Adjuvant radiotherapy for gastric cancer—end of the road?

It is rare that two similarly designed trials investigating adjuvant treatment of localised gastric cancer (GC), one conducted in the Western and one in the Eastern hemispheres, come to congruent results. The conclusions from the Dutch, Danish and Swedish CRITICS and the Korean ARTIST-2 trials are that postoperative radiotherapy following D2 gastrectomy is of no additional benefit compared with chemotherapy (CT) alone. The two prestigious study groups that performed these trials must be congratulated for answering a question burning for two decades in one of the most common human cancers. With over 1 million new cases annually, GC is the fifth most diagnosed malignancy worldwide.1Smyth E.C. Nilsson M. Grabsch H.I. van Grieken N.C.T. Lordick F. Gastric cancer.Lancet. 2020; 396: 635-648Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar Gastrectomy, including a D2 lymphadenectomy, is the mainstay of curative treatment for localised GC. However, survival rates are limited with surgery alone in patients with stages II and III GC.2Songun I. Putter H. Kranenbarg E.M. Sasako M. van de Velde C.J. Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial.Lancet Oncol. 2010; 11: 439-449Abstract Full Text Full Text PDF PubMed Scopus (1192) Google Scholar To increase survival, perioperative and adjuvant treatments have been established as standard of care, based on the results of randomised controlled trials.3Smyth E.C. Verheij M. Allum W. et al.Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2016; 27: v38-v49Abstract Full Text Full Text PDF PubMed Scopus (757) Google Scholar In the US Intergroup-0116 (INT-0116) trial, postoperative chemoradiotherapy (CRT) significantly improved survival compared with surgery alone (40% versus 28% at 5 years).4Macdonald J.S. Smalley S.R. 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: 725-730Crossref PubMed Scopus (2904) Google Scholar INT-0116 was, however, criticised for the fact that only 10% of all patients had an adequate D2 lymph node dissection. It has been suggested that adjuvant CRT compensated for poor locoregional control resulting from inadequate surgery. The UK MAGIC study showed that the addition of perioperative CT to surgery improves survival for patients with resectable oesophagogastric adenocarcinoma compared with surgery alone. Despite this, mortality in patients with localised disease at diagnosis remains high, with 5-year overall survival of only ∼40%.5Cunningham D. Allum W.H. Stenning S.P. et al.Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.N Engl J Med. 2006; 355: 11-20Crossref PubMed Scopus (4285) Google Scholar The value of adding adjuvant radiotherapy to perioperative CT in patients undergoing D2 gastrectomy has remained controversial, and The Dutch Gastric Cancer Study Group therefore designed the CRITICS study to compare perioperative CT with preoperative CT plus postoperative CRT. An important secondary per-protocol (PP) analysis of CRITICS is published in this issue of Annals of Oncology.6de Steur W.O. van Amelsfoort R.M. Hartgrink H.H. 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: 360-367Scopus (8) Google Scholar In Asian countries, D2 gastrectomy followed by adjuvant CT (S-1 monotherapy for 1 year or capecitabine plus oxaliplatin for 6 months) has been the standard of care based on the phase III ACTS-GC and CLASSIC trials.7Sakuramoto S. Sasako M. Yamaguchi T. et al.Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine.N Engl J Med. 2007; 357: 1810-1820Crossref PubMed Scopus (1982) Google Scholar,8Noh S.H. Park S.R. Yang H.K. 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: 1389-1396Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar The Korean ARTIST-1 study investigated whether CRT improved disease-free survival (DFS) compared with adjuvant CT alone.9Park S.H. Sohn T.S. 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: 3130-3136Crossref PubMed Scopus (263) Google Scholar Although the primary endpoint was not met in the ARTIST-I trial, better DFS was observed in the CRT arm for GC patients with positive lymph nodes. The authors sought to determine whether the combination of S-1 and oxaliplatin, as well as the addition of CRT, would improve DFS compared with standard single-agent S-1 in the adjuvant setting of D2-resected, node-positive, stage II or III GC. ARTIST-2 is a three-arm randomised trial evaluating three adjuvant CT/CRT regimens in resected GC patients and is also published in this issue of the journal.10Park S.H. Lim D.H. Sohn T.S. 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: 368-374Scopus (24) Google Scholar Table 1 outlines the profiles of both trials. The intent-to-treat analysis of the CRITICS trial data did not show a survival benefit for patients in the CRT versus the CT arm. However, in the PP analysis (defined as those patients who actually started postoperative treatment) the CT group had a better 5-year overall and event-free survival as compared with the CRT group. The results of the PP analysis rejected the hypothesis that postoperative CRT would improve survival compared with postoperative CT by 10%. The cumulative incidence rates in the PP analysis showed that peritoneal metastases occurred less often in the CT group. Peritoneal dissemination is associated with a very poor prognosis, which might explain the superior outcome of adjuvant CT versus adjuvant CRT in the PP analysis.6de Steur W.O. van Amelsfoort R.M. Hartgrink H.H. 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: 360-367Scopus (8) Google Scholar Admittedly, the PP analysis represents no more than a subset analysis, and therefore the results need to be interpreted with caution.Table 1Profile of CRITICS and ARTIST-2 trial reportsCRITICSARTIST-2StageIB-IVA (TNM 6th edition)II-III (AJCC 2010), LN positivePatient number478546ConceptPerioperative CT with or without adjuvant RTAdjuvant CT with or without RTAnalysisPer protocolIntention to treatInvolved countriesNL, SE, DKKRSurgeryD2 LNDaIncluding at least D1+ (stations 1-9 for both total and distal gastrectomy and 11p only for total gastrectomy) lymph node dissection. (88%); median 20 LN dissected; Maruyama index 1D2 LND (all); LNR 0.13CTECX or EOXS-1 for 1 year (Arm A); SOX for 6 months (Arm B)CRT45 Gy in 25 fractions of 1.8 Gy with capecitabin and cisplatin45 Gy in 25 fractions of 1.8 Gy with SOXPrimary endpointOSDFSSurvival outcomes5-year OS CT versus CRT 57.9% versus 45.9% [HR: CRT versus CT 1.62 (1.24-2.12; P = 0.0004)]3-year DFS: S-1 versus SOX versus SOX–RT 64.8%, 74.3%, and 72.8% [HR: SOX versus S-1 0.692 (0.409-0.987; P = 0.042); HR: SOX–RT versus S-1 0.724 (0.507-1.032; P = 0.074); HR: SOX–RT versus SOX 0.971 (0.663-1.421; P = 0.879)]AJCC, American Joint Committee on Cancer; CRT, chemoradiotherapy; CT, chemotherapy; DFS, disease-free survival; DK, Denmark; ECX, epirubicin, cisplatin, capecitabin; EOX, epirubicin, oxaliplatin, capecitabin; HR, hazard ratio; KR, South Korea; LN, lymph node; LND, lymph node dissection; LNR, lymph node ratio (positive lymph nodes/number of lymph nodes dissected); NL, Netherlands; OS, overall survival; RT, radiotherapy; SE, Sweden; SOX, S-1 plus oxaliplatin; TNM, tumour node metastasis classification.a Including at least D1+ (stations 1-9 for both total and distal gastrectomy and 11p only for total gastrectomy) lymph node dissection. Open table in a new tab AJCC, American Joint Committee on Cancer; CRT, chemoradiotherapy; CT, chemotherapy; DFS, disease-free survival; DK, Denmark; ECX, epirubicin, cisplatin, capecitabin; EOX, epirubicin, oxaliplatin, capecitabin; HR, hazard ratio; KR, South Korea; LN, lymph node; LND, lymph node dissection; LNR, lymph node ratio (positive lymph nodes/number of lymph nodes dissected); NL, Netherlands; OS, overall survival; RT, radiotherapy; SE, Sweden; SOX, S-1 plus oxaliplatin; TNM, tumour node metastasis classification. From studies using adjuvant treatment it has become clear that for many patients it is difficult to complete postoperative treatment. Even in trials with postoperative randomisation, such as the INT-0116 and the ARTIST-1 trials, only 64% and 75%, respectively, managed to complete adjuvant treatment as planned. In trials of perioperative treatment, the data for postoperative treatment adherence are even worse. In the MAGIC-trial, although 91% of patients completed preoperative treatment, only 55% started postoperative treatment and 42% completed full treatment. Postoperative CT completion rates are almost the same in the era of perioperative fluorouracil–oxaliplatin–docetaxel (FLOT) CT.11Al-Batran S.E. 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: 1948-1957Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar In the ARTIST-2 trial, the addition of RT to CT did not significantly reduce the rate of recurrence after D2 gastrectomy. DFS rates between patients treated with adjuvant CT and CRT were similar across all subgroups, including Lauren classification. Importantly, analysis of DFS in prespecified subgroups showed consistently longer DFS with adjuvant doublet CT than with S-1 monotherapy, including in subgroups defined according to stage, lymph node ratio, Lauren classification and type of surgery. The ARTIST-2 report could be criticised in that little information is provided on RT delivery, and there was no RT quality assurance program to monitor RT quality, which has been shown to be critically important in optimising outcomes in GC. Nevertheless, as the results are in line with previously reported randomised clinical trials involving adjuvant CRT,12Fuchs C.S. Niedzwiecki D. Mamon H.J. 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: 3671-3677Crossref PubMed Scopus (62) Google Scholar,13Cats A. Jansen E.P.M. van Grieken N.C.T. 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: 616-628Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar CRT should not be considered as the standard of care for patients with D2-resected, node-positive GC when adjuvant therapy is indicated, at least in Asian countries. In Western countries, the best evidence available today suggests that perioperative CT and D2 gastrectomy are preferrable as opposed to postoperative CRT (with or without adequate surgery). As previously demonstrated for rectal cancer, sequencing of treatment matters. As postoperative treatment is often difficult to deliver, we are convinced that the future of improving cure rates in localised GC is treatment in the preoperative period. Several trials with this focus are currently accruing patients, including the TOPGEAR (NCT02661971) and the CRITICS-2 trials (NCT02661971) in which CT or CRT or a combination is given preoperatively.14Leong T. Smithers B.M. 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: 2252-2258Crossref PubMed Scopus (122) Google Scholar,15Slagter A.E. Jansen E.P.M. van Laarhoven H.W.M. et al.CRITICS-II: a multicentre randomised phase II trial of neo-adjuvant chemotherapy followed by surgery versus neoadjuvant chemotherapy and subsequent chemoradiotherapy followed by surgery versus neoadjuvant chemoradiotherapy followed by surgery in resectable gastric cancer.BMC Cancer. 2018; 18: 877PubMed Google Scholar In addition, each single-treatment modality will continue to improve. Centralisation of surgery to specialised centres and minimally invasive surgical approaches (including robotically assisted surgery) will minimise surgical trauma and postoperative mortality and morbidity. Novel imaging-guided surgical techniques will augment surgical precision. In addition, prehabilitation programmes and improved perioperative nutritional support will optimise patients' physical ability to tolerate surgery well. We expect lower local recurrence rates, shorter postsurgical recovery periods and thereby better feasibility and tolerance to potentially active postoperative treatments, such as immunotherapy. Improvements in imaging technology, radiation planning and treatment delivery have enabled more accurate and precise radiation targeting of tumours while minimising the radiation dose to normal healthy tissues. This has expanded the dose range and indications for radiotherapy, whereby tumours can be effectively treated while side-effects are minimised. Finally, a better understanding of GC biology from genetics16Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (3343) Google Scholar to the immune landscape17Derks S. de Klerk L.K. Xu X. et al.Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas.Ann Oncol. 2020; 31: 1011-1020Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar allows for the development of more effective perioperative medical treatment. Currently, HER2-targeted treatment18Wagner A.D. Grabsch H.I. Mauer M. et al.EORTC-1203-GITCG – the “INNOVATION”-trial: effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate: a randomized phase II-intergroup trial of the EORTC-Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch Upper GI Cancer group.BMC Cancer. 2019; 19: 494PubMed Google Scholar and immunotherapy19Smyth E. Knödler M. Giraut A. et al.VESTIGE: adjuvant immunotherapy in patients with resected gastric and gastroesophageal cancer following preoperative chemotherapy with high risk for recurrence (N+ and/or R1): an open label randomized controlled phase-2-study.Front Oncol. 2019; 9: 1320Crossref PubMed Scopus (28) Google Scholar are under investigation in multinational trials. None declared.