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16 pages, 1754 KiB

Open AccessArticle

Evaluating Alternative Ramucirumab Doses as a Single Agent or with Paclitaxel in Second-Line Treatment of Locally Advanced or Metastatic Gastric/Gastroesophageal Junction Adenocarcinoma: Results from Two Randomized, Open-Label, Phase II Studies

by Manish A. Shah, Anghel Adrian Udrea, Igor Bondarenko, Was Mansoor, Raquel Guardeño Sánchez, Tomasz Sarosiek, Silvia Bozzarelli, Michael Schenker, Carlos Gomez-Martin, Carys Morgan, Mustafa Özgüroğlu, Joanna Pikiel, Haralabos P. Kalofonos, Elzbieta Wojcik, Tomas Buchler, Daniel Swinson, Irfan Cicin, Mano Joseph, Ihor Vynnychenko, Alexander Valerievich Luft, Peter C. Enzinger, Tomas Salek, Christos Papandreou, Christophe Tournigand, Evaristo Maiello, Ran Wei, David Ferry, Ling Gao, Joana M. Oliveira and Jaffer A. Ajani Show full author list Hide full author list

Cancers 2022, 14(5), 1168; https://doi.org/10.3390/cancers14051168 - 24 Feb 2022

Cited by 1 | Viewed by 4034

Abstract

Studies JVDB and JVCZ examined alternative ramucirumab dosing regimens as monotherapy or combined with paclitaxel, respectively, in patients with advanced/metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. For JVDB, randomized patients (N = 164) received ramucirumab monotherapy at four doses: 8 mg/kg every 2 weeks [...] Read more.

Studies JVDB and JVCZ examined alternative ramucirumab dosing regimens as monotherapy or combined with paclitaxel, respectively, in patients with advanced/metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma. For JVDB, randomized patients (N = 164) received ramucirumab monotherapy at four doses: 8 mg/kg every 2 weeks (Q2W) (registered dose), 12 mg/kg Q2W, 6 mg/kg weekly (QW), or 8 mg/kg on days 1 and 8 (D1D8) every 3 weeks (Q3W). The primary objectives were the safety and pharmacokinetics of ramucirumab monotherapy. For JVCZ, randomized patients (N = 245) received paclitaxel (80 mg/m²-D1D8D15) plus ramucirumab (8 mg/kg- or 12 mg/kg-Q2W). The primary objective was progression-free survival (PFS) of 12 mg/kg-Q2W arm versus placebo from RAINBOW using meta-analysis. Relative to the registered dose, exploratory dosing regimens (EDRs) led to higher ramucirumab serum concentrations in both studies. EDR safety profiles were consistent with previous studies. In JVDB, serious adverse events occurred more frequently in the 8 mg/kg-D1D8-Q3W arm versus the registered dose; 6 mg/kg-QW EDR had a higher incidence of bleeding/hemorrhage. In JVCZ, PFS was improved with the 12 mg/kg plus paclitaxel combination versus placebo in RAINBOW; however, no significant PFS improvement was observed between the 12 mg/kg and 8 mg/kg arms. The lack of a dose/exposure-response relationship in these studies supports the standard dose of ramucirumab 8 mg/kg-Q2W as monotherapy or in combination with paclitaxel as second-line treatment for advanced/metastatic gastric/GEJ adenocarcinoma. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Early GI Cancers (Esophageal, Gastric, and Colorectal Cancer))

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10 pages, 636 KiB

Open AccessArticle

Gastric Cancers Missed at Upper Endoscopy in Central Norway 2007 to 2016—A Population-Based Study

by Marianne Beck, Erling A. Bringeland, Gunnar Qvigstad and Reidar Fossmark

Cancers 2021, 13(22), 5628; https://doi.org/10.3390/cancers13225628 - 10 Nov 2021

Cited by 21 | Viewed by 2508

Abstract

Background: The rates of missed gastric cancers (MGC) at upper endoscopy (UE) has been reported at 5–10% in Western countries. We aimed to calculate the rate of MGC and identify factors associated with MGC. Methods: Retrospective population-based cohort study including 730 patients diagnosed [...] Read more.

Background: The rates of missed gastric cancers (MGC) at upper endoscopy (UE) has been reported at 5–10% in Western countries. We aimed to calculate the rate of MGC and identify factors associated with MGC. Methods: Retrospective population-based cohort study including 730 patients diagnosed with gastric adenocarcinoma in Central Norway 2007–2016. MGCs were incident gastric adenocarcinomas diagnosed 6–36 months after a previous UE. Factors associated with MGC were examined. Definitely missed (UE 6–12 months prior) and potentially missed (UE 12–36 months prior) MGCs were compared. Results: Sixty-seven (9.2%) of 730 gastric cancers were MGC. MGC were associated with localization (p = 0.009) and more frequent in the corpus, Lauren’s histological type (p = 0.028) and diffuse type more prevalent, and previous Billroth 2-operation (14.9% vs. 4.7%, p = 0.001). MGCs were diagnosed at earlier stages (p = 0.037). An ulceration was more common in patients with definitely missed than potentially MGC (40.9% vs. 17.8%, p = 0.041). Conclusions: MGC accounted for 9.2% of gastric cancers in Central Norway. MGC were associated with localization in the corpus, Lauren´s diffuse type and previous Billroth-2-operation. Intensified follow-up and adequate biopsy sampling of patients with gastric ulcerations could reduce the rate of missed gastric cancers. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Early GI Cancers (Esophageal, Gastric, and Colorectal Cancer))

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11 pages, 1879 KiB

Open AccessArticle

Impact of Immunoscore on the Management of Stage II Colon Cancer Patients: A Physician Survey

by Anup Kasi, Efrat Dotan, Graham M. Poage, Aurelie Catteau, Dewi Vernerey, Manju George and Afsaneh Barzi

Cancers 2021, 13(21), 5467; https://doi.org/10.3390/cancers13215467 - 30 Oct 2021

Cited by 4 | Viewed by 2483

Abstract

Background: Adjuvant chemotherapy use in stage II colon cancer is controversial. Current prognostic risk factors do not take the tumor immune microenvironment into account. Consideration of the Immunoscore, which measures the host immune response at the tumor site, may assist clinicians in reducing [...] Read more.

Background: Adjuvant chemotherapy use in stage II colon cancer is controversial. Current prognostic risk factors do not take the tumor immune microenvironment into account. Consideration of the Immunoscore, which measures the host immune response at the tumor site, may assist clinicians in reducing adjuvant chemotherapy use in patients who are unlikely to benefit from it. This study sought to determine the potential clinical utility of the Immunoscore, via its effect on medical oncologists’ recommendations for management of patients with stage II colon cancer. Methods: De-identified vignettes of 10 patients with stage II colon cancer were presented to 25 practicing medical oncologists. Each participant completed surveys indicating recommendations for adjuvant chemotherapy and surveillance strategies. An educational session was subsequently conducted, and the same patient profiles were re-presented but included immunoscore results. Participants were again asked to provide their recommendations. A participant was counted as influenced if their responses were altered after immunoscore test results were provided. Results: All but one participant (96%) altered a management recommendation for ≥1 case. For individual cases, a mean of 55% (range, 40–80%) of participants altered their recommendations for adjuvant chemotherapy and/or surveillance. For the immunoscore-high cases (low-risk of recurrence), recommendations for adjuvant chemotherapy use decreased from 60% to 31%. Conclusions: These results indicate a willingness by oncologists to integrate immunoscore information into clinical practice recommendations. Incorporation of immunoscore data resulted in the reduction of nonvalue care in the simulated population. Confirmation in prospective studies is planned. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Early GI Cancers (Esophageal, Gastric, and Colorectal Cancer))

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11 pages, 638 KiB

Open AccessArticle

Serum CXCL8 and Its Specific Receptor (CXCR2) in Gastric Cancer

by Elżbieta Pawluczuk, Marta Łukaszewicz-Zając, Mariusz Gryko, Agnieszka Kulczyńska-Przybik and Barbara Mroczko

Cancers 2021, 13(20), 5186; https://doi.org/10.3390/cancers13205186 - 15 Oct 2021

Cited by 16 | Viewed by 2235

Abstract

Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide. This malignancy is usually diagnosed at an advanced stage. Therefore, novel biomarkers useful in the early detection of GC are sorely needed. Some authors suggest the role of chemokines and their [...] Read more.

Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide. This malignancy is usually diagnosed at an advanced stage. Therefore, novel biomarkers useful in the early detection of GC are sorely needed. Some authors suggest the role of chemokines and their specific receptors in GC pathogenesis. The aim of the study was to investigate whether serum CXCL8 and its receptor (CXCR2) might be considered as potential candidates for biomarkers in the diagnosis and prognosis of GC. The study included 98 subjects: 64 GC patients and 34 healthy volunteers. CXCL8 and CXCR2 concentrations were assessed by the enzyme-linked immunosorbent assay (ELISA) method. Serum CXCL8 and CXCR2 concentrations were significantly higher in GC patients than in healthy controls, similar to the well-established tumor marker (CA19-9) and marker of inflammation (CRP). Diagnostic sensitivity of CXCL8 was the highest among all proteins tested and increased for the combined assessment with CA19-9. The area under the ROC curve for CXCL8 was higher than those for CXCR2 and classical tumor markers. Serum CXCL8 levels were indicated as a significant risk factor of GC occurrence. Our findings suggest that serum CXCL8 is a promising candidate for a biomarker in GC diagnosis and might be used as a significant predictor of GC risk. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Early GI Cancers (Esophageal, Gastric, and Colorectal Cancer))

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12 pages, 1116 KiB

Open AccessArticle

Modified Tumor Budding as a Better Predictor of Lymph Node Metastasis in Early Gastric Cancer: Possible Real-World Applications

by Kwangil Yim, Won Mo Jang and Sung Hak Lee

Cancers 2021, 13(14), 3405; https://doi.org/10.3390/cancers13143405 - 7 Jul 2021

Cited by 13 | Viewed by 3539

Abstract

Endoscopic resection (ER) is a minimally invasive treatment for early gastric cancer (EGC) with a low risk of lymph node metastasis (LNM). Recently, tumor budding (TB) has emerged as a potential predictor of LNM in EGC. We assessed the clinical significance of modified [...] Read more.

Endoscopic resection (ER) is a minimally invasive treatment for early gastric cancer (EGC) with a low risk of lymph node metastasis (LNM). Recently, tumor budding (TB) has emerged as a potential predictor of LNM in EGC. We assessed the clinical significance of modified TB (mTB) that excludes the signet ring cell component and compared several TB assessment methods. Two hundred and eighty-nine patients with EGC at Uijeongbu St. Mary’s Hospital from 2010 to 2021 were enrolled. In univariate analysis, age, size, depth of invasion, tumor type, histologic type, Lauren classification, lymphatic invasion, venous invasion, poorly differentiated carcinoma (“not otherwise specified” predominant), and TB were significantly associated with LNM. Multivariate regression analysis showed that mTB (difference area under the curve [dAUC] = 0.085 and 0.087) was superior to TB (dAUC = 0.054 and 0.057) in predicting LNM. In addition, total TB counts on representative slide sections (dAUC = 0.087 and 0.057) in assessing TB and mTB and the ITBCC method (dAUC = 0.085) in mTB were superior to the presence or absence method (dAUC = 0.042 and 0.029). The mTB significantly increases LNM prediction ability, which can provide important information for patients with EGC. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Early GI Cancers (Esophageal, Gastric, and Colorectal Cancer))

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12 pages, 876 KiB

Open AccessArticle

Multimodal Treatment in Metastatic Colorectal Cancer (mCRC) Improves Outcomes—The University College London Hospital (UCLH) Experience

by Nalinie Joharatnam-Hogan, William Wilson, Kai Keen Shiu, Giuseppe Kito Fusai, Brian Davidson, Daniel Hochhauser, John Bridgewater and Khurum Khan

Cancers 2020, 12(12), 3545; https://doi.org/10.3390/cancers12123545 - 27 Nov 2020

Cited by 10 | Viewed by 3591

Abstract

Background: Despite notable advances in the management of metastatic colorectal cancer (mCRC) over the last two decades, treatment intent in the vast majority of patients remains palliative due to technically unresectable disease, extensive disease, or co-morbidities precluding major surgery. Up to 30% of [...] Read more.

Background: Despite notable advances in the management of metastatic colorectal cancer (mCRC) over the last two decades, treatment intent in the vast majority of patients remains palliative due to technically unresectable disease, extensive disease, or co-morbidities precluding major surgery. Up to 30% of individuals with mCRC are considered potentially suitable for primary or metastasis-directed multimodal therapy, including surgical resection, ablative techniques, or stereotactic radiotherapy (RT), with the aim of improving survival outcomes. We reviewed the potential benefits of multimodal therapy on the survival of patients with mCRC treated at the UCLH. Methods: Clinical data on baseline characteristics, multimodal treatments, and survival outcomes were retrospectively collected from all patients with mCRC receiving systemic chemotherapy between January 2013 and April 2017. Primary outcome was the impact of multimodal therapy on overall survival, compared to systemic therapy alone, and the effect of different types of multimodal therapy on survival outcome, and was assessed using the Kaplan–Meier approach. All analyses were adjusted for age, gender, and side of primary tumour. Results: One-hundred and twenty-five patients with mCRC were treated during the study period (median age: 62 years (range 19–89). The liver was the most frequent metastatic site (78%; 97/125). A total of 52% (65/125) had ≥2 lines of systemic chemotherapy. Of the 125 patients having systemic chemotherapy, 74 (59%) underwent multimodal treatment to the primary tumour or metastasis. Median overall survival (OS) was 25.7 months [95% Confidence Interval (CI) 21.5–29.0], and 3-year survival, 26%. Univariate analysis demonstrated that patients who had additional procedures (surgery/ablation/RT) were significantly less likely to die (Hazard Ratio (HR) 0.18, 95% CI 0.12–0.29, p < 0.0001) compared to those receiving systemic chemotherapy alone. Increasing number of multimodal procedures was associated with an incremental increase in survival—with median OS 28.4 m, 35.7 m, and 64.8 m, respectively, for 1, 2, or ≥3 procedures (log-rank p < 0.0001). After exclusion of those who received systemic chemotherapy only (n = 51), metastatic resections were associated with improved survival (adjusted HR 0.36, 95% CI 0.20–0.63, p < 0.0001), confirmed in multivariate analysis. Multiple single-organ procedures did not improve survival. Conclusion: Multimodal therapy for metastatic bowel cancer is associated with significant survival benefit. Resection/radical RT of the primary and resection of metastatic disease should be considered to improve survival outcomes following multidisciplinary team (MDT) discussion and individual assessment of fitness. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Early GI Cancers (Esophageal, Gastric, and Colorectal Cancer))

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Review

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11 pages, 11939 KiB

Open AccessReview

COVID-19 and Its Impact on Upper Gastrointestinal (GI) Cancer Management

by Shalini Fernando, Mesel Veli, Borzoueh Mohammadi, Andrew Millar and Khurum Khan

Cancers 2021, 13(3), 397; https://doi.org/10.3390/cancers13030397 - 21 Jan 2021

Cited by 7 | Viewed by 3649

Abstract

Coronavirus disease 2019 (COVID-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has left dramatic footprints on human health and economy. Cancer, whilst not an infective disease, is prevalent in epidemic proportions and cannot be pretermitted due to the [...] Read more.

Coronavirus disease 2019 (COVID-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has left dramatic footprints on human health and economy. Cancer, whilst not an infective disease, is prevalent in epidemic proportions and cannot be pretermitted due to the impact of COVID-19. As we emanate from the second national lockdown in the UK with mixed feelings of hope and despair—due to vaccination and new COVID-19 variant, respectively—we reflect on the impact of the first wave on the provision on diagnosis and management of with upper gastrointestinal (UGI) cancers. This review provides a critical analysis of available literature on COVID-19 and its impact on cancer management in general and that of UGI cancers in particular. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Early GI Cancers (Esophageal, Gastric, and Colorectal Cancer))

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25 pages, 763 KiB

Open AccessEditor’s ChoiceReview

Artificial Intelligence for Histology-Based Detection of Microsatellite Instability and Prediction of Response to Immunotherapy in Colorectal Cancer

by Lindsey A. Hildebrand, Colin J. Pierce, Michael Dennis, Munizay Paracha and Asaf Maoz

Cancers 2021, 13(3), 391; https://doi.org/10.3390/cancers13030391 - 21 Jan 2021

Cited by 68 | Viewed by 9321

Abstract

Microsatellite instability (MSI) is a molecular marker of deficient DNA mismatch repair (dMMR) that is found in approximately 15% of colorectal cancer (CRC) patients. Testing all CRC patients for MSI/dMMR is recommended as screening for Lynch Syndrome and, more recently, to determine eligibility [...] Read more.

Microsatellite instability (MSI) is a molecular marker of deficient DNA mismatch repair (dMMR) that is found in approximately 15% of colorectal cancer (CRC) patients. Testing all CRC patients for MSI/dMMR is recommended as screening for Lynch Syndrome and, more recently, to determine eligibility for immune checkpoint inhibitors in advanced disease. However, universal testing for MSI/dMMR has not been uniformly implemented because of cost and resource limitations. Artificial intelligence has been used to predict MSI/dMMR directly from hematoxylin and eosin (H&E) stained tissue slides. We review the emerging data regarding the utility of machine learning for MSI classification, focusing on CRC. We also provide the clinician with an introduction to image analysis with machine learning and convolutional neural networks. Machine learning can predict MSI/dMMR with high accuracy in high quality, curated datasets. Accuracy can be significantly decreased when applied to cohorts with different ethnic and/or clinical characteristics, or different tissue preparation protocols. Research is ongoing to determine the optimal machine learning methods for predicting MSI, which will need to be compared to current clinical practices, including next-generation sequencing. Predicting response to immunotherapy remains an unmet need. Full article

(This article belongs to the Special Issue Diagnosis and Treatment of Early GI Cancers (Esophageal, Gastric, and Colorectal Cancer))

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