REVIEW ARTICLE
Systemic therapy for gastric cancer: Perioperative strategies and beyond
Christopher Cann MD,
Kristen K. Ciombor MD, MSCI,
Christopher Cann MD
Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorCorresponding Author
Kristen K. Ciombor MD, MSCI
Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Correspondence: Kristen K. Ciombor, MD, MSCI, Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, 777 Preston Research Bldg, 2220 Pierce Ave, Nashville, TN 37232, USA.
Email: [email protected]
Search for more papers by this authorChristopher Cann MD,
Kristen K. Ciombor MD, MSCI,
Christopher Cann MD
Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Search for more papers by this authorCorresponding Author
Kristen K. Ciombor MD, MSCI
Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Correspondence: Kristen K. Ciombor, MD, MSCI, Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, 777 Preston Research Bldg, 2220 Pierce Ave, Nashville, TN 37232, USA.
Email: [email protected]
Search for more papers by this authorAbstract
Each year, gastric cancer claims the lives of hundreds of thousands of patients worldwide. Despite surgical resection, the risk of residual disease, micrometastatic disease, and disease recurrence remain elevated. Herein, we review systemic therapy strategies in the neoadjuvant, adjuvant, and metastatic settings, including novel uses of immunotherapy, targeted therapies and cytotoxic chemotherapies, for the treatment of gastric cancer.
Open Research
DATA AVAILABILITY STATEMENT
Data are available from the corresponding author upon reasonable request.
REFERENCES
- 1Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014; 64(1): 9-29.
- 2 SEER Surveillance, Epidemiology and End Results Program 2022; https://seer.cancer.gov/statfacts/html/stomach.html, 2022.
- 3Zhu AL, Sonnenberg A. Is gastric cancer again rising? J Clin Gastroenterol. 2012; 46(9): 804-806.
- 4Correa P. Gastric cancer: two epidemics? Dig Dis Sci. 2011; 56(5): 1585-1586.
- 5Anderson WF, Camargo MC, Fraumeni JF, Jr., Correa P, Rosenberg PS, Rabkin CS. Age-specific trends in incidence of noncardia gastric cancer in US adults. JAMA. 2010; 303(17): 1723-1728.
- 6Wanebo HJ, Kennedy BJ, Chmiel J, Steele G, Jr., Winchester D, Osteen R. Cancer of the stomach. A patient care study by the American College of Surgeons. Ann Surg. 1993; 218(5): 583-592.
- 7Ronellenfitsch U, Schwarzbach M, Hofheinz R, et al. Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: systematic review with meta-analysis combining individual patient and aggregate data. Eur J Cancer. 2013; 49(15): 3149-3158.
- 8Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006; 355(1): 11-20.
- 9Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019; 393(10184): 1948-1957.
- 10Bang YJ, Van Cutsem E, Fuchs CS, et al. KEYNOTE-585: phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer. Future Oncol. 2019; 15(9): 943-952.
- 11Kaltenmeier C, Althans A, Mascara M, et al. Pathologic complete response following neoadjuvant therapy for gastric adenocarcinoma: a national cancer database analysis on incidence, predictors, and outcomes. Am Surg. 2021; 87(7): 1145-1154.
- 12Li Z, Shan F, Wang Y, et al. Correlation of pathological complete response with survival after neoadjuvant chemotherapy in gastric or gastroesophageal junction cancer treated with radical surgery: a meta-analysis. PLoS One. 2018; 13(1):e0189294.
- 13Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001; 345(10): 725-730.
- 14Smalley SR, Benedetti JK, Haller DG, et al. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol. 2012; 30(19): 2327-2333.
- 15Fuchs CS, Niedzwiecki D, Mamon HJ, et al. Adjuvant chemoradiotherapy with epirubicin, cisplatin, and fluorouracil compared with adjuvant chemoradiotherapy with fluorouracil and leucovorin after curative resection of gastric cancer: results from CALGB 80101 (Alliance). J Clin Oncol. 2017; 35(32): 3671-3677.
- 16Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet. 2012; 379(9813): 315-321.
- 17Noh SH, Park SR, Yang HK, et al. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol. 2014; 15(12): 1389-1396.
- 18Park SH, Sohn TS, Lee J, et al. Phase III trial to compare adjuvant chemotherapy with capecitabine and cisplatin versus concurrent chemoradiotherapy in gastric cancer: final report of the adjuvant chemoradiotherapy in stomach tumors trial, including survival and subset analyses. J Clin Oncol. 2015; 33(28): 3130-3136.
- 19Park SH, Lim DH, Sohn TS, et al. A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial. Ann Oncol. 2021; 32(3): 368-374.
- 20Lordick F, Nilsson M, Leong T. Adjuvant radiotherapy for gastric cancer-end of the road? Ann Oncol. 2021; 32(3): 287-289.
- 21Cats A, Jansen EPM, van Grieken NCT, et al. Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial. Lancet Oncol. 2018; 19(5): 616-628.
- 22de Steur WO, van Amelsfoort RM, Hartgrink HH, et al. Adjuvant chemotherapy is superior to chemoradiation after D2 surgery for gastric cancer in the per-protocol analysis of the randomized CRITICS trial. Ann Oncol. 2021; 32(3): 360-367.
- 23Wagner AD, Syn NL, Moehler M, et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017; 8:CD004064.
- 24Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer. Lancet. 2016; 388(10060): 2654-2664.
- 25King CR, Kraus MH, Aaronson SA. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science. 1985; 229(4717): 974-976.
- 26Klapper LN, Glathe S, Vaisman N, et al. The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc Natl Acad Sci U S A. 1999; 96(9): 4995-5000.
- 27Petit AM, Rak J, Hung MC, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol. 1997; 151(6): 1523-1530.
- 28Park YS, Hwang HS, Park HJ, et al. Comprehensive analysis of HER2 expression and gene amplification in gastric cancers using immunohistochemistry and in situ hybridization: which scoring system should we use? Hum Pathol. 2012; 43(3): 413-422.
- 29Barros-Silva JD, Leitão D, Afonso L, et al. Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients. Br J Cancer. 2009; 100(3): 487-493.
- 30Takehana T, Kunitomo K, Kono K, et al. Status of c-erbB-2 in gastric adenocarcinoma: a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay. Int J Cancer. 2002; 98(6): 833-837.
- 31Albarello L, Pecciarini L, Doglioni C. HER2 testing in gastric cancer. Adv Anat Pathol. 2011; 18(1): 53-59.
- 32Bartley AN, Washington MK, Ventura CB, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med. 2016; 140(12): 1345-1363.
- 33Van Cutsem E, Bang YJ, Feng-Yi F, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015; 18(3): 476-484.
- 34Ieni A, Barresi V, Giuffrè G, et al. HER2 status in advanced gastric carcinoma: a retrospective multicentric analysis from Sicily. Oncol Lett. 2013; 6(6): 1591-1594.
- 35Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376(9742): 687-697.
- 36Makiyama A, Sukawa Y, Kashiwada T, et al. Randomized, phase II study of trastuzumab beyond progression in patients with HER2-positive advanced gastric or gastroesophageal junction cancer: WJOG7112G (T-ACT Study). J Clin Oncol. 2020; 38(17): 1919-1927.
- 37Tabernero J, Hoff PM, Shen L, et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018; 19(10): 1372-1384.
- 38Satoh T, Xu RH, Chung HC, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN: a randomized, phase III study. J Clin Oncol. 2014; 32(19): 2039-2049.
- 39Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 2020; 382(25): 2419-2430.
- 40Hindson J. KEYNOTE-811: pembrolizumab in advanced HER2(+) gastric cancer. Nat Rev Gastroenterol Hepatol. 2022; 19: 79.
- 41Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite Instability as a Biomarker for PD-1 Blockade. Clin Cancer Res. 2016; 22(4): 813-820.
- 42Yan L, Zhang W. Precision medicine becomes reality-tumor type-agnostic therapy. Cancer Commun (Lond). 2018; 38(1): 6.
- 43Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017; 357(6349): 409-413.
- 44 Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487(7407): 330-337.
- 45Howitt BE, Shukla SA, Sholl LM, et al. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol. 2015; 1(9): 1319-1323.
- 46Lee V, Murphy A, Le DT, Diaz LA, Jr. Mismatch repair deficiency and response to immune checkpoint blockade. Oncologist. 2016; 21(10): 1200-1211.
- 47Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021; 398(10294): 27-40.
- 48Kang YK, Chen LT, Ryu MH, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022; 23: 234-247.
- 49Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020; 38(1): 1-10.
- 50Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011; 29(30): 3968-3976.
- 51Chen Z, Yuan J, Xu Y, et al. From AVATAR mice to patients: RC48-ADC exerted promising efficacy in advanced gastric cancer with HER2 expression. Front Pharmacol. 2021; 12:757994.
- 52Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014; 383(9911): 31-39.
- 53Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15(11): 1224-1235.
- 54Chakrabarti S, Wintheiser G, Tella SH, Oxencis C, Mahipal A. TAS-102: a resurrected novel fluoropyrimidine with expanding role in the treatment of gastrointestinal malignancies. Pharmacol Ther. 2021; 224:107823.
- 55Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015; 372(20): 1909-1919.
- 56Shitara K, Doi T, Dvorkin M, et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018; 19(11): 1437-1448.
- 57Ilson DH, Tabernero J, Prokharau A, et al. Efficacy and safety of trifluridine/tipiracil treatment in patients with metastatic gastric cancer who had undergone gastrectomy: subgroup analyses of a randomized clinical trial. JAMA Oncol. 2020; 6(1):e193531.
Citing Literature
