Summary
Despite recent advances in the treatment of gastric cancer, mortality related to this disease is still substantial. Surgery and chemotherapy represent the cornerstones of patient management. Targeted treatments that include anti-angiogenic agents and the advent of immunotherapies can contribute to improved patient prognosis. Herein, we present an Austrian consensus on the systemic treatment of patients with gastric adenocarcinoma and lower gastroesophageal junction, including those with human epidermal growth factor receptor 2 (HER2)-positive disease. The consensus considers the curative setting, as well as first-line to late-line systemic treatment options in the palliative setting. For HER2-positive disease, first-line and second-line therapies are discussed, as well as HER2 testing. Potential future therapies are also listed, with a focus on anti-angiogenic treatments and checkpoint inhibition, which might provide a further step forward in the management of patients with gastric cancer.
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References
Noone AM, Howlader N, Krapcho M, Miller D, Bishop K, Altekruse SF, et al. SEER cancer statistics review, 1975–2013, National Cancer Institute. Bethesda, MD, USA. 2015. http://seer.cancer.gov/csr/1975_2013/ (Created 11.2015), SEER datasubmission, posted to the SEER web site, April 2016.
Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20. https://doi.org/10.1056/NEJMoa055531.
FLOT4-AIO Investigators, Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, 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):1948–57. https://doi.org/10.1016/S0140-6736(18)32557-1.
Smyth EC, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, ESMO Guidelines Committee. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(suppl 5):v38–v49. https://doi.org/10.1093/annonc/mdw350.
Wöll E, Eisterer W, Gerger A, Kühr T, Prager GW, Rumpold H, et al. Treatment algorithm for patients with gastric adenocarcinoma: an Austrian consensus on systemic therapy. Anticancer Res. 2019;39(9):4589–96. https://doi.org/10.21873/anticanres.13638.
Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, et al. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016;17(12):1697–708. https://doi.org/10.1016/S1470-2045(16)30531-9.
Smyth EC, Wotherspoon A, Peckitt C, Gonzalez D, Hulkki-Wilson S, Eltahir Z, et al. Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the medical research council adjuvant gastric Infusional chemotherapy (MAGIC) trial. JAMA Oncol. 2017;3(9):1197–203. https://doi.org/10.1001/jamaoncol.2016.6762.
Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011;29(13):1715–21. https://doi.org/10.1200/JCO.2010.33.0597.
GO2 Trial Investigators, Hall PS, Swinson D, Cairns DA, Waters JS, Petty R, Allmark C, et al. Efficacy of reduced-intensity chemotherapy with oxaliplatin and capecitabine on quality of life and cancer control among older and frail patients with advanced Gastroesophageal cancer: the GO2 phase 3 randomized clinical trial. JAMA Oncol. 2021;7(6):869–77. https://doi.org/10.1001/jamaoncol.2021.0848. Erratum in: JAMA Oncol. 2021 Aug 1;7(8):1249.
Vermillion SA, Hsu FC, Dorrell RD, Shen P, Clark CJ. Modified frailty index predicts postoperative outcomes in older gastrointestinal cancer patients. J Surg Oncol. 2017;115(8):997–1003. https://doi.org/10.1002/jso.24617.
Yoshida K, Kodera Y, Kochi M, Ichikawa W, Kakeji Y, Sano T, et al. Addition of docetaxel to oral fluoropyrimidine improves efficacy in patients with stage III gastric cancer: interim analysis of JACCRO GC-07, a randomized controlled trial. J Clin Oncol. 2019;37(15):1296–304. https://doi.org/10.1200/JCO.18.01138.
ARTIST 2 investigators, Park SH, Lim DH, Sohn TS, Lee J, Zang DY, Kim ST, 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):368–74. https://doi.org/10.1016/j.annonc.2020.11.017.
CRITICS investigators, Cats A, Jansen EPM, van Grieken NCT, Sikorska K, Lind P, Nordsmark M, 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):616–28. https://doi.org/10.1016/S1470-2045(18)30132-3.
Cats A, Sikorska K, Verheij M. Adjuvant therapy in resectable gastric cancer-the CRITICS trial—Authors’ reply. Lancet Oncol. 2018;19(7):e331. https://doi.org/10.1016/S1470-2045(18)30436-4.
Slagter AE, Jansen EPM, van Laarhoven HWM, van Sandick JW, van Grieken NCT, Sikorska K, et al. CRITICS-II: a multicentre randomised phase II trial of neo-adjuvant chemotherapy followed by surgery versus neo-adjuvant chemotherapy and subsequent chemoradiotherapy followed by surgery versus neo-adjuvant chemoradiotherapy followed by surgery in resectable gastric cancer. Bmc Cancer. 2018;18(1):877. https://doi.org/10.1186/s12885-018-4770-2.
Park SH, Sohn TS, Lee J, Lim DH, Hong ME, Kim KM, 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):3130–6. https://doi.org/10.1200/JCO.2014.58.3930.
CROSS Group, Van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074–84. https://doi.org/10.1056/NEJMoa1112088.
Anderson E, LeVee A, Kim S, Atkins K, Guan M, Placencio-Hickok V, et al. A comparison of clinicopathologic outcomes across neoadjuvant and adjuvant treatment modalities in resectable gastric cancer. JAMA Netw Open. 2021;4(12):e2138432. https://doi.org/10.1001/jamanetworkopen.2021.38432.
Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384(13):1191–203.
Rivera F, Izquierdo-Manuel M, García-Alfonso P, Martínez de Castro E, Gallego J, Limón ML, et al. 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;145:158–67. https://doi.org/10.1016/j.ejca .2020.12.005.
Hofheinz RD, Hegewisch-Becker S, Kunzmann V, Thuss-Patience P, Fuchs M, Homann N, et al. 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(6):1322–31. https://doi.org/10.1002/ijc.33696.
Petrillo A, Pompella L, Tirino G, Pappalardo A, Laterza MM, Caterino M, et al. Perioperative treatment in resectable gastric cancer: current perspectives and future directions. Cancers. 2019;11(3):399. https://doi.org/10.3390/cancers11030399.
Hofheinz R, Haag G, Ettrich T, Borchert K, Kretzschmar A, Teschendorf C, et al. Perioperative trastuzumab and pertuzumab in combination with FLOT versus FLOT alone for HER2-positive resectable esophagogastric adenocarcinoma: final results of the PETRARCA multicenter randomized phase II trial of the AIO. J Clin Oncol. 2020;38:4502–4502.
Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Cheng K, et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018;19(10):1372–84.
Wagner AD. NCT02205047—neoadjuvant study using trastuzumab or trastuzumab with pertuzumab in gastric or gastroesophageal junction adenocarcinoma (INNOVATION). ClinicalTrials.gov 2016.. https://clinicaltrials.gov/ct2/show/NCT02205047. Accessed 11 May 2022.
Bang YJ, Van Cutsem E, Fuchs CS, Ohtsu A, Tabernero J, Ilson DH, et al. KEYNOTE-585: phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer. Future Oncol. 2019;15(9):943–52. https://doi.org/10.2217/fon-2018-0581.
Smyth E, Knödler M, Giraut A, Mauer M, Nilsson M, Van Grieken N, et al. VESTIGE: adjuvant immunotherapy in patients with resected esophageal, gastroesophageal junction and gastric cancer following preoperative chemotherapy with high risk for recurrence (N+ and/or R1): an open label randomized controlled phase-2-study. Front Oncol. 2020;9:1320. https://doi.org/10.3389/fonc.2019.01320.
Al-Batran SE, Pauligk C, Hofheinz R, Lorenzen S, Wicki A, Siebenhuener AR, et al. Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esphagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK. J Clin Oncol. 2019;37(15_suppl):TPS4142–TPS4142.
Cohen R, Pudlarz T, Garcia-Larnicol ML, Vernerey D, Dray X, Clavel L, et al. Localized MSI/dMMR gastric cancer patients, perioperative immunotherapy instead of chemotherapy: The GERCOR NEONIPIGA phase II study is opened to recruitment. Bull Cancer. 2020;107(4):438–46. https://doi.org/10.1016/j.bulcan.2019.11.016. French.
Cunningham D, Stenning SP, Smyth EC, Okines AF, Allum WH, Rowley S, et al. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2–3 trial. Lancet Oncol. 2017;18(3):357–70. https://doi.org/10.1016/S1470-2045(17)30043-8.
Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, 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):3968–76. https://doi.org/10.1200/JCO.2011.36.2236.
REGARD Trial Investigators, Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, 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):31–9. https://doi.org/10.1016/S0140-6736(13)61719-5.
RAINBOW Study Group, Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, 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):1224–35. https://doi.org/10.1016/S1470-2045(14)70420-6.
Al-Batran SE, Bankstahl US. NCT02661971—perioperative ramucirumab in combination with FLOT versus FLOT alone for resectable esophagogastric adenocarcinoma—RAMSES—a phase II/III trial of the AIO. ClinicalTrials.gov. 2017.
Joshi SS, Badgwell BD. Current treatment and recent progress in gastric cancer. CA Cancer J Clin. 2021;71(3):264–79. https://doi.org/10.3322/caac.21657.
Sahin U, Türeci Ö, Manikhas G, Lordick F, Rusyn A, Vynnychenko I, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32(5):609–19. https://doi.org/10.1016/j.annonc.2021.02.005.
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B. Sonnweber, M. Schaber and E. Wöll declare that they have no competing interests.
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Sonnweber, B., Schaber, M. & Wöll, E. Neoadjuvant treatment in gastric cancer. memo 15, 211–215 (2022). https://doi.org/10.1007/s12254-022-00823-8
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DOI: https://doi.org/10.1007/s12254-022-00823-8