between January 2016 and November 2022.

Results

We identified six patients with upper gastrointestinal irAEs: four affected by metastatic melanoma (three treated with nivolumab and one with nivolumab plus ipilimumab), one by unresectable cutaneous squamous cell carcinoma (treated with cemiplimab), and one by metastatic non-small-cell lung cancer (treated with pembrolizumab). Proton pump inhibitors and oral corticosteroids have been the mainstay of the management, and thus one patient had to receive intravenous methylprednisolone with hospitalisation, fasting, and parenteral nutrition. Based on the literature and our experience, we proposed a classification of ICI-induced upper gastrointestinal toxicity, with symptom and endoscopic sign grading. Each step of severity has been also correlated with a proposed diagnosis and clinical management.

Conclusions

During ICI treatment, upper gastrointestinal symptoms can be a red flag for developing severe oesophago-gastro-duodenal toxicity that can impact patients’ quality of life and therapeutic plan. We recommend carefully investigating these symptoms, choosing a multidisciplinary approach to decide if an oesophagogastroduodenoscopy with random biopsy is indicated. [18]-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography might represent a promising complementary diagnostic tool. Steroids still represent the cornerstone of treatment, as for other irAEs.