Adjuvant and neoadjuvant treatment of gastric cancer
- Craig Earle, MD, MSc, FRCPC
Craig Earle, MD, MSc, FRCPC
- Director, Health Services Research Program
- Cancer Care Center and the Ontario Institute for Cancer Research
- Harvey Mamon, MD, PhD
Harvey Mamon, MD, PhD
- Associate Professor of Radiation Oncology
- Harvard Medical School
- Section Editors
- Richard M Goldberg, MD
Richard M Goldberg, MD
- Section Editor — Gastrointestinal Cancer
- Director of the West Virginia University Cancer Institute and the Mary Babb Randolph Cancer Center
- Professor of Medicine
- Laurence S. & Jean J. DeLynn Chair of Oncology
- Christopher G Willett, MD
Christopher G Willett, MD
- Section Editor — Radiation Therapy
- Duke University Medical School
The incidence of gastric cancer has been declining steadily since the 1930s, yet it remains a major cause of cancer death in the United States . The high mortality rate reflects the prevalence of advanced disease at presentation . In population-based series of Western populations, the five-year survival rate for patients with completely resected stage I gastric cancer is approximately 70 to 75 percent, while it drops to 35 percent or less for stage II disease and beyond (table 1) . These sobering results have spawned efforts to improve the treatment results for this group of patients using adjuvant (postoperative) or neoadjuvant (preoperative) therapies. (See "Surgical management of invasive gastric cancer", section on 'Prognosis'.)
The positive impact of such therapies on survival in patients with resected gastric cancer has become clearer over time, although there is no consensus as to the best approach. In many parts of the world, chemotherapy alone (either following surgery or combined preoperative and postoperative administration, as in the multinational MAGIC trial ) is the preferred treatment strategy. On the other hand, a large American Intergroup trial (INT0116) demonstrating a significant survival benefit for chemoradiotherapy after complete resection resulted in the adoption of this strategy in the United States, despite concerns that inadequate surgical staging (particularly the extent of lymphadenectomy) may have led to an overestimation of benefit . The issues surrounding extent of lymph node dissection in gastric cancer are discussed in detail elsewhere. (See "Surgical management of invasive gastric cancer", section on 'Extent of lymph node dissection'.)
Another controversial issue is the management of cancers arising at the esophagogastric junction (EGJ). The classification and management of these tumors have evolved over time. In the 2010 edition of the tumor, node, metastasis (TNM) staging manual, tumors arising at the EGJ or in the cardia of the stomach (figure 1) within 5 cm of the EGJ that extend into the EGJ or esophagus (the so-called Siewert III EGJ tumors ) were staged and treated as esophageal (table 2) rather than stomach cancers . However, tumors that arise beyond 5 cm of the EGJ, or are within 5 cm of the EGJ but without extension to the esophagus or EGJ are still classified and treated as gastric cancers. In the most recent eighth edition staging classification from 2017 , tumors involving the EGJ with a tumor epicenter no more than 2 cm into the proximal stomach are staged as esophageal cancers, while EGJ tumors with their epicenter located more than 2 cm into the proximal stomach are staged as stomach cancers, as are all cardia cancers not involving the EGJ. (See "Diagnosis and staging of esophageal cancer", section on 'TNM staging criteria' and "Clinical features, diagnosis, and staging of gastric cancer", section on 'TNM staging criteria'.)
This topic review will focus on adjuvant and neoadjuvant therapies for noncardia gastric cancer. The epidemiology, staging, and surgical treatment of gastric cancers and multimodality approaches for treatment of esophageal and EGJ tumors are covered separately. (See "Epidemiology of gastric cancer" and "Clinical features, diagnosis, and staging of gastric cancer" and "Surgical management of invasive gastric cancer" and "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus" and "Multimodality approaches to potentially resectable esophagogastric junction and gastric cardia adenocarcinomas".)
OVERVIEW OF THE THERAPEUTIC APPROACH
●Complete surgical resection is a prerequisite for cure of gastric cancer. However, the poor long-term survival rates after surgery alone for patients with locally advanced gastric and esophagogastric junction (EGJ) cancer have led to the exploration of a variety of adjuvant (postoperative) and neoadjuvant (preoperative) treatment strategies incorporating chemotherapy with or without radiation therapy (RT). The survival benefit from combined modality therapy as compared with surgery alone has become clearer over time.
- Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017; 67:7.
- Agboola O. Adjuvant treatment in gastric cancer. Cancer Treat Rev 1994; 20:217.
- Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355:11.
- Macdonald 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; 345:725.
- Rüdiger Siewert J, Feith M, Werner M, Stein HJ. Adenocarcinoma of the esophagogastric junction: results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients. Ann Surg 2000; 232:353.
- American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.117.
- Ajani JA, In H, Sano T, et al.. Stomach.. In: AJCC Cancer Staging Manual, 8th, Amin MB. (Ed), AJCC, Chicago 2017. p.203.
- Bang 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; 379:315.
- Verheij M, et al. A multicenter randomized phase III trial of neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy in resectable gastric cancer: First results from the CRITICS study (abstract). J Clin Oncol 34, 2016 (suppl; abstr 4000). Abstract available online at http://meetinglibrary.asco.org/content/165706-176 (Accessed on July 18, 2016).
- Gunderson LL, Sosin H. Adenocarcinoma of the stomach: areas of failure in a re-operation series (second or symptomatic look) clinicopathologic correlation and implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 1982; 8:1.
- Allum WH, Hallissey MT, Ward LC, Hockey MS. A controlled, prospective, randomised trial of adjuvant chemotherapy or radiotherapy in resectable gastric cancer: interim report. British Stomach Cancer Group. Br J Cancer 1989; 60:739.
- Drognitz O, Henne K, Weissenberger C, et al. Long-term results after intraoperative radiation therapy for gastric cancer. Int J Radiat Oncol Biol Phys 2008; 70:715.
- Krämling HJ, Wilkowski R, Dühmke E, et al. [Adjuvant intraoperative radiotherapy of stomach carcinoma]. Langenbecks Arch Chir Suppl Kongressbd 1996; 113:211.
- Shridhar R, Dombi GW, Weber J, et al. Adjuvant radiation therapy increases overall survival in node-positive gastric cancer patients with aggressive surgical resection and lymph node dissection: a SEER database analysis. Am J Clin Oncol 2012; 35:216.
- Dent DM, Werner ID, Novis B, et al. Prospective randomized trial of combined oncological therapy for gastric carcinoma. Cancer 1979; 44:385.
- Moertel CG, Childs DS, O'Fallon JR, et al. Combined 5-fluorouracil and radiation therapy as a surgical adjuvant for poor prognosis gastric carcinoma. J Clin Oncol 1984; 2:1249.
- Smalley 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; 30:2327.
- Gordon MA, Gundacker HM, Benedetti J, et al. Assessment of HER2 gene amplification in adenocarcinomas of the stomach or gastroesophageal junction in the INT-0116/SWOG9008 clinical trial. Ann Oncol 2013; 24:1754.
- Fuchs CS, Tepper JE, Niedzwiecke D, et al. Postoperative adjuvant chemoradiation for gastric or gastroesophageal junction (GEJ) adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (CRT) compared with bolus 5-FU/LV before and after CRT: Intergroup trial CALGB 80101 (abstract 4003). J Clin Oncol 2011; 29:256s. Abstract available online at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=82318 (Accessed on June 29, 2011).
- Park 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; 33:3130.
- O'Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994; 331:502.
- Lee J, Lim DH, Kim S, et al. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol 2012; 30:268.
- Grau JJ, Martín M, Fuster J, et al. Impact of adjuvant chemotherapy in the long-term outcome of patients with resected gastric cancer. J Surg Oncol 2003; 82:234.
- Ronellenfitsch U, Schwarzbach M, Hofheinz R, et al. Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction, and lower esophagus. Cochrane Database Syst Rev 2013; :CD008107.
- Diaz-Nieto R, Orti-Rodríguez R, Winslet M. Post-surgical chemotherapy versus surgery alone for resectable gastric cancer. Cochrane Database Syst Rev 2013; :CD008415.
- Oba K, Paoletti X, Alberts S, et al. Disease-free survival as a surrogate for overall survival in adjuvant trials of gastric cancer: a meta-analysis. J Natl Cancer Inst 2013; 105:1600.
- Earle CC, Maroun JA. Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: revisiting a meta-analysis of randomised trials. Eur J Cancer 1999; 35:1059.
- Elimova E, Janjigian YY, Mulcahy M, et al. It Is Time to Stop Using Epirubicin to Treat Any Patient With Gastroesophageal Adenocarcinoma. J Clin Oncol 2017; 35:475.
- Zhang XL, Shi HJ, Cui SZ, et al. Prospective, randomized trial comparing 5-FU/LV with or without oxaliplatin as adjuvant treatment following curative resection of gastric adenocarcinoma. Eur J Surg Oncol 2011; 37:466.
- Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol 2011; 29:4387.
- Macdonald JS. Gastric cancer: Nagoya is not New York. J Clin Oncol 2011; 29:4348.
- Noh 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; 15:1389.
- Yu C, Yu R, Zhu W, et al. Intensity-modulated radiotherapy combined with chemotherapy for the treatment of gastric cancer patients after standard D1/D2 surgery. J Cancer Res Clin Oncol 2012; 138:255.
- Kim TH, Park SR, Ryu KW, et al. Phase 3 trial of postoperative chemotherapy alone versus chemoradiation therapy in stage III-IV gastric cancer treated with R0 gastrectomy and D2 lymph node dissection. Int J Radiat Oncol Biol Phys 2012; 84:e585.
- Zhu WG, Xua DF, Pu J, et al. A randomized, controlled, multicenter study comparing intensity-modulated radiotherapy plus concurrent chemotherapy with chemotherapy alone in gastric cancer patients with D2 resection. Radiother Oncol 2012; 104:361.
- Kwon HC, Kim MC, Kim KH, et al. Adjuvant chemoradiation versus chemotherapy in completely resected advanced gastric cancer with D2 nodal dissection. Asia Pac J Clin Oncol 2010; 6:278.
- Bamias A, Karina M, Papakostas P, et al. A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer. Cancer Chemother Pharmacol 2010; 65:1009.
- Elimova E, Ajani JA. Surgical Resection First for Localized Gastric Adenocarcinoma: Are There Adjuvant Options? J Clin Oncol 2015; 33:3085.
- Dai Q, Jiang L, Lin RJ, et al. Adjuvant chemoradiotherapy versus chemotherapy for gastric cancer: a meta-analysis of randomized controlled trials. J Surg Oncol 2015; 111:277.
- Ahmed S, Iqbal N, Yadav S, et al. Time to adjuvant therapy and other variables in localized gastric and gastroesophageal junction (GEJ) cancer (IJGC-D-13-00162). J Gastrointest Cancer 2014; 45:284.
- Kang SY, Ahn MS, Song GW, et al. Does the timing of adjuvant chemotherapy for gastric cancer influence patient outcome? Acta Oncol 2015; 54:1231.
- Park HS, Jung M, Kim HS, et al. Proper timing of adjuvant chemotherapy affects survival in patients with stage 2 and 3 gastric cancer. Ann Surg Oncol 2015; 22:224.
- Greenleaf EK, Kulaylat AN, Hollenbeak CS, et al. Timing of Adjuvant Chemotherapy and Impact on Survival for Resected Gastric Cancer. Ann Surg Oncol 2016; 23:4203.
- Kim S, Lim DH, Lee J, et al. An observational study suggesting clinical benefit for adjuvant postoperative chemoradiation in a population of over 500 cases after gastric resection with D2 nodal dissection for adenocarcinoma of the stomach. Int J Radiat Oncol Biol Phys 2005; 63:1279.
- Kulig J, Kolodziejczyk P, Sierzega M, et al. Adjuvant chemotherapy with etoposide, adriamycin and cisplatin compared with surgery alone in the treatment of gastric cancer: a phase III randomized, multicenter, clinical trial. Oncology 2010; 78:54.
- Neri B, de Leonardis V, Romano S, et al. Adjuvant chemotherapy after gastric resection in node-positive cancer patients: a multicentre randomised study. Br J Cancer 1996; 73:549.
- Gold JS, Al Natour RH, Saund MS, et al. Population-based outcome of stage IA-IIA resected gastric adenocarcinoma: who should get adjuvant treatment? Ann Surg Oncol 2013; 20:2304.
- In H, Kantor O, Sharpe SM, et al. Adjuvant Therapy Improves Survival for T2N0 Gastric Cancer Patients with Sub-optimal Lymphadenectomy. Ann Surg Oncol 2016; 23:1956.
- Boige V, Pignon J, Saint-Aubert B, et al. Final results of a randomized trial comparing preoperative 5-fluorouracil/cisplatin to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial (abstract). J Clin Oncol 2007; 25:200s.
- Schuhmacher C, Gretschel S, Lordick F, et al. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954. J Clin Oncol 2010; 28:5210.
- Kobayashi T, Kimura T. [Long-term outcome of preoperative chemotherapy with 5'-deoxy-5-fluorouridine (5'-DFUR) for gastric cancer]. Gan To Kagaku Ryoho 2000; 27:1521.
- Nio Y, Koike M, Omori H, et al. A randomized consent design trial of neoadjuvant chemotherapy with tegafur plus uracil (UFT) for gastric cancer--a single institute study. Anticancer Res 2004; 24:1879.
- Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011; 29:1715.
- Xiong BH, Cheng Y, Ma L, Zhang CQ. An updated meta-analysis of randomized controlled trial assessing the effect of neoadjuvant chemotherapy in advanced gastric cancer. Cancer Invest 2014; 32:272.
- Al Batran S-E, Homann N, Schmalenberg H, et al. Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial (abstract). J Clin Oncol 35, 2017 (suppl; abstr 4004). Abstract available online at http://abstracts.asco.org/199/AbstView_199_191595.html (Accessed on July 06, 2017).
- Li ZY, Koh CE, Bu ZD, et al. Neoadjuvant chemotherapy with FOLFOX: improved outcomes in Chinese patients with locally advanced gastric cancer. J Surg Oncol 2012; 105:793.
- Ahn HS, Jeong SH, Son YG, et al. Effect of neoadjuvant chemotherapy on postoperative morbidity and mortality in patients with locally advanced gastric cancer. Br J Surg 2014; 101:1560.
- Al-Batran SE, Hofheinz RD, Pauligk C, 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; 17:1697.
- Stahl M, Walz MK, Stuschke M, et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol 2009; 27:851.
- Ajani JA, Winter K, Okawara GS, et al. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol 2006; 24:3953.
- Ajani JA, Mansfield PF, Janjan N, et al. Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. J Clin Oncol 2004; 22:2774.
- Ajani JA, Mansfield PF, Crane CH, et al. Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome. J Clin Oncol 2005; 23:1237.
- Smyth EC, Fassan M, Cunningham D, et al. Effect of Pathologic Tumor Response and Nodal Status on Survival in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial. J Clin Oncol 2016; 34:2721.
- Saunders JH, Bowman CR, Reece-Smith AM, et al. The role of adjuvant platinum-based chemotherapy in esophagogastric cancer patients who received neoadjuvant chemotherapy prior to definitive surgery. J Surg Oncol 2017; 115:821.
- Cascinu S, Scartozzi M, Labianca R, et al. High curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxorubicin, 6S-leucovorin, glutathione, and filgastrim in patients with locally advanced, unresectable gastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Br J Cancer 2004; 90:1521.
- Gallardo-Rincón D, Oñate-Ocaña LF, Calderillo-Ruiz G. Neoadjuvant chemotherapy with P-ELF (cisplatin, etoposide, leucovorin, 5-fluorouracil) followed by radical resection in patients with initially unresectable gastric adenocarcinoma: a phase II study. Ann Surg Oncol 2000; 7:45.
- Nakajima T, Ota K, Ishihara S, et al. Combined intensive chemotherapy and radical surgery for incurable gastric cancer. Ann Surg Oncol 1997; 4:203.
- Yoshikawa T, Sasako M, Yamamoto S, et al. Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer. Br J Surg 2009; 96:1015.
- Lowy AM, Feig BW, Janjan N, et al. A pilot study of preoperative chemoradiotherapy for resectable gastric cancer. Ann Surg Oncol 2001; 8:519.
- Ajani JA, Komaki R, Putnam JB, et al. A three-step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially resectable carcinoma of the esophagus or gastroesophageal junction. Cancer 2001; 92:279.
- Saikawa Y, Kubota T, Kumagai K, et al. Phase II study of chemoradiotherapy with S-1 and low-dose cisplatin for inoperable advanced gastric cancer. Int J Radiat Oncol Biol Phys 2008; 71:173.
- Ychou M, Pignon JP, Lasser P, et al. Phase III preliminary results of preoperative fluorouracil (F) and cisplatin (P) versus surgery alone in adenocarcinoma of the stomach and lower esophagus (ASLE): FNLCC 94012-FFCD 9703 trial (abstract). J Clin Oncol 2006; 24:185s.
- Leong T, Smithers BM, Haustermans K, et al. TOPGEAR: A Randomized, Phase III Trial of Perioperative ECF Chemotherapy with or Without Preoperative Chemoradiation for Resectable Gastric Cancer: Interim Results from an International, Intergroup Trial of the AGITG, TROG, EORTC and CCTG. Ann Surg Oncol 2017; 24:2252.
- https://clinicaltrials.gov/ct2/show/NCT01748773?term=01748773&rank=1 (Accessed on July 18, 2016).
- Smyth EC, Verheij M, Allum W, et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27:v38.
- OVERVIEW OF THE THERAPEUTIC APPROACH
- PATIENTS WHO HAVE ALREADY UNDERGONE POTENTIALLY CURATIVE RESECTION
- Adjuvant chemoradiotherapy
- - Intergroup 0116
- - CALGB 80101
- - ARTIST trial
- Adjuvant chemotherapy
- - Benefits
- - Choice of regimen
- Japanese S-1 trial
- CLASSIC trial
- Chemotherapy versus chemoradiotherapy
- Timing of adjuvant therapy
- Patient selection for adjuvant therapy
- PATIENTS WITH POTENTIALLY RESECTABLE DISEASE NOT YET RESECTED
- Neoadjuvant/perioperative chemotherapy
- - MAGIC trial
- - French FNLCC/FFCD trial
- - EORTC trial 40954
- - Meta-analysis
- - Choice of regimen and patient selection
- Non-epirubicin-containing regimens
- - FLOT
- Neoadjuvant chemoradiotherapy
- Management of poor responders
- INITIALLY LOCALLY UNRESECTABLE NONMETASTATIC DISEASE
- ONGOING RESEARCH
- POSTTREATMENT CANCER SURVEILLANCE
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS