Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score.

BACKGROUND & AIMS: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need. METHODS: Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204). RESULTS: Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response. CONCLUSIONS: The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation. LAY SUMMARY: The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.

The targeted therapy revolution in neuroendocrine tumors: in search of biomarkers for patient selection and response evaluation.

The molecular events of tumorigenesis in neuroendocrine tumors are poorly understood. Understanding of the molecular alterations will lead to the identification of molecular markers, providing new targets for therapeutics. The purpose of this review was to critically analyze the genetic abnormalities in neuroendocrine tumors, with the aim of identifying biomarkers that indicate a response to agents developed against these targets and to serve as an understanding for the combinations of different active compounds. Human epidermal growth factor receptor 1/2 (EGFR and HER2), vascular endothelial growth factor receptors, hepatocyte growth factor receptor (c-Met), platelet-derived growth factor receptor, insulin-like growth factor, phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway, and heat shock proteins are all interesting candidate biomarkers with involvement in carcinogenesis and tumor evolution of several neoplasms, including neuroendocrine tumors. Some of them have already been evaluated both as targets and also as biomarkers in clinical trials conducted in advanced neuroendocrine tumor settings, and others should encourage further investigations into innovative therapeutic opportunities.

Preoperative chemotherapy in upfront resectable colorectal liver metastases: New elements for an old dilemma?

The use of preoperative or "neoadjuvant" chemotherapy (NAC) has long been controversial for resectable colorectal liver metastases (CRLM). The European Society of Medical Oncology (ESMO) 2023 guidelines on metastatic colorectal cancer (CRC) indicate a combination of surgical/technical and oncologic/prognostic criteria as the two determinants for allocating patients to NAC or upfront hepatectomy. However, surgical and technical criteria have evolved, and oncologic prognostic criteria date from the pre-modern chemotherapy era and lack prospective validation. The traditional literature is interpreted as not supporting the use of NAC because several studies fail to demonstrate a benefit in overall survival (OS) compared to upfront surgery; however, OS may not be the most appropriate endpoint to consider. Moreover, the commonly quoted studies against NAC contain many limitations that may explain why NAC failed to demonstrate its value. The query of the recent literature focused primarily on other aspects than OS, such as surgical technique, the impact of side effects of chemotherapy, the histological growth pattern of metastases, or the detection of circulating tumor DNA, shows data that support a more widespread use of NAC. These should prompt a critical reappraisal of the use of NAC, leading to a more precise selection of patients who could benefit from it.

Is Computed-Tomography-Based Body Composition a Reliable Predictor of Chemotherapy-Related Toxicity in Pancreatic Cancer Patients?

BACKGROUND: Malnutrition, loss of weight and of skeletal muscle mass are frequent in pancreatic cancer patients, a majority of which will undergo chemotherapy over the course of their disease. Available data suggest a negative prognostic role of these changes in body composition on disease outcomes; however, it is unclear whether tolerance to chemotherapeutic treatment is similarly and/or negatively affected. We aimed to explore this association by retrospectively assessing changes in body composition and chemotherapy-related toxicity in a cohort of advanced pancreatic cancer patients. METHODS: Body composition was evaluated through clinical parameters and through radiological assessment of muscle mass, skeletal muscle area, skeletal muscle index and skeletal muscle density; and an assessment of fat distribution by subcutaneous adipose tissue and visceral adipose tissue. We performed descriptive statistics, pre/post chemotherapy comparisons and uni- and multivariate analyses to assess the relation between changes in body composition and toxicity. RESULTS: Toxicity risk increased with an increase of skeletal muscle index (OR: 1.03) and body mass index (OR: 1.07), whereas it decreased with an increase in skeletal muscle density (OR: 0.96). Multivariate analyses confirmed a reduction in the risk of toxicity only with an increase in skeletal muscle density (OR: 0.96). CONCLUSIONS: This study suggests that the retrospective analysis of changes in body composition is unlikely to be useful to predict toxicity to gemcitabine-nab-paclitaxel.

Neo-Adjuvant Treatment in Primary Resectable Pancreatic Cancer: A Systematic Review and PRISMA-Compliant Updated Metanalysis of Oncological Outcomes.

BACKGROUND: Despite advances in treatment, the prognosis of resectable pancreatic adenocarcinoma remains poor. Neoadjuvant therapy (NAT) has gained great interest in hopes of improving survival. However, the results of available studies based on different treatment approaches, such as chemotherapy and chemoradiotherapy, showed contrasting results. The aim of this systematic review and meta-analysis is to clarify the benefit of NAT compared to upfront surgery (US) in primarily resectable pancreatic adenocarcinoma. METHODS: A PRISMA literature review identified 139 studies, of which 15 were finally included in the systematic review and meta-analysis. All data from eligible articles was summarized in a systematic summary and then used for the meta-analysis. Specifically, we used HR for OS and DFS and risk estimates (odds ratios) for the R0 resection rate and the N+ rate. The risk of bias was correctly assessed according to the nature of the studies included. RESULTS: From the pooled HRs, OS for NAT patients was better, with an HR for death of 0.80 (95% CI: 0.72-0.90) at a significance level of less than 1%. In the sub-group analysis, no difference was found between patients treated with chemoradiotherapy or chemotherapy exclusively. The meta-analysis of seven studies that reported DFS for NAT resulted in a pooled HR for progression of 0.66 (95% CI: 0.56-0.79) with a significance level of less than 1%. A significantly lower risk of positive lymph nodes (OR: 0.45; 95% CI: 0.32-0.63) and an improved R0 resection rate (OR: 1.70; 95% CI: 1.23-2.36) were also found in patients treated with NAT, despite high heterogeneity. CONCLUSIONS: NAT is associated with improved survival for patients with resectable pancreatic adenocarcinoma; however, the optimal treatment strategy has yet to be defined, and further studies are required.

Proteomics of immune cells from liver tumors reveals immunotherapy targets.

Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer tissue as well as monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their anti-tumor activity synergistically with PD-L1 blockade in mouse models. Our data reveal new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer.

The Screening and COnsensus Based on Practices and Evidence (SCOPE) Program Results of a Survey on Daily Practice Patterns for Patients with Metastatic Colorectal Cancer-A Swiss Perspective in the Context of an International Viewpoint.

In Switzerland, physicians do not have national guidelines for metastatic colorectal cancer (mCRC) patient care and utilize international versions for management recommendations. Moreover, information about adherence to these guidelines and real-world practice patterns in Switzerland or other countries is lacking. The Screening and COnsensus based on Practices and Evidence (SCOPE) program were designed by an international expert panel of gastrointestinal oncologists to gather real-world insights in the current clinical setting to manage patients with mCRC who have received prior treatment. We sought to understand general practice patterns, the influence of molecular diagnostics (e.g., testing for KRAS, NRAS, BRAF, and MSI), tumor sidedness, and patient-centric factors on treatment selection utilizing in-person surveys and three hypothetical patient case scenarios. Here, we describe and evaluate the Swiss data from the SCOPE program within the context of an international viewpoint and discuss the findings of our analysis. In general, we find that the real-world clinical decisions of Swiss physicians (SWI) closely follow international (INT) recommendations and guidelines, largely paralleling their regional and international counterparts in using the two approved treatments in the third- and fourth-line settings, namely trifluridine-tipiracil and regorafenib. Finally, our data suggest a tendency toward the use of trifluridine-tipiracil (SWI: 79%; INT: 66%) over regorafenib (SWI: 18%; INT: 18%) as the preferred third-line treatment choice in mCRC patients regardless of KRAS status.

Body composition as a predictor of chemotherapy-related toxicity in pancreatic cancer patients: A systematic review.

Objectives: The objective of this systematic review was to assess associations between quantitative body composition measures extracted from imaging examinations and chemotherapy-related toxicity in pancreatic cancer patients. A secondary objective was to evaluate the different definitions of sarcopenia across included studies. Methods: This systematic review was conducted according to the PRISMA statement. A comprehensive literature search of three electronic databases was performed by two authors. For each eligible article, information was collected concerning the clinical setting; basic study; population characteristics; technical; body composition features evaluated; CA 19.9 tumor marker levels; chemotherapy drugs administered; toxicities (hematologic, nausea/vomiting, diarrhea, neuropathy, reduction of number of cycles, overall toxicity); association of body composition values with toxicities. The overall quality of the included studies was critically evaluated. Results: After the initial retrieval of 1137 articles, the systematic review included 12 articles (1/12 in the neo-adjuvant setting; 2/12 in the adjuvant setting; 3/12 in the metastatic setting; 2/12 in the unresectable setting; the other 4/12 included more than one clinical setting). The number of patients included ranged between 17 and 251; mean/median age ranged between 63 and 77 years; the percentage of sarcopenic patients ranged between 23 and 76%. The most frequent body composition parameter evaluated was skeletal muscle index (11/12). Chemotherapy regimens included gemcitabine (as monotherapy or in combination with other drugs); FOLFIRINOX and S-1. Among the trials including gemcitabine, 2/9 demonstrated an association with toxicity, whereas 7/9 did not; among those including FOLFIRINOX, one demonstrated associated toxicity whereas the others did not. Altogether, 4/12 papers demonstrated an association between the body composition values and the development of chemotherapy-related toxicities. Conclusions: There is a wide variability of results about the association of body composition and chemotherapy-related toxicity in PC patients. Furthermore, cut-off values to define sarcopenia in PC patients are not yet uniformly defined. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022337753, identifier CRD42022337753.

18F-FDG PET Radiomics as Predictor of Treatment Response in Oesophageal Cancer: A Systematic Review and Meta-Analysis.

The best treatment strategy for oesophageal cancer patients achieving a complete clinical response after neoadjuvant chemoradiation is a burning topic. The available diagnostic tools, such as 18F-FDG PET/CT performed routinely, cannot accurately evaluate the presence or absence of the residual tumour. The emerging field of radiomics may encounter the critical challenge of personalised treatment. Radiomics is based on medical image analysis, executed by extracting information from many image features; it has been shown to provide valuable information for predicting treatment responses in oesophageal cancer. This systematic review with a meta-analysis aims to provide current evidence of 18F-FDG PET-based radiomics in predicting response treatments following neoadjuvant chemoradiotherapy in oesophageal cancer. A comprehensive literature review identified 1160 studies, of which five were finally included in the study. Our findings provided that pooled Area Under the Curve (AUC) of the five selected studies was relatively high at 0.821 (95% CI: 0.737-0.904) and not influenced by the sample size of the studies. Radiomics models exhibited a good performance in predicting pathological complete responses (pCRs). This review further strengthens the great potential of 18F-FDG PET-based radiomics to predict pCRs in oesophageal cancer patients who underwent neoadjuvant chemoradiotherapy. Additionally, our review imparts additional support to prospective studies on 18F-FDG PET radiomics for a tailored treatment strategy of oesophageal cancer patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021274636.

A Pilot, Prospective, Observational Study to Investigate the Value of NGS in Liquid Biopsies to Predict Tumor Response After Neoadjuvant Chemo-Radiotherapy in Patients With Locally Advanced Rectal Cancer: The LiBReCa Study.

Introduction: Circulating tumor DNA (ctDNA) correlates with the response to therapy in different types of cancer. However, in patients with locally advanced rectal cancer (LARC), little is known about how ctDNA levels change with neoadjuvant chemoradiation (Na-ChRT) and how they correlate with treatment response. This work aimed to explore the value of serial liquid biopsies in monitoring response after Na-ChRT with the hypothesis that this could become a reliable biomarker to identify patients with a complete response, candidates for non-operative management. Materials and Methods: Twenty-five consecutive LARC patients undergoing long-term Na-ChRT therapy were included. Applying next-generation sequencing (NGS), we characterized DNA extracted from formalin-fixed paraffin embedded diagnostic biopsy and resection tissue and plasma ctDNA collected at the following time points: the first and last days of radiotherapy (T0, Tend), at 4 (T4), 7 (T7) weeks after radiotherapy, on the day of surgery (Top), and 3-7 days after surgery (Tpost-op). On the day of surgery, a mesenteric vein sample was also collected (TIMV). The relationship between the ctDNA at those time-points and the tumor regression grade (TRG) of the surgical specimen was statistically explored. Results: We found no association between the disappearance of ctDNA mutations in plasma samples and pathological complete response (TRG1) as ctDNA was undetectable in the majority of patients from Tend on. However, we observed that the poor (TRG 4) response to Na-ChRT was significantly associated with a positive liquid biopsy at the Top. Conclusions: ctDNA evaluation by NGS technology may identify LARC patients with poor response to Na-ChRT. In contrast, this technique does not seem useful for identifying patients prone to developing a complete response.

Phase I dose-finding study of vandetanib in combination with gemcitabine in locally advanced unresectable or metastatic pancreatic adenocarcinoma.

OBJECTIVES: Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and RET (REarranged during Transfection) signaling. The primary objective of this open-label phase I trial was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of vandetanib in combination with gemcitabine in patients with unresectable, locally advanced or metastatic pancreatic adenocarcinoma (PAC). METHODS: Patients received vandetanib (100 or 300 mg/day) plus gemcitabine (1,000 mg/m(2) i.v. on days 1, 8 and 15 per 28-day cycle) until disease progression, unacceptable toxicity or withdrawal of patient consent. The MTD was determined by the assessment of dose-limiting toxicity (DLT) during the first 28 days of treatment. RESULTS: Fifteen patients were treated. No DLTs occurred in the first cohort of vandetanib 100 mg (n = 3) and recruitment continued at the 300-mg dose level. At the 300-mg dose, 3 out of 12 patients (including 2 in the expansion cohort) experienced DLTs (aphasia, elevated liver enzymes and neutropenia; all of them grade 3), thus exceeding the MTD. No objective responses were observed, with stable disease being the best response in 78% of evaluable patients. CONCLUSIONS: Vandetanib 100 mg/day is the RD in combination with gemcitabine in the treatment of patients with advanced PAC.

Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.

BACKGROUND: Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era. METHODS: 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. FINDINGS: 40.0% (299/747) of the tumours harboured a KRAS mutation, 14.5% (108/743) harboured a PIK3CA mutation (of which 68.5% [74/108] were located in exon 9 and 20.4% [22/108] in exon 20), 4.7% (36/761) harboured a BRAF mutation, and 2.6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6.7% (17/253) versus 35.8% (126/352; odds ratio [OR] 0.13, 95% CI 0.07-0.22; p<0.0001), a median PFS of 12 weeks versus 24 weeks (hazard ratio [HR] 1.98, 1.66-2.36; p<0.0001), and a median overall survival of 32 weeks versus 50 weeks (1.75, 1.47-2.09; p<0.0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8.3% (2/24) in carriers of BRAF mutations versus 38.0% in BRAF wild types (124/326; OR 0.15, 95% CI 0.02-0.51; p=0.0012); and 7.7% (1/13) in carriers of NRAS mutations versus 38.1% in NRAS wild types (110/289; OR 0.14, 0.007-0.70; p=0.013). PIK3CA exon 9 mutations had no effect, whereas exon 20 mutations were associated with a worse outcome compared with wild types, with a response rate of 0.0% (0/9) versus 36.8% (121/329; OR 0.00, 0.00-0.89; p=0.029), a median PFS of 11.5 weeks versus 24 weeks (HR 2.52, 1.33-4.78; p=0.013), and a median overall survival of 34 weeks versus 51 weeks (3.29, 1.60-6.74; p=0.0057). Multivariate analysis and conditional inference trees confirmed that, if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutations (in that order) gives additional information about outcome. Objective response rates in our series were 24.4% in the unselected population, 36.3% in the KRAS wild-type selected population, and 41.2% in the KRAS, BRAF, NRAS, and PIK3CA exon 20 wild-type population. INTERPRETATION: While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS, and PIK3CA exon 20 mutations are significantly associated with a low response rate. Objective response rates could be improved by additional genotyping of BRAF, NRAS, and PIK3CA exon 20 mutations in a KRAS wild-type population. FUNDING: Belgian Federation against Cancer (Stichting tegen Kanker).

Occurence of RAS reversion in metastatic colorectal cancer patients treated with bevacizumab.

BACKGROUND: A disappearance of RAS mutations in the plasma of about 50% of mCRCs (metastatic colorectal cancers) treated with bevacizumab-based chemotherapy has been reported. Our aim was to evaluate the same issue at tissue level. MATERIALS AND METHODS: Using next-generation sequencing and real-time PCR approaches, we characterized the primary tumor (PT) and paired liver metastases in 28 RAS mutant mCRCs. Patients were subdivided into 3 treatment groups: 1) bevacizumab plus chemotherapy; 2) chemotherapy alone; 3) any systemic therapy (control group). In groups 1 and 2, liver metastases were resected after removal of PT and subsequent neoadjuvant systemic therapy. RESULTS: RAS mutant alleles are at the same percentage in PT and liver metastases in the control group, while a significant reduction of the level of RAS mutations was detected in 57.1% of cases in group 1 and in 8.3% of cases in group 2. Differences among groups are statistically significant (p = 0.038). CONCLUSIONS: Most of mCRC patients treated with bevacizumab-containing regimens experience a strong reduction of RAS mutant cells, suggesting bevacizumab as particularly active against RAS mutant cells. This finding might have potential therapeutic implications, as anti-EGFR could be reconsidered in primarily RAS mutant patients reverted to a wild-type status after bevacizumab exposure.

Treatment landscape of metastatic pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with a dismal prognosis. The lack of symptoms in the early phase of the disease makes early diagnosis challenging, and about 80-85% of the patients are diagnosed only after the disease is locally advanced or metastatic. The current front-line treatment landscape in local stages comprises surgical resection and adjuvant chemotherapy. In Switzerland, although both FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens are feasible and comparable in the first-line setting, FOLFIRINOX is preferred in the treatment of fit (Eastern Cooperative Oncology Group [ECOG] performance status [PS]: 0-1), young (<65 years old) patients with few comorbidities and normal liver function, while gemcitabine plus nab-paclitaxel is used to treat less fit (ECOG PS: 1-2) and more vulnerable patients. In the second-line setting of advanced PDAC, there is currently only one approved regimen, based on the phase III NAPOLI-1 trial. Furthermore, the use of liposomal-irinotecan in the second line is supported by real-world data. Beyond the standard of care, various alternative treatment modalities are being explored in clinical studies. Immunotherapy has demonstrated only limited benefits until now, and only in cases of high microsatellite instability (MSI-H). However, data on the benefit of poly (ADP-ribose) polymerase (PARP) inhibition as maintenance therapy in patients with germline BRCA-mutated tumors might signal of an advance in targeted therapy. Currently, there is a lack of molecular and genetic biomarkers for optimal stratification of patients and in guiding treatment decisions. Thus, identification of predictive and prognostic biomarkers and evaluating novel treatment strategies are equally relevant for improving the prognosis of metastatic pancreatic cancer patients.

Advanced Gastric Cancer: Current Treatment Landscape and a Future Outlook for Sequential and Personalized Guide: Swiss Expert Statement Article.

BACKGROUND: Gastric cancer is a leading cause of cancer-related deaths worldwide. Several treatment possibilities have been investigated, but only a few show clinically meaningful results. SUMMARY: Systemic treatment options for advanced gastric cancer (aGC) have evolved over the recent years, implementing the growing molecular knowledge of this heterogeneous disease. Molecular profiling (at least for HER-2-expression, microsatellite instability status, Epstein-Barr virus expression, and programmed death ligand-1 expression/combined positive score [CPS]) is recommended for all therapy-fit patients prior to the start of a systemic treatment and is crucial for decisions on treatment strategy and drug selection. Various examples like the application of trastuzumab in the HER-2-positive subgroup underline the benefits of this approach starting from the first-line setting. A combination of platinum and fluoropyrimidine remains the first-line chemotherapy backbone in the treatment of advanced gastric cancer. Triplet combinations adding taxanes to the doublet regimen are reserved for certain scenarios. Unfortunately, almost all patients who receive first-line treatment (with or without anti-HER-2 blockade) progress and <70% are eligible for a second-line therapy. The addition of monoclonal antibodies has substantially improved outcomes in this setting. As such, ramucirumab has led to significant and clinically meaningful advancements in the second-line treatment. Furthermore, immuno-oncology with checkpoint inhibition and immune stimulation has evolved in the field of aGC. Recent first-line data show a significant survival benefit in aGC patients with a CPS ≥ 5 under immunochemotherapy. Nonetheless, the impact of immunotherapy combinations and immunochemotherapy remains an area of investigation. Key Message: In this review, we highlight recent improvements in the treatment landscape of advanced gastric cancer, the heterogeneity of this disease, and possible personalized targets.

Molecular characterization and response to cetuximab in a patient with refractory squamous cell anal carcinoma.

There are no standard chemotherapeutic options for patients with squamous cell anal carcinoma, relapsing and progressing on palliative cisplatin-based regimens. Similarly to other malignant conditions, monoclonal antibodies directed against the epidermal growth factor receptor may represent an attractive therapeutic strategy. Here we describe a patient who, based on molecular profile, benefited from the combination of irinotecan and cetuximab.

Metastatic Colorectal Carcinoma after Second Progression and the Role of Trifluridine-Tipiracil (TAS-102) in Switzerland.

BACKGROUND: Metastatic colorectal carcinoma (mCRC) is one of the most prevalent types of cancer worldwide. After tumor progression with first- and second-line treatment, trifluridine (FTD) and tipiracil (TPI) has been shown to be a treatment option. SUMMARY: Data from a pivotal phase 3 trial (RECOURSE) and an ongoing phase 3b trial (PRECONNECT) have shown that, in mCRC patients who experienced disease progression after 2 lines of standard therapy, treatment with FTD/TPI is safe and efficacious. Other third-line options include regorafenib, rechallenge with previous treatment lines or personalized approaches based on comprehensive molecular profiling. Randomized trials or sequential studies aiming for the right treatment sequence or predefined subtypes for FTD/TPI or regorafenib as well for rechallenge are missing. However, FTD/TPI as well as regorafenib are recommended by the current ESMO, German S3, and National Comprehensive Cancer Network (NCCN) guidelines in the same situation, thus offering physicians a number of alternatives for the treatment of mCRC patients after the second progression. Key Message: This narrative review summarizes published data and their impact for FTD/TPI as well for regorafenib and rechallenge chemotherapy in clinical practice settings of refractory situations of colorectal cancer.

Response to oxaliplatin with cetuximab in minor salivary gland adenoid cystic carcinoma.

Esophageal localization of adenoid cystic carcinoma of minor salivary glands is rare; it may occur in the early to mid-sixties' age group and is more frequently encountered in men than women. In the majority of cases, it arises from subepithelial glands of the middle to lower third of the esophagus, a similar distribution as squamous cell carcinoma. Prognosis depends mostly on tumor staging and resectability, which represents the only chance of cure. Due to the extreme rarity of this condition, there is limited experience with systemic therapy for advanced disease. We report a case of a patient with metastatic primary esophageal adenoid cystic carcinoma progressing on platinum- and irinotecan-based regimens, who achieved an objective response with oxaliplatin-based chemotherapy in combination with cetuximab.

Detection rate of unknown primary tumour by using somatostatin receptor PET/CT in patients with metastatic neuroendocrine tumours: a meta-analysis.

PURPOSE: The high diagnostic performance of somatostatin receptor positron emission tomography with computed tomography (PET/CT) in neuroendocrine tumours (NETs) was demonstrated by several articles. However, only some studies evaluated the detection rate (DR) of this imaging method in patients with metastatic NETs and unknown primary tumours (CUP-NETs). Therefore, we aimed to perform a meta-analysis to add evidence-based data in this setting. METHODS: A comprehensive computer literature search of studies listed in PubMed/MEDLINE, EMBASE, and Cochrane library databases through December 2018 and regarding the use of somatostatin receptor PET/CT in patients with CUP-NETs was carried out. Pooled DR of CUP-NETs by using somatostatin receptor PET/CT was calculated. A pooled analysis evaluating the percentage of change of management by using somatostatin receptor PET/CT in these patients was also performed. RESULTS: Twelve studies on the use of somatostatin receptor PET/CT in detecting CUP-NETs in 383 metastatic patients were included. The meta-analysis of all these studies provided the following DR on a per patient-based analysis: 56% (95% confidence interval (95% CI): 48-63%). Moderate heterogeneity among the selected studies was found (I2 = 50%), whereas a significant publication bias was excluded by Egger's test (p = 0.45). The most common primary tumour sites were the bowel and the pancreas. A change of management by using somatostatin receptor PET/CT was demonstrated in 20% (95% CI: 10-33%) of patients with CUP-NET. CONCLUSIONS: Somatostatin receptor PET/CT is very useful in detecting CUP-NETs in patients with metastatic disease. More studies on the change of management by using this imaging method in this setting are needed.

Radiolabelled choline versus PSMA PET/CT in prostate cancer restaging: a meta-analysis.

Both radiolabelled choline and prostate specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) could be used in patients with biochemical recurrent prostate cancer (BRPCa). We aimed to perform a meta-analysis about the head-to-head comparison of detection rate (DR) between these methods in BRPCa. A comprehensive literature search of studies listed in PubMed/MEDLINE, EMBASE and Cochrane library databases through October 2018 and regarding the head-to-head comparison of DR between radiolabelled choline and PSMA PET/CT in BRPCa was carried out. Overall pooled DR was calculated on a per patient-based analysis; subgroup analyses taking into account different prostate-specific antigen (PSA) cut-off values were performed. Five studies (257 BRPCa patients) were included. The meta-analysis provided the following overall DR: 56% [95% confidence interval (95% CI): 37-75%] for radiolabelled choline PET/CT and 78% (95% CI: 70-84%) for radiolabelled PSMA PET/CT. Significant difference of DR was found only in patients with PSA ≤ 1 ng/ml [the DR of radiolabelled choline and PSMA PET/CT were 27% (95% CI: 17-39%) and 54% (95% CI: 43-65%), respectively]. Radiolabelled PSMA PET/CT proved to be clearly superior in detecting BRPCa lesions at low PSA levels (≤ 1 ng/ml) when compared to radiolabelled choline PET/CT. On the other hand, the superiority of radiolabelled PSMA PET/CT was less evident in patients with PSA > 1 ng/ml. More studies and in particular cost-effectiveness analyses comparing these imaging methods are warranted.