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1
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Yang W, Niu Y, Sun Y. Current neoadjuvant therapy for operable locally advanced esophageal cancer. Med Oncol 2023; 40:252. [PMID: 37498350 DOI: 10.1007/s12032-023-02097-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/19/2023] [Indexed: 07/28/2023]
Abstract
Locally advanced esophageal cancer has a poor prognosis, while an increasing number of patients are diagnosed with that. Neoadjuvant therapy has become a hot topic in treating locally advanced esophageal cancer to improve its survival benefit. The efficacy of neoadjuvant therapy followed by surgery has been confirmed by many studies, and neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy are included in the guidelines. In recent years, targeted therapy and immunotherapy have emerged, and more studies are evaluating the efficacy of combining them with neoadjuvant therapy for operable esophageal cancer patients. Even though the preliminary data is disappointing, many trials are still under investigation without improving survival benefits. New indexes used as surrogate endpoints (e.g., major pathologic response and pathological complete response) are emerging to accelerate the development and approval of neoadjuvant drugs. This review summarized the research progress in neoadjuvant therapy for locally advanced esophageal cancer and discussed which primary endpoint should be used in neoadjuvant therapy trials.
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Affiliation(s)
- Wenwei Yang
- National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yaru Niu
- National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yongkun Sun
- National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- National Cancer Center, National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang, 065001, China.
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2
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Sarma B, Sarma G, Nath J. Radiotherapy target volumes in esophageal cancer: The twisting kaleidoscope. JOURNAL OF RADIATION AND CANCER RESEARCH 2023. [DOI: 10.4103/jrcr.jrcr_25_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023] Open
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Valkema MJ, Mostert B, Lagarde SM, Wijnhoven BPL, van Lanschot JJB. The effectivity of targeted therapy and immunotherapy in patients with advanced metastatic and non-metastatic cancer of the esophagus and esophago-gastric junction. Updates Surg 2023; 75:313-323. [PMID: 35836094 PMCID: PMC9852184 DOI: 10.1007/s13304-022-01327-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/03/2022] [Indexed: 01/24/2023]
Abstract
Therapies that target specific tumor drivers or immune checkpoints are increasingly explored for esophageal cancer patients. This review addresses developments in therapies with targeted anti-human epidermal growth factor receptor 2 (HER2) agents and immune checkpoint inhibitors in patients with stage IV esophageal cancer. First-line palliative treatment with the anti-HER2 agent trastuzumab in combination with chemotherapy has been approved for use in patients with HER2 positive gastro-esophageal adenocarcinoma. Neoadjuvant chemoradiotherapy plus perioperative trastuzumab however has not demonstrated a survival benefit in advanced esophageal cancer patients eligible for surgery. Potentially better responses are expected with dual agent anti-HER2 therapy instead of monotherapy. In the metastatic setting, the antibody-drug conjugate trastuzumab deruxtecan is effective after progression on trastuzumab. Nivolumab and pembrolizumab, antibodies blocking the programmed cell death 1 (PD-1) receptor on T cells, have recently gained approval for clinical use in esophageal cancer patients for specific indications. Synergistic effects might be achieved with combinations of immune checkpoint inhibitors that target PD-1 on T cells or PD ligand 1 (PD-L1) on tumor cells and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) receptor on T cells. Multiple clinical trials investigating combinations of targeted and immunotherapies, with or without (neo)adjuvant chemo(radio)therapy, for curative and palliative treatment, are underway, and are expected to deliver a long-awaited improvement in the prognosis of esophageal cancer patients.
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Affiliation(s)
- M. J. Valkema
- Department of Surgery, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
| | - B. Mostert
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
| | - S. M. Lagarde
- Department of Surgery, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
| | - B. P. L. Wijnhoven
- Department of Surgery, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
| | - J. J. B. van Lanschot
- Department of Surgery, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
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Matani H, Sahu D, Paskewicz M, Gorbunova A, Omstead AN, Wegner R, Finley GG, Jobe BA, Kelly RJ, Zaidi AH, Goel A. Prognostic and predictive biomarkers for response to neoadjuvant chemoradiation in esophageal adenocarcinoma. Biomark Res 2022; 10:81. [PMCID: PMC9664643 DOI: 10.1186/s40364-022-00429-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/31/2022] [Indexed: 11/16/2022] Open
Abstract
Abstract
Background
Esophageal adenocarcinoma is a lethal disease. For locally advanced patients, neoadjuvant chemoradiotherapy followed by surgery is the standard of care. Risk stratification relies heavily on clinicopathologic features, particularly pathologic response, which is inadequate, therefore establishing the need for new and reliable biomarkers for risk stratification.
Methods
Thirty four patients with locally advanced esophageal adenocarcinoma were analyzed, of which 21 received a CROSS regimen with carboplatin, paclitaxel, and radiation. Capture-based targeted sequencing was performed on the paired baseline and post-treatment samples. Differentially mutated gene analysis between responders and non-responders of treatment was performed to determine predictors of response. A univariate Cox proportional hazard regression was used to examine associations between gene mutation status and overall survival.
Results
A 3-gene signature, based on mutations in EPHA5, BCL6, and ERBB2, was identified that robustly predicts response to the CROSS regimen. For this model, sensitivity was 84.6% and specificity was 100%. Independently, a 9 gene signature was created using APC, MAP3K6, ETS1, CSF3R, PDGFRB, GATA2, ARID1A, PML, and FGF6, which significantly stratifies patients into risk categories, prognosticating for improved relapse-free (p = 4.73E-03) and overall survival (p = 3.325E-06). The sensitivity for this model was 73.33% and the specificity was 94.74%.
Conclusion
We have identified a 3-gene signature (EPHA5, BCL6, and ERBB2) that is predictive of response to neoadjuvant chemoradiotherapy and a separate prognostic 9-gene classifier that predicts survival outcomes. These panels provide significant potential for personalized management of locally advanced esophageal cancer.
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Kumar R, Tchelebi L, Anker CJ, Sharma N, Bianchi NA, Dragovic J, Goodman KA, Herman JM, Jiang Y, Jones WE, Kennedy TJ, Lee P, Kundranda M, Russo S, Small W, Suh WW, Yee N, Jabbour SK. American Radium Society (ARS) Appropriate Use Criteria (AUC) for Locoregional Gastric Adenocarcinoma: Systematic Review and Guidelines. Am J Clin Oncol 2022; 45:391-402. [PMID: 35947781 PMCID: PMC10865426 DOI: 10.1097/coc.0000000000000930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The objective of this study was to systematically evaluate the data regarding the use of neoadjuvant, perioperative, surgical, and adjuvant treatment options in localized gastric cancer patients and to develop Appropriate Use Criteria recommended by a panel of experts convened by the American Radium Society. METHODS Preferred reporting items for systematic reviews and meta-analyses methodology was used to develop an extensive analysis of peer-reviewed phase 2/2R/3 trials, as well as meta-analyses found within the Ovid Medline database between 2010 and 2020. The expert panel then rated the appropriateness of various treatments in 5 representative clinical scenarios through a well-established consensus methodology (modified Delphi). RESULTS For patients with medically operable locally advanced gastric cancer, the strongest recommendation was for perioperative chemotherapy based on high-quality data. Acceptable alternatives included surgery followed by either chemotherapy or concurrent chemoradiotherapy (CRT). For patients with upfront resection of stages I to III gastric cancer (no neoadjuvant therapy), the group strongly recommended adjuvant therapy with either chemotherapy alone or CRT, based on high-quality data. For patients with locally advanced disease who received preoperative chemotherapy without tumor regression, the group strongly recommended postoperative chemotherapy or postoperative CRT. Finally, for medically inoperable gastric cancer patients, there was moderate consensus recommending definitive concurrent CRT. CONCLUSIONS The addition of chemotherapy and/or radiation, either in the neoadjuvant, adjuvant, or perioperative setting, results in improved survival rates for patients compared with surgery alone. For inoperable patients, definitive CRT is a reasonable treatment option, though largely palliative.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yixing Jiang
- UT Health Cancer Center, University of Texas Health Science Center, San Antonio
| | | | | | - Percy Lee
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Suzanne Russo
- School of Medicine, University Hospitals, Case Western Reserve University, Cleveland, OH
| | - William Small
- Department of Radiation Oncology, Stritch School of Medicine, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL
| | - Wonsuk W. Suh
- Ridley-Tree Cancer Center Santa Barbara at Sansum Clinic, Santa Barbara, CA
| | - Nelson Yee
- Northwell Health Cancer Institute, Mount Kisco
| | - Salma K. Jabbour
- Panel Chair, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
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Guimond E, Tsai CJ, Hosni A, O'Kane G, Yang J, Barry A. Safety and Tolerability of Metastasis Directed Radiotherapy in the Era of Evolving Systemic, Immune and Targeted Therapies. Adv Radiat Oncol 2022; 7:101022. [PMID: 36177487 PMCID: PMC9513086 DOI: 10.1016/j.adro.2022.101022] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 07/02/2022] [Indexed: 11/17/2022] Open
Abstract
AbstractPurpose Systemic, immune, and target therapies are growing in use in the management of metastatic cancers. The aim of this review was to describe up-to-date published data on the safety and tolerability of metastasis-directed hypofractionated radiation therapy (RT) when combined with newer systemic, immune, and targeted therapies and to provide suggested strategies to mitigate potential toxicities in the clinical setting. Methods and Materials A comprehensive search was performed for the time period between 1946 and August 2021 using predetermined keywords describing the use of noncentral nervous system palliative RT with commonly used targeted systemic therapies on PubMed and Medline databases. A total of 1022 articles were screened, and 130 met prespecified criteria to be included in this review. Results BRAF and MEK inhibitors are reported to be toxic when given concurrently with RT; suspension 3 days and 1 to 2 days, respectively, prior and post-RT is suggested. Cetuximab, erlotinib/gefitinib, and osimertinib were generally safe to use concomitantly with conventional radiation. But in a palliative/hypofractionated RT setting, suspending cetuximab during radiation week, erlotinib/gefitinib 1 to 2 days, and osimertinib ≥2 days pre- and post-RT is suggested. Vascular endothelial growth factor inhibitors such as bevacizumab reported substantial toxicities, and the suggestion is to suspend 4 weeks before and after radiation. Less data exist on sorafenib and sunitinib; 5 to 10 days suspension before and after RT should be considered. As a precaution, until further data are available, for cyclin-dependent kinase 4-6 inhibitors, consideration of suspending treatment 1 to 2 days before and after RT should be given. Ipilimumab should be suspended 2 days before and after RT, and insufficient data exist for other immunotherapy agents. Trastuzumab and pertuzumab are generally safe to use in combination with RT, but insufficient data exist for other HER2 target therapy. Conclusions Suggested approaches are described, using up-to-date literature, to aid clinicians in navigating the integration of newer targeted agents with hypofractionated palliative and/or ablative metastatic RT. Further prospective studies are required.
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Affiliation(s)
- Elizabeth Guimond
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada
- University of Toronto, Toronto, Ontario
- Corresponding author: Elizabeth Guimond, MD, FRCPC
| | - Chiaojung Jillian Tsai
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ali Hosni
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada
- University of Toronto, Toronto, Ontario
| | - Grainne O'Kane
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada
- University of Toronto, Toronto, Ontario
| | - Jonathan Yang
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Aisling Barry
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada
- University of Toronto, Toronto, Ontario
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Optimising Multimodality Treatment of Resectable Oesophago-Gastric Adenocarcinoma. Cancers (Basel) 2022; 14:cancers14030586. [PMID: 35158854 PMCID: PMC8833621 DOI: 10.3390/cancers14030586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/15/2022] [Accepted: 01/20/2022] [Indexed: 12/23/2022] Open
Abstract
Simple Summary Oesophageal (food pipe) and stomach cancers are amongst the hard-to-treat cancers that result in significant illness and deaths around the globe. Over the last few decades, there has been remarkable progress in the treatment of these cancers as a result of advances in diagnosis, surgical techniques, systemic therapy and radiotherapy. However, even if caught in the early stages, most patients with these cancers will unfortunately have their cancers come back, usually becoming widespread and difficult to treat. Therefore, optimising the early treatment strategy of these cancers is essential to improve the outcome and reduce the risk of recurrence. There are currently various geographically influenced standard of care management practices of early stomach and oesophageal cancers, ranging from using chemotherapy before and after surgery to the use of combined chemoradiotherapy before surgery and more recently the use of immunotherapy after surgery. However, it is not very clear if one strategy is significantly better than the others and there are some ongoing studies aiming to directly compare these treatment options. In addition, our understanding of the molecular and genetic features of these cancers can help improve our clinical practice and inform our choice of the best treatment strategy for the individual patient. Abstract Oesophago–gastric adenocarcinoma remains a leading cause of cancer-related morbidity and mortality worldwide. Although there has been an enormous progress in the multimodality management of resectable oesophago–gastric adenocarcinoma, most patients still develop a recurrent disease that eventually becomes resistant to systemic therapy. Currently, there is no global consensus on the optimal multimodality approach and there are variations in accepted standards of care, ranging from preoperative chemoradiation to perioperative chemotherapy and, more recently, adjuvant immune checkpoint inhibitors. Ongoing clinical trials are aimed to directly compare multimodal treatment options as well as the additional benefit of targeted therapies and immunotherapies. Furthermore, our understanding of the molecular and genetic features of oesophago–gastric cancer has improved significantly over the last decade and these data may help inform the best approach for the individual patient, utilising biomarker selection and precision medicine.
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Charalampakis N, Tsakatikas S, Schizas D, Kykalos S, Tolia M, Fioretzaki R, Papageorgiou G, Katsaros I, Abdelhakeem AAF, Sewastjanow-Silva M, Rogers JE, Ajani JA. Trimodality treatment in gastric and gastroesophageal junction cancers: Current approach and future perspectives. World J Gastrointest Oncol 2022; 14:181-202. [PMID: 35116110 PMCID: PMC8790425 DOI: 10.4251/wjgo.v14.i1.181] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/28/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric and gastroesophageal junction (GEJ) cancers represent an aggressive group of malignancies with poor prognosis even when diagnosed in relatively early stage, with an increasing incidence both in Asia and in Western countries. These cancers are characterized by heterogeneity as a result of different pathogenetic mechanisms as shown in recent molecular analyses. Accordingly, the understanding of phenotypic and genotypic correlations/classifications has been improved. Current therapeutic strategies have also advanced and moved beyond surgical extirpation alone, with the incorporation of other treatment modalities, such as radiation and chemotherapy (including biologics). Chemoradiotherapy has been used as postoperative treatment after suboptimal gastrectomy to ensure local disease control but also improvement in survival. Preoperative chemoradiotherapy/chemotherapy has been employed to increase the chance of a successful R0 resection and pathologic complete response rate, which is associated with improved long-term outcomes. Several studies have defined various chemotherapy regimens to accompany radiation (before and after surgery). Recently, addition of immunotherapy after trimodality of gastroesophageal cancer has produced an advantage in disease-free interval. Targeted agents used in the metastatic setting are being investigated in the early setting with mixed results. The aim of this review is to summarize the existing data on trimodality approaches for gastric and GEJ cancers, highlight the remaining questions and present the current research effort addressing them.
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Affiliation(s)
- Nikolaos Charalampakis
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus 18537, Greece
| | - Sergios Tsakatikas
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus 18537, Greece
| | - Dimitrios Schizas
- TheFirst Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens 11527, Greece
| | - Stylianos Kykalos
- TheSecond Propedeutic Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, Athens 11527, Greece
| | - Maria Tolia
- Department of Radiation Oncology, University Hospital of Crete, Heraklion 71110, Greece
| | - Rodanthi Fioretzaki
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus 18537, Greece
| | - Georgios Papageorgiou
- Department of Medical Oncology, Metaxa Cancer Hospital of Piraeus, Piraeus 18537, Greece
| | - Ioannis Katsaros
- Department of General Surgery, Metaxa Cancer Hospital of Piraeus, Piraeus 18537, Greece
| | - Ahmed Adel Fouad Abdelhakeem
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Matheus Sewastjanow-Silva
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Jane E Rogers
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
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El Gharib K, Khoury M, Kourie HR. HER2 in gastric adenocarcinoma: where do we stand today? Per Med 2021; 19:67-78. [PMID: 34881639 DOI: 10.2217/pme-2021-0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: HER2 is a proto-oncogene expressed in 10-30% of gastric adenocarcinomas and is an ideal target for inhibition in malignancy with high recurrence and dismal survival rates. Materials & methods: A systematic search was conducted via PubMed, Google Scholar and the clinicaltrials.gov database to report the results of ongoing and past studies investigating HER2 inhibitors in gastric cancer. Results: Twenty-five studies were included; ToGA trial is the pivotal trial approving the use of trastuzumab in metastatic gastric cancer, followed by more studies investigating other HER2 inhibitors in this setting, as well as in local and locoregional malignancy. Conclusion: Anti-HER2 molecules are proving efficacy and safety in gastric cancer; the evidence is growing and association with other cancer agents is under investigation.
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Affiliation(s)
- Khalil El Gharib
- Department of Internal Medicine, Staten Island University Hospital, NY 10305, USA
| | - Makram Khoury
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University, Beirut, 17-5208, Lebanon
| | - Hampig Raphael Kourie
- Hematology-Oncology Department, Faculty of Medicine, Saint Joseph University, Beirut, 17-5208, Lebanon
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Lin SH, Willers H, Krishnan S, Sarkaria JN, Baumann M, Lawrence TS. Moving Beyond the Standard of Care: Accelerate Testing of Radiation-Drug Combinations. Int J Radiat Oncol Biol Phys 2021; 111:1131-1139. [PMID: 34454045 PMCID: PMC9159468 DOI: 10.1016/j.ijrobp.2021.08.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 08/09/2021] [Indexed: 12/28/2022]
Abstract
Radiation therapy is a major treatment modality used in > 60% of cancer patients as definitive local treatment for inoperable locoregionally confined tumors and as palliative therapy. Although cytotoxic chemotherapy enhances the effectiveness of treatment, the benefit over radiation therapy alone is modest. There is a need to enhance the effectiveness of local tumor control over what sequentially or concurrently administered cytotoxic chemotherapy provides. Although many biological pathways are known to enhance the effectiveness of radiation therapy, there is currently a paucity of drugs approved for use in combination. Several clinical trials have tested the effectiveness of combining targeted agents or immunotherapies with radiation therapy, but the results of these trials have been negative, likely stemming from the relative lack of preclinical evidence using appropriate experimental standardization or model systems. Accelerating the identification of agents tested in an appropriate clinical context and experimental systems or models would greatly enhance the potential to bring forward early testing of drugs that would not only be safe but also more effective. This article provides an overview of the opportunities and challenges of developing therapeutics to combine with radiation therapy, and some guidance toward preclinical and early clinical testing to improve the chance that advanced phase testing of drug-radiation combinations would be successful in the long term.
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Affiliation(s)
- Steven H Lin
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Henning Willers
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Sunil Krishnan
- Department of Radiation Oncology, Mayo Clinic Jacksonville, Jacksonville, Florida
| | - Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic Rochester, Rochester, Minnesota
| | | | - Theodore S Lawrence
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan
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Cameron RB, Ajani JA, Wu AJ. Adjuvant nivolumab after preoperative chemoradiotherapy and surgery in esophageal cancer: A shifting paradigm. J Thorac Cardiovasc Surg 2021; 164:433-437. [PMID: 34663521 DOI: 10.1016/j.jtcvs.2021.08.082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/21/2021] [Accepted: 08/06/2021] [Indexed: 01/01/2023]
Affiliation(s)
- Robert B Cameron
- Division of Thoracic Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, Calif; Division of Thoracic Surgery, Department of Surgery and Perioperative Care, West Los Angeles VA Medical Center, Los Angeles, Calif.
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Tex
| | - Abraham J Wu
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
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12
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Vošmik M, Kopecký J, John S, Kubeček O, Lochman P, Banni AM, Hruška L, Sirák I. Combined Therapy of Locally Advanced Oesophageal and Gastro-Oesophageal Junction Adenocarcinomas: State of the Art and Aspects of Predictive Factors. Cancers (Basel) 2021; 13:4591. [PMID: 34572818 PMCID: PMC8469285 DOI: 10.3390/cancers13184591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 11/17/2022] Open
Abstract
The following main treatment approaches are currently used in locally advanced adenocarcinomas of the oesophagus and gastrooesophageal junction (GOJ): preoperative chemoradiotherapy and surgery, and perioperative chemotherapy and surgery. While preoperative chemoradiotherapy is used primarily in oesophageal tumours, perioperative chemotherapy is the treatment of choice in Western countries for gastric cancer. The optimal treatment strategy for GOJ adenocarcinoma is still not clear. In comparison to other malignancies, biomarkers are used as predictive factors in distal oesophageal and GOJ adenocarcinomas in a very limited way, and moreover, only in metastatic stages (e.g., HER2 status, or microsatellite instability status). The aim of the article is to provide an overview of current treatment options in locally advanced adenocarcinomas of oesophagus and GOJ based on the latest evidence, including the possible potential of predictive biomarkers in optimizing treatment.
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Affiliation(s)
- Milan Vošmik
- Department of Oncology and Radiotherapy, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, 500 05 Hradec Králové, Czech Republic; (J.K.); (S.J.); (O.K.); (A.M.B.); (L.H.); (I.S.)
| | - Jindřich Kopecký
- Department of Oncology and Radiotherapy, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, 500 05 Hradec Králové, Czech Republic; (J.K.); (S.J.); (O.K.); (A.M.B.); (L.H.); (I.S.)
| | - Stanislav John
- Department of Oncology and Radiotherapy, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, 500 05 Hradec Králové, Czech Republic; (J.K.); (S.J.); (O.K.); (A.M.B.); (L.H.); (I.S.)
| | - Ondřej Kubeček
- Department of Oncology and Radiotherapy, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, 500 05 Hradec Králové, Czech Republic; (J.K.); (S.J.); (O.K.); (A.M.B.); (L.H.); (I.S.)
| | - Petr Lochman
- Department of Surgery, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, 500 05 Hradec Králové, Czech Republic;
- Department of Field Surgery, Faculty of Military Health Sciences, University of Defence, 500 05 Hradec Králové, Czech Republic
| | - Aml Mustafa Banni
- Department of Oncology and Radiotherapy, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, 500 05 Hradec Králové, Czech Republic; (J.K.); (S.J.); (O.K.); (A.M.B.); (L.H.); (I.S.)
| | - Libor Hruška
- Department of Oncology and Radiotherapy, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, 500 05 Hradec Králové, Czech Republic; (J.K.); (S.J.); (O.K.); (A.M.B.); (L.H.); (I.S.)
| | - Igor Sirák
- Department of Oncology and Radiotherapy, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, 500 05 Hradec Králové, Czech Republic; (J.K.); (S.J.); (O.K.); (A.M.B.); (L.H.); (I.S.)
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Goodman KA, Ou FS, Hall NC, Bekaii-Saab T, Fruth B, Twohy E, Meyers MO, Boffa DJ, Mitchell K, Frankel WL, Niedzwiecki D, Noonan A, Janjigian YY, Thurmes PJ, Venook AP, Meyerhardt JA, O'Reilly EM, Ilson DH. Randomized Phase II Study of PET Response-Adapted Combined Modality Therapy for Esophageal Cancer: Mature Results of the CALGB 80803 (Alliance) Trial. J Clin Oncol 2021; 39:2803-2815. [PMID: 34077237 PMCID: PMC8407649 DOI: 10.1200/jco.20.03611] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/01/2021] [Accepted: 04/01/2021] [Indexed: 12/12/2022] Open
Abstract
PURPOSE To evaluate the use of early assessment of chemotherapy responsiveness by positron emission tomography (PET) imaging to tailor therapy in patients with esophageal and esophagogastric junction adenocarcinoma. METHODS After baseline PET, patients were randomly assigned to an induction chemotherapy regimen: modified oxaliplatin, leucovorin, and fluorouracil (FOLFOX) or carboplatin-paclitaxel (CP). Repeat PET was performed after induction; change in maximum standardized uptake value (SUV) from baseline was assessed. PET nonresponders (< 35% decrease in SUV) crossed over to the alternative chemotherapy during chemoradiation (50.4 Gy/28 fractions). PET responders (≥ 35% decrease in SUV) continued on the same chemotherapy during chemoradiation. Patients underwent surgery at 6 weeks postchemoradiation. Primary end point was pathologic complete response (pCR) rate in nonresponders after switching chemotherapy. RESULTS Two hundred forty-one eligible patients received Protocol treatment, of whom 225 had an evaluable repeat PET. The pCR rates for PET nonresponders after induction FOLFOX who crossed over to CP (n = 39) or after induction CP who changed to FOLFOX (n = 50) was 18.0% (95% CI, 7.5 to 33.5) and 20% (95% CI, 10 to 33.7), respectively. The pCR rate in responders who received induction FOLFOX was 40.3% (95% CI, 28.9 to 52.5) and 14.1% (95% CI, 6.6 to 25.0) in responders to CP. With a median follow-up of 5.2 years, median overall survival was 48.8 months (95% CI, 33.2 months to not estimable) for PET responders and 27.4 months (95% CI, 19.4 months to not estimable) for nonresponders. For induction FOLFOX patients who were PET responders, median survival was not reached. CONCLUSION Early response assessment using PET imaging as a biomarker to individualize therapy for patients with esophageal and esophagogastric junction adenocarcinoma was effective, improving pCR rates in PET nonresponders. PET responders to induction FOLFOX who continued on FOLFOX during chemoradiation achieved a promising 5-year overall survival of 53%.
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Affiliation(s)
| | - Fang-Shu Ou
- Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN
| | - Nathan C. Hall
- Hospital of the University of Pennsylvania, Philadelphia, PA
| | | | - Briant Fruth
- Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN
| | - Erin Twohy
- Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN
| | | | | | | | | | | | - Anne Noonan
- The Ohio State University Wexner Medical Center, Columbus, OH
| | | | - Paul J. Thurmes
- Metro Minnesota Community Oncology Research Consortium, Minneapolis, MN
| | - Alan P. Venook
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA
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14
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Siddiqui AZ, Almhanna K. Beyond Chemotherapy, PD-1, and HER-2: Novel Targets for Gastric and Esophageal Cancer. Cancers (Basel) 2021; 13:4322. [PMID: 34503132 PMCID: PMC8430615 DOI: 10.3390/cancers13174322] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/14/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Together, gastric cancer and esophageal cancer (EC) possess two of the highest incidence rates amongst all cancers. They exhibit poor prognoses in which the 5-year survival rate is dismal. In addition to cytotoxic chemotherapy, treatment efforts have been geared toward targeting human epidermal growth factor receptor 2 (HER-2), vascular endothelial growth factor (VEGF), and programmed death ligand-1 (PD-1). Although ample success has been recorded with these agents, gastric and esophageal cancer remain lethal, and further research into potential treatment alternatives is needed. In this article, we will review some of the targets at the forefront of investigation such as claudin, Dickkopf-related protein 1 (DKK-1), fibroblast growth factor receptor (FGFR), and matrix metalloproteinases (MMPs). These innovative target pathways are in the midst of clinical trials to be implemented in the treatment algorithm for this patient population. Ultimately, exploiting the oncogenic tendencies of these potential biomarkers creates an opportunity for precise treatment and improved prognosis for these cancers. Lastly, research aimed toward reversing PD-1 antibodies resistance by combining it with other novel agents or other treatment modalities is underway in order to expand existing treatment options for this patient population.
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Affiliation(s)
- Ali Zubair Siddiqui
- University of Mississippi Medical Center, University of Mississippi School of Medicine, Jackson, MS 39216, USA
| | - Khaldoun Almhanna
- The Brown University Oncology Research Group, The Rhode Island Hospital/Lifespan Cancer Institute, Providence, RI 02903, USA;
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15
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Grieb BC, Agarwal R. HER2-Directed Therapy in Advanced Gastric and Gastroesophageal Adenocarcinoma: Triumphs and Troubles. Curr Treat Options Oncol 2021; 22:88. [PMID: 34424404 PMCID: PMC8436174 DOI: 10.1007/s11864-021-00884-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2021] [Indexed: 01/22/2023]
Abstract
OPINION STATEMENT Gastric and gastroesophageal junction (GEJ) cancers represent the third leading cause of malignancy-associated death worldwide. Approximately 15-20% of these adenocarcinomas overexpress the human epidermal growth factor receptor 2 (HER2), a pro-proliferative receptor tyrosine kinase that has been therapeutically exploited in other disease contexts. The landmark ToGA trial demonstrated that trastuzumab, an anti-HER2 antibody, could improve overall survival for patients with HER2 overexpressing advanced gastric and GEJ adenocarcinomas. In the ensuing decade, great effort has been made to refine and expand this therapeutic strategy through a variety of avenues including optimization of chemotherapy backbones, identifying potential synergy with immune checkpoint inhibition, deployment of alternative HER2-targeted antibodies, use of small molecule inhibitors, and development of HER2-directed antibody drug conjugates. While the results of these efforts have had variable success, they have led to a greater understanding of the mechanisms of both primary and acquired resistance to HER2-directed therapies, laying the groundwork for future investigations. Recently, KEYNOTE-811 and DESTINY-Gastric01 have led to the FDA approvals of pembrolizumab in combination with trastuzumab and chemotherapy in the 1st-line advanced setting and trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki) in the 2nd-line setting, respectively. Herein, we review these significant works as well as discuss the ongoing investigations they have inspired, which aim to find and utilize additional means for targeting HER2 in gastric and GEJ cancers.
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Affiliation(s)
- Brian C Grieb
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Rajiv Agarwal
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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16
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Bordry N, Astaras C, Ongaro M, Goossens N, Frossard JL, Koessler T. Recent advances in gastrointestinal cancers. World J Gastroenterol 2021; 27:4493-4503. [PMID: 34366620 PMCID: PMC8326255 DOI: 10.3748/wjg.v27.i28.4493] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/11/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal cancers occur in a total of eight different locations, each of them with a different standard of care. This article is not an exhaustive review of what has been published in 2020. We have concentrated on the thirteen phase III randomized studies that are practice-changing. All these studies are oral presentations which have been given in one of the four major oncology congresses, namely American Society of Clinical Oncology (ASCO), ASCO gastrointestinal (GI), European Society of Medical Oncology (ESMO) and ESMO-GI. We provide a concise view of these major trials and their main outcomes, and put these results into context.
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Affiliation(s)
- Natacha Bordry
- Department of Oncology, University Hospital of Geneva (HUG), Genève 1205, Switzerland
| | - Christoforos Astaras
- Department of Oncology, University Hospital of Geneva (HUG), Genève 1205, Switzerland
| | - Marie Ongaro
- Divison of Gastroenterology and Hepatology, University Hospital of Geneva (HUG), Genève 1205, Switzerland
| | - Nicolas Goossens
- Divison of Gastroenterology and Hepatology, University Hospital of Geneva (HUG), Genève 1205, Switzerland
| | - Jean Louis Frossard
- Divison of Gastroenterology and Hepatology, University Hospital of Geneva (HUG), Genève 1205, Switzerland
| | - Thibaud Koessler
- Department of Oncology, University Hospital of Geneva (HUG), Genève 1205, Switzerland
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17
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Laxague F, Schlottmann F. Esophagogastric junction adenocarcinoma: Preoperative chemoradiation or perioperative chemotherapy? World J Clin Oncol 2021; 12:557-564. [PMID: 34367928 PMCID: PMC8317651 DOI: 10.5306/wjco.v12.i7.557] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/10/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
Multimodal treatment is currently the standard of care for locally advanced esophagogastric junction (EGJ) adenocarcinoma due to poor results after surgery alone. Neoadjuvant therapy is intended to shrink the tumor and eliminate potential circulating tumor cells. However, which neoadjuvant treatment is best for patients with EGJ tumors remains controversial. We aimed to compare outcomes of preoperative chemoradiation and perioperative chemotherapy for EGJ adenocarcinomas. For this purpose, we performed a thorough review of the literature describing neoadjuvant treatments for EGJ adenocarcinomas or comparing both therapies. Although some studies have shown better locoregional control and higher rates of complete pathologic response after chemoradiation, data suggest that both types of neoadjuvant therapy have similar survival benefits. As current data are heterogeneous and many studies have included significantly different types of patients in their analysis, future studies with better patient selection are still needed to define which neoadjuvant therapy should be chosen. In addition, targeted therapies and immunotherapy have promising results and should be further explored.
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Affiliation(s)
- Francisco Laxague
- Department of Surgery, Hospital Alemán of Buenos Aires, Buenos Aires 1118, Argentina
| | - Francisco Schlottmann
- Department of Surgery, Hospital Alemán of Buenos Aires, Buenos Aires 1118, Argentina
- Division of Esophageal and Gastric Surgery, Hospital Alemán of Buenos Aires, Buenos Aires 1118, Argentina
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18
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Stroes CI, van den Ende T, Derks S, van Laarhoven HWM. A systematic review of HER2 blockade for the curative treatment of gastroesophageal adenocarcinoma: Successes achieved and opportunities ahead. Cancer Treat Rev 2021; 99:102249. [PMID: 34171733 DOI: 10.1016/j.ctrv.2021.102249] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/11/2021] [Accepted: 06/13/2021] [Indexed: 01/29/2023]
Abstract
INTRODUCTION Despite multimodality treatment for curatively-treated gastroesophageal adenocarcinoma (GEA), prognosis remains dismal. The benefit of adding trastuzumab to chemotherapy for advanced Human Epidermal Growth Factor 2 (HER2) positive GEA has been established in the ToGA trial. However, it remains unclear if HER2 inhibition might also be beneficial in the curative setting. Therefore, we conducted a systematic review to investigate the role of HER2 inhibitors for the curative treatment of GEA. METHODS A systematic literature search was performed in PubMed, EMBASE, CENTRAL, and clinicaltrials.gov to identify clinical trials investigating HER2 inhibition for the curative treatment of GEA. Study quality was assessed using the GRADE methodology. RESULTS From the 1825 studies retrieved, 17 were included (seven published articles; three published conference abstracts; seven ongoing studies). From the published studies, eight studies investigated single-agent HER2 inhibition. Four studies had a nonrandomized design, and two were randomized controlled trials. Two published studies were assessed as high-quality. The addition of single-agent HER2 inhibition to chemo(radio)therapy showed a pathological complete response rate (pCR) of 22.2% (range, 9.6-25%) and dual HER2 inhibition of 34.5% (34-35%). Two-year disease-free survival (DFS) was 51.0% (40-71%) with single-agent and 70.0% (70-70%) with dual HER2 therapy. DISCUSSION Dual-agent HER2 inhibition showed promising pCR rates and DFS. Given the limited additional toxicity of the addition of HER2 targeting agents and the potential benefit of dual-targeting, further investigation is required in a phase III randomized clinical trial. Next steps include combining checkpoint inhibitors and HER2 blockade given the suggested synergism, as well as investigating new anti-HER2 agents.
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Affiliation(s)
- Charlotte I Stroes
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
| | - Tom van den Ende
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
| | - Sarah Derks
- Amsterdam UMC, VU University, Department of Medical Oncology, Cancer Center Amsterdam, De Boelelaan 1117, 1118, 1081HV Amsterdam, the Netherlands; Oncode Institute, Jaarbeursplein 6, 3521AL Utrecht, the Netherlands
| | - Hanneke W M van Laarhoven
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Cancer Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
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19
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Abstract
Trimodality therapy, or the use of concurrent chemoradiation followed by surgery, is the cornerstone of contemporary management of esophageal cancer. This article discusses the landmark trials and most current data to understand the concepts, applications, and outcomes from trimodality therapy in locally advanced esophageal cancer.
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Affiliation(s)
- Ammara A Watkins
- Division of Thoracic Surgery and Interventional Pulmonology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 185 Pilgrim Road, Boston, MA 02215, USA
| | - Jessica A Zerillo
- Division of Medical Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Shapiro 9, Boston, MA 02215, USA
| | - Michael S Kent
- Division of Thoracic Surgery and Interventional Pulmonology, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 185 Pilgrim Road, Boston, MA 02215, USA.
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20
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Jabbour SK, Williams TM, Sayan M, Miller ED, Ajani JA, Chang AC, Coleman N, El-Rifai W, Haddock M, Ilson D, Jamorabo D, Kunos C, Lin S, Liu G, Prasanna PG, Rustgi AK, Wong R, Vikram B, Ahmed MM. Potential Molecular Targets in the Setting of Chemoradiation for Esophageal Malignancies. J Natl Cancer Inst 2021; 113:665-679. [PMID: 33351071 PMCID: PMC8600025 DOI: 10.1093/jnci/djaa195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 10/03/2020] [Accepted: 11/30/2020] [Indexed: 11/14/2022] Open
Abstract
Although the development of effective combined chemoradiation regimens for esophageal cancers has resulted in statistically significant survival benefits, the majority of patients treated with curative intent develop locoregional and/or distant relapse. Further improvements in disease control and survival will require the development of individualized therapy based on the knowledge of host and tumor genomics and potentially harnessing the host immune system. Although there are a number of gene targets that are amplified and proteins that are overexpressed in esophageal cancers, attempts to target several of these have not proven successful in unselected patients. Herein, we review our current state of knowledge regarding the molecular pathways implicated in esophageal carcinoma, and the available agents for targeting these pathways that may rationally be combined with standard chemoradiation, with the hope that this commentary will guide future efforts of novel combinations of therapy.
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Affiliation(s)
- Salma K Jabbour
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA
| | - Terence M Williams
- Department of Radiation Oncology, The Ohio State University, Columbus, OH, USA
- Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Mutlay Sayan
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA
| | - Eric D Miller
- Department of Radiation Oncology, The Ohio State University, Columbus, OH, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew C Chang
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Department of Surgery, Section of Thoracic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Norman Coleman
- National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Wael El-Rifai
- Department of Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA
| | - Michael Haddock
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
| | - David Ilson
- Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | | | - Charles Kunos
- Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Steven Lin
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Geoffrey Liu
- Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada
| | - Pataje G Prasanna
- Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Anil K Rustgi
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Rosemary Wong
- Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Bhadrasain Vikram
- Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
| | - Mansoor M Ahmed
- Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
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21
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Hofheinz RD, Hegewisch-Becker S, Kunzmann V, Thuss-Patience P, Fuchs M, Homann N, Graeven U, Schulte N, Merx K, Pohl M, Held S, Keller R, Tannapfel A, Al-Batran SE. Trastuzumab in combination with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel as perioperative treatment for patients with human epidermal growth factor receptor 2-positive locally advanced esophagogastric adenocarcinoma: A phase II trial of the Arbeitsgemeinschaft Internistische Onkologie Gastric Cancer Study Group. Int J Cancer 2021; 149:1322-1331. [PMID: 34019698 DOI: 10.1002/ijc.33696] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/16/2021] [Accepted: 05/07/2021] [Indexed: 01/11/2023]
Abstract
Perioperative chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) is a mainstay in the treatment of esophagogastric adenocarcinomas (EGA). Trastuzumab improved survival when added to chemotherapy in patients with HER-2-positive metastatic EGA. We investigated the combination of trastuzumab and FLOT as perioperative treatment in patients with locally advanced EGA. A multicenter phase II study evaluated the efficacy and toxicity of perioperative FLOT (24-hours 5-FU 2600 mg/m2 , leucovorin 200 mg/m2 , oxaliplatin 85 mg/mg2 , docetaxel 50 mg/m2 , trastuzumab 6 mg/kg then 4 mg/kg d1, repeated d15 for four cycles preoperatively and postoperatively followed by 9 cycles of trastuzumab monotherapy) in patients with HER-2 positive EGA. Patients had ≥cT2, any N, M0 EGA. The primary endpoint was the rate of centrally assessed pathological complete response (pCR). Secondary endpoints comprised disease-free (DFS) and overall survival (OS), R0 resection rate, toxicity and surgical morbidity. Fifty-six evaluable patients (median age 62 years) were included; n = 40 had tumors originating from the esophagogastric junction; T stage was (cT2/3/4/unknown): 4/42/8/2; n = 50 patients had cN+ disease. Main adverse events grades 3-4: leukopenia (17.9%), neutropenia (46.6%) and diarrhea (17.0%). All patients underwent tumor resections. R0 resection rate was 92.9%. Eight patients had anastomotic leakage. One postoperative death occurred. pCR was found in 12 patients (21.4%) and a further n = 14 patients (25.0%) had near complete response. Median DFS was 42.5 months and the 3-year OS rate was 82.1%. The primary endpoint of achieving a pCR >20% was reached. No unexpected safety issues were observed. Survival data are promising.
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Affiliation(s)
- Ralf-Dieter Hofheinz
- Interdisziplinäres Tumorzentrum, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany
| | | | - Volker Kunzmann
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Peter Thuss-Patience
- Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, Charité, Universitätsmedizin Berlin, Berlin, Germany
| | - Martin Fuchs
- Klinikum Bogenhausen, Klinik für Gastroenterologie, Hepatologie, Gastroenterologische Onkologie München, München, Germany
| | - Nils Homann
- Medizinische Klinik II Wolfsburg, Wolfsburg, Germany
| | - Ullrich Graeven
- Klinik für Hämatologie, Onkologie und Gastroenterologie, Kliniken Mariahilf, Mönchengladbach, Germany
| | - Nadine Schulte
- Interdisziplinäres Tumorzentrum, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany
| | - Kirsten Merx
- Interdisziplinäres Tumorzentrum, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany
| | - Michael Pohl
- Medizinische Universitätsklinik Bochum, Knappschaftskrankenhaus, Bochum, Germany
| | | | | | - Andrea Tannapfel
- Institut für Pathologie der Ruhr-Universität Bochum, Bochum, Germany
| | - Salah-Eddin Al-Batran
- Institute of Clinical Cancer Research (IKF) at Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt am Main, Germany
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22
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Eyck BM, van Lanschot JJB, Hulshof MCCM, van der Wilk BJ, Shapiro J, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, Cuesta MA, Blaisse RJB, Busch OR, Creemers GJM, Punt CJA, Plukker JTM, Verheul HMW, Spillenaar Bilgen EJ, van der Sangen MJC, Rozema T, Ten Kate FJW, Beukema JC, Piet AHM, van Rij CM, Reinders JG, Tilanus HW, Steyerberg EW, van der Gaast A. Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial. J Clin Oncol 2021; 39:1995-2004. [PMID: 33891478 DOI: 10.1200/jco.20.03614] [Citation(s) in RCA: 404] [Impact Index Per Article: 101.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
PURPOSE Preoperative chemoradiotherapy according to the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer. We aimed to assess long-term outcome of this regimen. METHODS From 2004 through 2008, we randomly assigned 366 patients to either five weekly cycles of carboplatin and paclitaxel with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery, or surgery alone. Follow-up data were collected through 2018. Cox regression analyses were performed to compare overall survival, cause-specific survival, and risks of locoregional and distant relapse. The effect of neoadjuvant chemoradiotherapy beyond 5 years of follow-up was tested with time-dependent Cox regression and landmark analyses. RESULTS The median follow-up was 147 months (interquartile range, 134-157). Patients receiving neoadjuvant chemoradiotherapy had better overall survival (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.89). The effect of neoadjuvant chemoradiotherapy on overall survival was not time-dependent (P value for interaction, P = .73), and landmark analyses suggested a stable effect on overall survival up to 10 years of follow-up. The absolute 10-year overall survival benefit was 13% (38% v 25%). Neoadjuvant chemoradiotherapy reduced risk of death from esophageal cancer (HR, 0.60; 95% CI, 0.46 to 0.80). Death from other causes was similar between study arms (HR, 1.17; 95% CI, 0.68 to 1.99). Although a clear effect on isolated locoregional (HR, 0.40; 95% CI, 0.21 to 0.72) and synchronous locoregional plus distant relapse (HR, 0.43; 95% CI, 0.26 to 0.72) persisted, isolated distant relapse was comparable (HR, 0.76; 95% CI, 0.52 to 1.13). CONCLUSION The overall survival benefit of patients with locally advanced resectable esophageal or junctional cancer who receive preoperative chemoradiotherapy according to CROSS persists for at least 10 years.
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Affiliation(s)
- Ben M Eyck
- Department of Surgery, Erasmus Medical Center Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - J Jan B van Lanschot
- Department of Surgery, Erasmus Medical Center Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.,Formerly at Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Maarten C C M Hulshof
- Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Berend J van der Wilk
- Department of Surgery, Erasmus Medical Center Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Joel Shapiro
- Department of Surgery, Erasmus Medical Center Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Pieter van Hagen
- Department of Surgery, Erasmus Medical Center Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Mark I van Berge Henegouwen
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Bas P L Wijnhoven
- Department of Surgery, Erasmus Medical Center Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Hanneke W M van Laarhoven
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Geke A P Hospers
- Comprehensive Cancer Center, University of Groningen-University Medical Center Groningen, Groningen, the Netherlands
| | - Johannes J Bonenkamp
- Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Miguel A Cuesta
- Department of Surgery, Amsterdam University Medical Centers, Location VUmc, Amsterdam, the Netherlands
| | | | - Olivier R Busch
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Cornelis J A Punt
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.,Formerly at Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - John Th M Plukker
- Department of Surgery, University of Groningen-University Medical Center Groningen, Groningen, the Netherlands
| | - Henk M W Verheul
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.,Formerly at Department of Medical Oncology, Amsterdam University Medical Centers, Location VUmc, Amsterdam, the Netherlands
| | | | | | - Tom Rozema
- Verbeeten Institute, Tilburg, the Netherlands.,Formerly at Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Fiebo J W Ten Kate
- Formerly at Department of Pathology, Erasmus MC-University Medical Center Rotterdam, the Netherlands
| | - Jannet C Beukema
- Department of Radiation Oncology, University of Groningen-University Medical Center Groningen, Groningen, the Netherlands
| | - Anna H M Piet
- Department of Radiation Oncology, Amsterdam University Medical Center, Location VUmc, Amsterdam, the Netherlands
| | - Caroline M van Rij
- Department of Radiation Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | | | - Hugo W Tilanus
- Formerly at Department of Surgery, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Ewout W Steyerberg
- Department of Public Health, Erasmus MC-University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
| | - Ate van der Gaast
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
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23
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Zhu Y, Zhu X, Wei X, Tang C, Zhang W. HER2-targeted therapies in gastric cancer. Biochim Biophys Acta Rev Cancer 2021; 1876:188549. [PMID: 33894300 DOI: 10.1016/j.bbcan.2021.188549] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/27/2021] [Accepted: 04/14/2021] [Indexed: 02/07/2023]
Abstract
Molecular targeted therapy of cancer has always been the focus of clinicians. Among those therapeutic targets, the human epidermal growth factor receptor-2 (HER-2) signaling pathway is one of the most popular targets for translational research in cancer. However, unlike prospect in breast cancer, HER-2 inhibitor trastuzumab is the only molecular targeted drug approved by US Food and Drug Administration (FDA) for the first-line treatment of HER-2 positive advanced gastric cancer. On this basis, a variety of novel HER2- targeted drugs for gastric cancer are under development, and related clinical researches are in full swing, including small molecular kinase inhibitors (e.g., afatinib, neratinib, pyrotinib), antibody-drug conjugates (e.g., DS-8201a, RC48-ADC) and other novel therapies (e.g., ZW25, CAR-T, BVAC-B). In this study, we will summarize the recent advances in anti-HER-2 agents, potential mechanisms of resistance to HER2-targeted therapy in HER2-positive gastric cancer. We will also discuss the future prospects of potential strategies to overcome anti-HER-2 resistance and development of novel anti-HER-2 approaches for the treatment of HER2-positive gastric cancer patients.
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Affiliation(s)
- Yinxing Zhu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Xuedan Zhu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Xiaowei Wei
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Cuiju Tang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
| | - Wenwen Zhang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
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24
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Lau DK, Athauda A, Chau I. Neoadjuvant and adjuvant multimodality therapies in resectable esophagogastric adenocarcinoma. Expert Opin Pharmacother 2021; 22:1429-1441. [PMID: 33688789 DOI: 10.1080/14656566.2021.1900823] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: Gastric and esophageal adenocarcinoma is a leading cause of cancer-related death globally. Surgery is the cornerstone modality for cure where feasible. Clinical studies over the past two decades have provided evidence for the use of perioperative chemotherapy and chemoradiotherapy to improve patient outcomes. However, there remains no global consensus in the optimal use of these therapies.Areas covered: In this review, the authors summarize the latest evidence for perioperative multimodality therapy in resectable esophagogastric adenocarcinoma including the use of combination chemotherapy and targeted therapy containing regimens. In addition, the authors discuss some of the clinical and molecular biomarkers, such as PET imaging and microsatellite instability which can inform future practice and further clinical investigation.Expert opinion: A multimodal approach has been proven to improve survival outcomes over surgery alone. Whilst there is no global standard of care for multi-modality therapies in resectable OG cancer, clinical trials are refining the use of chemotherapy and radiotherapy in the neoadjuvant and adjuvant settings. Further investigation is on-going to further optimize therapy and the integration of molecular targeted agents.
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Affiliation(s)
- David K Lau
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton and London, UK
| | - Avani Athauda
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton and London, UK
| | - Ian Chau
- GI and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton and London, UK
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25
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Cummings D, Wong J, Palm R, Hoffe S, Almhanna K, Vignesh S. Epidemiology, Diagnosis, Staging and Multimodal Therapy of Esophageal and Gastric Tumors. Cancers (Basel) 2021; 13:582. [PMID: 33540736 PMCID: PMC7867245 DOI: 10.3390/cancers13030582] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/14/2021] [Accepted: 01/25/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric and esophageal tumors are diverse neoplasms that involve mucosal and submucosal tissue layers and include squamous cell carcinomas, adenocarcinomas, spindle cell neoplasms, neuroendocrine tumors, marginal B cell lymphomas, along with less common tumors. The worldwide burden of esophageal and gastric malignancies is significant, with esophageal and gastric cancer representing the ninth and fifth most common cancers, respectively. The approach to diagnosis and staging of these lesions is multimodal and includes a combination of gastrointestinal endoscopy, endoscopic ultrasound, and cross-sectional imaging. Likewise, therapy is multidisciplinary and combines therapeutic endoscopy, surgery, radiotherapy, and systemic chemotherapeutic tools. Future directions for diagnosis of esophageal and gastric malignancies are evolving rapidly and will involve advances in endoscopic and endosonographic techniques including tethered capsules, optical coherence tomography, along with targeted cytologic and serological analyses.
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Affiliation(s)
- Donelle Cummings
- Division of Gastroenterology and Hepatology, Department of Medicine, New York Medical College, New York City Health and Hospitals Corporation-Metropolitan Hospital Center, 1901 First Avenue, New York, NY 10029, USA;
| | - Joyce Wong
- Division of Surgery, Mid Atlantic Kaiser Permanente, 700 2nd St. NE, 6th Floor, Washington, DC 20002, USA;
| | - Russell Palm
- Department of Radiation Oncology, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA; (R.P.); (S.H.)
| | - Sarah Hoffe
- Department of Radiation Oncology, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA; (R.P.); (S.H.)
| | - Khaldoun Almhanna
- Division of Hematology/Oncology, Lifespan Cancer Institute, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 593 Eddy St, George 312, Providence, RI 02903, USA;
| | - Shivakumar Vignesh
- Division of Gastroenterology and Hepatology, Department of Medicine, SUNY Downstate Health Sciences University, MSC 1196, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
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26
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Rivera F, Izquierdo-Manuel M, García-Alfonso P, Martínez de Castro E, Gallego J, Limón ML, Alsina M, López L, Galán M, Falcó E, Manzano JL, González E, Muñoz-Unceta N, López C, Aranda E, Fernández E, Jorge M, Jiménez-Fonseca P. Perioperative trastuzumab, capecitabine and oxaliplatin in patients with HER2-positive resectable gastric or gastro-oesophageal junction adenocarcinoma: NEOHX phase II trial. Eur J Cancer 2021; 145:158-167. [PMID: 33485079 DOI: 10.1016/j.ejca.2020.12.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/30/2020] [Accepted: 12/02/2020] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Perioperative chemotherapy improves overall survival (OS) and disease-free survival (DFS) compared with surgery alone in patients with resectable gastric adenocarcinoma (GA) or gastro-oesophageal junction adenocarcinoma (GEJA). The addition of trastuzumab to chemotherapy improves outcomes in patients with HER2-positive advanced gastric cancer (GC), and we aimed to explore its role in the perioperative setting. MATERIAL AND METHODS This Spanish, multicentre, open-label phase II trial evaluated the efficacy and toxicity of perioperative capecitabine, oxaliplatin and trastuzumab (XELOX-T) in patients with HER2-positive resectable GA or GEJA. The primary end-point was 18-months DFS; and secondary end-points included pathological complete response (pCR) rate, R0 resection rate, OS and toxicity (NCT01130337). RESULTS Thirty-six patients were included. After three cycles of preoperative treatment, 14 patients (38% of the intention-to-treat population) had partial response and 18 (50%) had stable disease. Surgery was performed in 31 patients: 28 (90%) had R0 resection, three (9.6%) had a pCR and three (9.6%) died due to surgical complications. A total of 24 patients received post-operative XELOX-T, 22 of whom completed trastuzumab maintenance. Main grade III/IV toxicities included diarrhoea (33%), nausea and vomiting (8%). After a median follow-up of 24.1 months, 18-month DFS was 71% (95% confidence interval [CI], 53-83%); and an update after 102 months of follow-up showed a median OS of 79.9 months and a 60-month OS of 58% (95% CI, 40-73%). CONCLUSIONS These data suggest that perioperative XELOX-T in patients with HER2-positive GA and GEJA is feasible and active. Further investigation in randomised studies is warranted.
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Affiliation(s)
- Fernando Rivera
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
| | | | - Pilar García-Alfonso
- Medical Oncology Department, Hospital Universitario Gregorio Marañón, Madrid, Spain.
| | - Eva Martínez de Castro
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
| | - Javier Gallego
- Medical Oncology Department, Hospital General Universitario de Elche, Alicante, Spain.
| | - María Luisa Limón
- Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
| | - María Alsina
- Medical Oncology Department, Hospital Universitari Vall d'Hebron and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
| | - Luis López
- Medical Oncology Department, Hospital Universitario Virgen de la Salud, Toledo, Spain.
| | - Maica Galán
- Medical Oncology Department, Institut Catala d'Oncologia (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.
| | - Esther Falcó
- Medical Oncology Department, Hospital Universitario Sont Llatzer, Palma de Mallorca, Spain.
| | - José Luis Manzano
- Medical Oncology Department, Institut Catala d'Oncologia (ICO), Hospital Universitario Germans Trias i Pujol, Badalona, Spain.
| | - Encarna González
- Medical Oncology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain.
| | - Nerea Muñoz-Unceta
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
| | - Carlos López
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
| | - Enrique Aranda
- Medical Oncology Department, Hospital Universitario Reina Sofía, IMIBIC, UCO, Córdoba, Spain.
| | - Eva Fernández
- Medical Oncology Department, Hospital Universitario de Valme, Sevilla, Spain.
| | - Mónica Jorge
- Medical Oncology Department, Hospital Xeral Cies, Vigo, Spain.
| | - Paula Jiménez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.
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27
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Anker CJ, Dragovic J, Herman JM, Bianchi NA, Goodman KA, Jones WE, Kennedy TJ, Kumar R, Lee P, Russo S, Sharma N, Small W, Suh WW, Tchelebi LT, Jabbour SK. Executive Summary of the American Radium Society Appropriate Use Criteria for Operable Esophageal and Gastroesophageal Junction Adenocarcinoma: Systematic Review and Guidelines. Int J Radiat Oncol Biol Phys 2021; 109:186-200. [PMID: 32858113 DOI: 10.1016/j.ijrobp.2020.08.050] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE Limited guidance exists regarding the relative effectiveness of treatment options for nonmetastatic, operable patients with adenocarcinoma of the esophagus or gastroesophageal junction (GEJ). In this systematic review, the American Radium Society (ARS) gastrointestinal expert panel convened to develop Appropriate Use Criteria (AUC) evaluating how neoadjuvant and/or adjuvant treatment regimens compared with each other, surgery alone, or definitive chemoradiation in terms of response to therapy, quality of life, and oncologic outcomes. METHODS AND MATERIALS Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) methodology was used to develop an extensive analysis of peer-reviewed phase 2R and phase 3 randomized controlled trials as well as meta-analyses found within the Ovid Medline, Cochrane Central, and Embase databases between 2009 to 2019. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in 4 broadly representative clinical scenarios through a well-established consensus methodology (modified Delphi). RESULTS For a medically operable nonmetastatic patient with a cT3 and/or cN+ adenocarcinoma of the esophagus or GEJ (Siewert I-II), the panel most strongly recommends neoadjuvant chemoradiation. For a cT2N0M0 patient with high-risk features, the panel recommends neoadjuvant chemoradiation as usually appropriate. For patients found to have pathologically involved nodes (pN+) who did not receive any neoadjuvant therapy, the panel recommends adjuvant chemoradiation as usually appropriate. These guidelines assess the appropriateness of various dose-fractionating schemes and target volumes. CONCLUSIONS Chemotherapy and/or radiation regimens for esophageal cancer are still evolving with many areas of active investigation. These guidelines are intended for the use of practitioners and patients who desire information about the management of operable esophageal adenocarcinoma.
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Affiliation(s)
- Christopher J Anker
- Division of Radiation Oncology, University of Vermont Larner College of Medicine, Burlington, Vermont.
| | - Jadranka Dragovic
- Department of Radiation Oncology, Henry Ford Cancer Institute, Henry Ford Hospital, Detroit, Michigan
| | - Joseph M Herman
- Department of Radiation Medicine, Zucker School of Medicine at Hofstra/Northwell, Lake Success, New York
| | - Nancy A Bianchi
- Department of Reference and Education, Dana Medical Library, University of Vermont, Burlington, Vermont
| | - Karyn A Goodman
- Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York City, New York
| | - William E Jones
- Department of Radiation Oncology, UT Health Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - Timothy J Kennedy
- Department of Surgical Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
| | - Rachit Kumar
- Division of Radiation Oncology, Banner MD Anderson Cancer Center, Gilbert, Arizona
| | - Percy Lee
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Suzanne Russo
- Department of Radiation Oncology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio
| | - Navesh Sharma
- Department of Radiation Oncology, Penn State Cancer Institute, Hershey, Pennsylvania
| | - William Small
- Department of Radiation Oncology, Loyola University Chicago, Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, Illinois
| | - W Warren Suh
- Department of Radiation Oncology, University of California at Los Angeles, Ridley-Tree Cancer Center, Santa Barbara, California
| | - Leila T Tchelebi
- Department of Radiation Oncology, Penn State Cancer Institute, Hershey, Pennsylvania
| | - Salma K Jabbour
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
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28
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Abstract
PURPOSE OF REVIEW To provide an up-to-date review on the management of cancers of the stomach and esophagogastric junction (EGJ). RECENT FINDINGS Microsatellite instable (MSI) high status in gastric cancer may portend a relatively good prognosis and indicate that adjuvant chemotherapy is of no added benefit to primary surgical management. In the preoperative treatment of HER2 (ErbB2)-positive EGJ adenocarcinoma with chemoradiotherapy, the addition of trastuzumab, a recombinant humanized mAb directed against the extracellular domain of Her2, failed to improve outcome over conventional chemoradiotherapy alone. Escalating the dose of radiation in combined chemoradiotherapy regimens did not improve survival over conventional dose radiotherapy in the nonoperative management of EGJ cancer. The use of proton vs. conventional external beam radiation therapy, although potentially less toxic, did not improve therapy outcome with preoperative or definitive chemoradiotherapy in EGJ cancer. In metastatic HER2-positive gastric cancer, after disease progression on trastuzumab, continuation of trastuzumab did not improve progression free or overall survival compared with second-line chemotherapy alone. However, in the setting or prior trastuzumab therapy in metastatic HER2-positive gastric cancer, the new agent trastuzumab deruxtecan achieved significant rates of response, progression free and overall survival compared with standard chemotherapy. After initial chemotherapy for metastatic esophagogastric cancer, maintenance therapy with the anti PDL-1 agent avelumab was no better than chemotherapy alone. SUMMARY MSI high gastric cancer has a better prognosis and may not require adjuvant chemotherapy. Trastuzumab, added to preoperative chemoradiotherapy in HER2-positive esophageal adenocarcinoma, does not improve outcome. Dose escalation of radiotherapy in the nonoperative management of EGJ cancer does not improve local control or survival, and proton therapy may not achieve superior outcomes compared with external beam radiotherapy. In metastatic HER2-positive gastric cancer, continuing trastuzumab into second-line chemotherapy does not add benefit; however, the novel agent trastuzumab deruxtecan has substantial activity after prior trastuzumab-based therapy.
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29
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Khalafi S, Lockhart AC, Livingstone AS, El-Rifai W. Targeted Molecular Therapies in the Treatment of Esophageal Adenocarcinoma, Are We There Yet? Cancers (Basel) 2020; 12:E3077. [PMID: 33105560 PMCID: PMC7690268 DOI: 10.3390/cancers12113077] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/14/2020] [Accepted: 10/20/2020] [Indexed: 02/07/2023] Open
Abstract
Esophageal adenocarcinoma is one of the leading causes of cancer-related deaths worldwide. The incidence of esophageal adenocarcinoma has increased at an alarming rate in the Western world and long-term survival remains poor. Current treatment approaches involve a combination of surgery, chemotherapy, and radiotherapy. Unfortunately, standard first-line approaches are met with high rates of recurrence and metastasis. More recent investigations into the distinct molecular composition of these tumors have uncovered key genetic and epigenetic alterations involved in tumorigenesis and progression. These discoveries have driven the development of targeted therapeutic agents in esophageal adenocarcinoma. While many agents have been studied, therapeutics targeting the human epidermal growth factor receptor (HER2) and vascular endothelial growth factor (VEGF) pathways have demonstrated improved survival. More recent advances in immunotherapies have also demonstrated survival advantages with monoclonal antibodies targeting the programmed death ligand 1 (PD-L1). In this review we highlight recent advances of targeted therapies, specifically agents targeting receptor tyrosine kinases, small molecule kinase inhibitors, and immune checkpoint inhibitors. While targeted therapeutics and immunotherapies have significantly improved survival, the benefits are limited to patients whose tumors express biomarkers such as PD-L1 and HER2. Survival remains poor for the remainder of patients with esophageal adenocarcinoma, underscoring the critical need for development of novel treatment strategies.
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Affiliation(s)
- Shayan Khalafi
- Department of Surgery, Miler School of Medicine, University of Miami, Miami, FL 33136, USA; (S.K.); (A.S.L.)
| | - Albert Craig Lockhart
- Department of Medicine, Miler School of Medicine, University of Miami, Miami, FL 33136, USA;
- Sylvester Comprehensive Cancer Center, Miler School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Alan S. Livingstone
- Department of Surgery, Miler School of Medicine, University of Miami, Miami, FL 33136, USA; (S.K.); (A.S.L.)
| | - Wael El-Rifai
- Department of Surgery, Miler School of Medicine, University of Miami, Miami, FL 33136, USA; (S.K.); (A.S.L.)
- Department of Medicine, Miler School of Medicine, University of Miami, Miami, FL 33136, USA;
- Department of Veterans Affairs, Miami Healthcare System, Miami, FL 33136, USA
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