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Multimodality Treatments in Metastatic Gastric Cancer

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Gastroenterology & Hepatopancreatobiliary Medicine".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 34674

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Dr. Angelica Petrillo

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1. Medical Oncology Unit, Ospedale del Mare, Naples, Italy
2. Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy
Interests: gastric cancer; esophageal diseases; pancreatic cancer; cancer biomarkers; oncology; prognosis; treatment; tumors; chemotherapy
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Dear Colleagues,

Gastric cancer represents one of the most frequent and lethal tumors worldwide today, finding itself in the fifth place in incidence and the third in mortality. Surgery remains the only curative treatment for localized tumors, but only 20% of patients are suitable for surgery due to the lack of specific symptoms and the late diagnosis, especially in Western countries. Additionally, even in patients who receive curative treatment, rates of locoregional relapse and distant metastasis remain high. Palliative chemotherapy is the principal treatment in cases of metastatic disease even if the prognosis of patients receiving chemotherapy is still poor. Therefore, a multidisciplinary evaluation is important in order to improve the efficacy of active treatments. In this context, there is an unmet need for a better understanding of genetic alterations and prognostic and predictive factors in order to choose the best tailored therapy for each patient.

The aim of this Special Issue is to focus on the results and problems of multimodality treatment in metastatic gastric cancer, the search for prognostic and predictive factors, and the evaluation of novel strategies for individualized treatment. We are inviting relevant original research, systematic reviews, meta-analyses, and short communications covering the above-mentioned topics.

Dr. Angelica Petrillo
Guest Editor

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Keywords

Target therapy
Surgical treatment
Nutrition and cancer
Locoregional treatment
Multimodality therapy
Prognostic factors
Predictive factors
Molecular classification
HIPEC
Immunotherapy

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Published Papers (9 papers)

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Editorial

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3 pages, 178 KiB

Open AccessEditorial

Multimodality Treatment in Metastatic Gastric Cancer: Working Together to Tailor the Continuum of Care

by Angelica Petrillo

J. Clin. Med. 2021, 10(23), 5492; https://doi.org/10.3390/jcm10235492 - 24 Nov 2021

Cited by 1 | Viewed by 1295

Abstract

Gastric cancer (GC) represents one of the most frequent and lethal tumors worldwide today, finding itself in fifth place in terms of incidence and third in terms of mortality [...] Full article

(This article belongs to the Special Issue Multimodality Treatments in Metastatic Gastric Cancer)

Research

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15 pages, 2170 KiB

Open AccessArticle

The Prognostic Role of Early Skeletal Muscle Mass Depletion in Multimodality Management of Patients with Advanced Gastric Cancer Treated with First Line Chemotherapy: A Pilot Experience from Modena Cancer Center

by Margherita Rimini, Annarita Pecchi, Francesco Prampolini, Chiara Bussei, Massimiliano Salati, Daniela Forni, Francesca Martelli, Filippo Valoriani, Fabio Canino, Alessandro Bocconi, Fabio Gelsomino, Linda Reverberi, Stefania Benatti, Federico Piacentini, Renata Menozzi, Massimo Dominici, Gabriele Luppi and Andrea Spallanzani

J. Clin. Med. 2021, 10(8), 1705; https://doi.org/10.3390/jcm10081705 - 15 Apr 2021

Cited by 8 | Viewed by 2344

Abstract

Background: Few data about the link between nutritional status and survival are available in the metastatic gastric cancer (GC) setting. The aim of this work was to evaluate the prognostic role of tissue modifications during treatment and the benefit of a scheduled nutritional assessment in this setting. Methods: Clinical and laboratory variables of 40 metastatic GC patients treated at Modena Cancer Center were retrieved: 20 received a nutritional assessment on the oncology’s discretion, the other 20 received a scheduled nutritional assessment at baseline and every 2–4 weeks. Anthropometric parameters were calculated on Computed Tomography (CT) images at the baseline and after 3 months of chemotherapy. Results: A correlation between baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS), Lymphocyte to Monocyte Ratio (LMR), C-reactive protein (PCR), Prognostic Nutritional Index (PNI) and Overall survival (OS) was highlighted. Among the anthropometric parameters, early skeletal muscle mass depletion (ESMMD) >10% in the first months of treatment significantly impacted on mOS (p = 0.0023). A link between ESMMD and baseline LDH > 460 U/L, baseline CRP > 2.2 mg/dL and weight decrease during treatment emerged. Patients evaluated with a nutritional scheduled support experienced a mean gain in subcutaneous and visceral fat of 11.4% and 10.21%, respectively. Conclusion: We confirm the prognostic impact of ESMMD > 10% during chemotherapy in metastatic GC. The prognostic role of a scheduled nutritional assessment deserves further confirmation in large prospective trials. Full article

(This article belongs to the Special Issue Multimodality Treatments in Metastatic Gastric Cancer)

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13 pages, 8017 KiB

Open AccessArticle

Role of Baseline Computed-Tomography-Evaluated Body Composition in Predicting Outcome and Toxicity from First-Line Therapy in Advanced Gastric Cancer Patients

by Silvia Catanese, Giacomo Aringhieri, Caterina Vivaldi, Francesca Salani, Saverio Vitali, Irene Pecora, Valentina Massa, Monica Lencioni, Enrico Vasile, Rachele Tintori, Francesco Balducci, Alfredo Falcone, Carla Cappelli and Lorenzo Fornaro

J. Clin. Med. 2021, 10(5), 1079; https://doi.org/10.3390/jcm10051079 - 5 Mar 2021

Cited by 13 | Viewed by 2214

Abstract

Sarcopenia is recognised as a predictor of toxicity and survival in localised and locally advanced gastric cancer (GC). Its prognostication power in advanced unresectable or metastatic GC (aGC) is debated. The survival impact of visceral and subcutaneous fat distribution (visceral fat area (VFA)/subcutaneous fat area (SFA)) is ambiguous. Our aim was to determine the influence of body composition parameters (BCp) on toxicity and survival in aGC patients undergoing palliative treatment. BCp were retrospectively assessed by baseline computed tomography for 78 aGC patients who received first-line chemotherapy from March 2010 to January 2017. Correlations between BCp and toxicity and survival were calculated by χ²-test and by log-rank-test and Cox-model, respectively. Sarcopenia fails to show association with progression-free survival (PFS) (p = 0.44) and overall survival (OS) (p = 0.88). However, sarcopenia influences the development of high-grade neutropenia (p = 0.048) and mucositis (p = 0.054). VFA/SFA (high vs. all the rest) results as a strong predictor of objective response (p = 0.02) and outcome (PFS, p = 0.001; OS, p = 0.02). At multivariate analysis for PFS, prognostic factors are VFA/SFA (p = 0.03) and a neutrophil–lymphocyte ratio >3. The same factors remain significant for OS (each p = 0.03) along with Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.008) and number of metastatic sites ≥2 (p < 0.001). In our cohort of aGC, VFA/SFA exhibit a robust impact on survival, with a higher sensitivity than sarcopenia. Full article

(This article belongs to the Special Issue Multimodality Treatments in Metastatic Gastric Cancer)

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12 pages, 1635 KiB

Open AccessCommunication

The Mutational Concordance of Fixed Formalin Paraffin Embedded and Fresh Frozen Gastro-Oesophageal Tumours Using Whole Exome Sequencing

by Irene Y. Chong, Naureen Starling, Alistair Rust, John Alexander, Lauren Aronson, Marta Llorca-Cardenosa, Ritika Chauhan, Asif Chaudry, Sacheen Kumar, Kerry Fenwick, Ioannis Assiotis, Nik Matthews, Ruwaida Begum, Andrew Wotherspoon, Monica Terlizzo, David Watkins, Ian Chau, Christopher J. Lord, Syed Haider, Sheela Rao and David Cunningham Show full author list Hide full author list

J. Clin. Med. 2021, 10(2), 215; https://doi.org/10.3390/jcm10020215 - 9 Jan 2021

Cited by 7 | Viewed by 2692

Abstract

1. Background: The application of massively parallel sequencing has led to the identification of aberrant druggable pathways and somatic mutations within therapeutically relevant genes in gastro-oesophageal cancer. Given the widespread use of formalin-fixed paraffin-embedded (FFPE) samples in the study of this disease, it would be beneficial, especially for the purposes of biomarker evaluation, to assess the concordance between comprehensive exome-wide sequencing data from archival FFPE samples originating from a prospective clinical study and those derived from fresh-frozen material. 2. Methods: We analysed whole-exome sequencing data to define the mutational concordance of 16 matched fresh-frozen and FFPE gastro-oesophageal tumours (N = 32) from a prospective clinical study. We assessed DNA integrity prior to sequencing and then identified coding mutations in genes that have previously been implicated in other cancers. In addition, we calculated the mutant-allele heterogeneity (MATH) for these samples. 3. Results: Although there was increased degradation of DNA in FFPE samples compared with frozen samples, sequencing data from only two FFPE samples failed to reach an adequate mapping quality threshold. Using a filtering threshold of mutant read counts of at least ten and a minimum of 5% variant allele frequency (VAF) we found that there was a high median mutational concordance of 97% (range 80.1–98.68%) between fresh-frozen and FFPE gastro-oesophageal tumour-derived exomes. However, the majority of FFPE tumours had higher mutant-allele heterogeneity (MATH) scores when compared with corresponding frozen tumours (p < 0.001), suggesting that FFPE-based exome sequencing is likely to over-represent tumour heterogeneity in FFPE samples compared to fresh-frozen samples. Furthermore, we identified coding mutations in 120 cancer-related genes, including those associated with chromatin remodelling and Wnt/β-catenin and Receptor Tyrosine Kinase signalling. 4. Conclusions: These data suggest that comprehensive genomic data can be generated from exome sequencing of selected DNA samples extracted from archival FFPE gastro-oesophageal tumour tissues within the context of prospective clinical trials. Full article

(This article belongs to the Special Issue Multimodality Treatments in Metastatic Gastric Cancer)

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Review

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16 pages, 278 KiB

Open AccessReview

The Emerging Role of Liquid Biopsy in Gastric Cancer

by Csongor György Lengyel, Sadaqat Hussain, Dario Trapani, Khalid El Bairi, Sara Cecilia Altuna, Andreas Seeber, Andrew Odhiambo, Baker Shalal Habeeb and Fahmi Seid

J. Clin. Med. 2021, 10(10), 2108; https://doi.org/10.3390/jcm10102108 - 13 May 2021

Cited by 29 | Viewed by 6320

Abstract

(1) Background: Liquid biopsy (LB) is a novel diagnostic method with the potential of revolutionizing the prevention, diagnosis, and treatment of several solid tumors. The present paper aims to summarize the current knowledge and explore future possibilities of LB in the management of metastatic gastric cancer. (2) Methods: This narrative review examined the most recent literature on the use of LB-based techniques in metastatic gastric cancer and the current LB-related clinical trial landscape. (3) Results: In gastric cancer, the detection of circulating cancer cells (CTCs) has been recognized to have a prognostic role in all the disease stages. In the setting of localized disease, cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) qualitative and quantitative detection have the potential to inform on the risk of cancer recurrence and metastatic dissemination. In addition, gastric cancer-released exosomes may play an essential part in metastasis formation. In the metastatic setting, the levels of cfDNA show a positive correlation with tumor burden. There is evidence that circulating tumor microemboli (CTM) in the blood of metastatic patients is an independent prognostic factor for shorter overall survival. Gastric cancer-derived exosomal microRNAs or clonal mutations and copy number variations detectable in ctDNA may contribute resistance to chemotherapy or targeted therapies, respectively. There is conflicting and limited data on CTC-based PD-L1 verification and cfDNA-based Epstein–Barr virus detection to predict or monitor immunotherapy responses. (4) Conclusions: Although preliminary studies analyzing LBs in patients with advanced gastric cancer appear promising, more research is required to obtain better insights into the molecular mechanisms underlying resistance to systemic therapies. Moreover, validation and standardization of LB methods are crucial before introducing them in clinical practice. The feasibility of repeatable, minimally invasive sampling opens up the possibility of selecting or dynamically changing therapies based on prognostic risk or predictive biomarkers, such as resistance markers. Research is warranted to exploit a possible transforming area of cancer care. Full article

(This article belongs to the Special Issue Multimodality Treatments in Metastatic Gastric Cancer)

25 pages, 2054 KiB

Open AccessReview

Bone Metastases from Gastric Cancer: What We Know and How to Deal with Them

by Angelica Petrillo, Emilio Francesco Giunta, Annalisa Pappalardo, Davide Bosso, Laura Attademo, Cinzia Cardalesi, Anna Diana, Antonietta Fabbrocini, Teresa Fabozzi, Pasqualina Giordano, Margaret Ottaviano, Mario Rosanova, Antonia Silvestri, Piera Federico and Bruno Daniele

J. Clin. Med. 2021, 10(8), 1777; https://doi.org/10.3390/jcm10081777 - 19 Apr 2021

Cited by 12 | Viewed by 5033

Abstract

Gastric cancer (GC) is the third cause of cancer-related death worldwide; the prognosis is poor especially in the case of metastatic disease. Liver, lymph nodes, peritoneum, and lung are the most frequent sites of metastases from GC; however, bone metastases from GC have been reported in the literature. Nevertheless, it is unclear how the metastatic sites may affect the prognosis. In particular, knowledge about the impact of bone metastases on GC patients’ outcome is scant, and this may be related to the rarity of bone lesions and/or their underestimation at the time of diagnosis. In fact, there is still a lack of specific recommendation for their detection at the diagnosis. Then, the majority of the evidences in this field came from retrospective analysis on very heterogeneous study populations. In this context, the aim of this narrative review is to delineate an overview about the evidences existing about bone metastases in GC patients, focusing on their incidence and biology, the prognostic role of bone involvement, and their possible implication in the treatment choice. Full article

(This article belongs to the Special Issue Multimodality Treatments in Metastatic Gastric Cancer)

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23 pages, 756 KiB

Open AccessReview

How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches

by Michele Ghidini, Angelica Petrillo, Andrea Botticelli, Dario Trapani, Alessandro Parisi, Anna La Salvia, Elham Sajjadi, Roberto Piciotti, Nicola Fusco and Shelize Khakoo

J. Clin. Med. 2021, 10(7), 1412; https://doi.org/10.3390/jcm10071412 - 1 Apr 2021

Cited by 9 | Viewed by 3973

Abstract

Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease. Full article

(This article belongs to the Special Issue Multimodality Treatments in Metastatic Gastric Cancer)

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24 pages, 5287 KiB

Open AccessReview

Efficacy of Surgery for the Treatment of Gastric Cancer Liver Metastases: A Systematic Review of the Literature and Meta-Analysis of Prognostic Factors

by Gianpaolo Marte, Andrea Tufo, Francesca Steccanella, Ester Marra, Piera Federico, Angelica Petrillo and Pietro Maida

J. Clin. Med. 2021, 10(5), 1141; https://doi.org/10.3390/jcm10051141 - 9 Mar 2021

Cited by 18 | Viewed by 6644

Abstract

Background: In the last 10 years, the management of patients with gastric cancer liver metastases (GCLM) has changed from chemotherapy alone, towards a multidisciplinary treatment with liver surgery playing a leading role. The aim of this systematic review and meta-analysis is to assess the efficacy of hepatectomy for GCLM and to analyze the impact of related prognostic factors on long-term outcomes. Methods: The databases PubMed (Medline), EMBASE, and Google Scholar were searched for relevant articles from January 2010 to September 2020. We included prospective and retrospective studies that reported the outcomes after hepatectomy for GCLM. A systematic review of the literature and meta-analysis of prognostic factors was performed. Results: We included 40 studies, including 1573 participants who underwent hepatic resection for GCLM. Post-operative morbidity and 30-day mortality rates were 24.7% and 1.6%, respectively. One-year, 3-years, and 5-years overall survival (OS) were 72%, 37%, and 26%, respectively. The 1-year, 3-years, and 5-years disease-free survival (DFS) were 44%, 24%, and 22%, respectively. Well-moderately differentiated tumors, pT1–2 and pN0–1 adenocarcinoma, R0 resection, the presence of solitary metastasis, unilobar metastases, metachronous metastasis, and chemotherapy were all strongly positively associated to better OS and DFS. Conclusion: In the present study, we demonstrated that hepatectomy for GCLM is feasible and provides benefits in terms of long-term survival. Identification of patient subgroups that could benefit from surgical treatment is mandatory in a multidisciplinary setting. Full article

(This article belongs to the Special Issue Multimodality Treatments in Metastatic Gastric Cancer)

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16 pages, 282 KiB

Open AccessReview

Precision Medicine to Treat Advanced Gastroesophageal Adenocarcinoma: A Work in Progress

by Valentina Gambardella, Tania Fleitas, Noelia Tarazona, Federica Papaccio, Marisol Huerta, Susana Roselló, Francisco Gimeno-Valiente, Desamparados Roda and Andrés Cervantes

J. Clin. Med. 2020, 9(9), 3049; https://doi.org/10.3390/jcm9093049 - 22 Sep 2020

Cited by 19 | Viewed by 2928

Abstract

Gastroesophageal adenocarcinoma (GEA) represents a heterogeneous disease and, when diagnosed as locally advanced or metastatic, it is characterized by poor prognosis. During the last few years, several molecular classifications have been proposed to try to personalize treatment for those patients diagnosed with advanced disease. Nevertheless, despite the great effort, precision medicine is still far from being a reality. The improvement in the molecular analysis due to the application of high throughput technologies based on DNA and RNA sequencing has opened a novel scenario leading to the personalization of treatment. The possibility to target epidermal growth factor receptor (HER)2, Claudine, Fibroblast Growth Factor Receptors (FGFR), and other alterations with a molecular matched therapy could significantly improve clinical outcomes over advanced gastric cancer patients. On the other hand, the development of immunotherapy could also represent a promising strategy in a selected population. In this review, we sought to describe the novel pathways implicated in GEA progression and the results of the molecular matched therapies. Full article

(This article belongs to the Special Issue Multimodality Treatments in Metastatic Gastric Cancer)

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