Open access Review How I treat gastric adenocarcinoma Maria Alsina,‍ ‍ 1,2 Josep Maria Miquel,1 Marc Diez,1 Sandra Castro,3 Josep Tabernero1,2 To cite: Alsina M, Miquel JM, Abstract Diagnosis, staging and treatment planning Diez M, et al. How I treat gastric Gastric and gastro-oesophageal junction cancer (GC) Patients with GC represent a particularly adenocarcinoma. ESMO Open represents a worldwide problem, this being the fifth most fragile population. Symptomatology normally 2019;4:e000521. doi:10.1136/ common malignancy. The fragility of patients with GC only appears once the tumour has increased esmoopen-2019-000521 together with the aggressiveness of this tumour makes in size to the point where it interferes with it as one of the most difficult neoplasias to manage. the nutritional process, resulting in these Received 29 March 2019 This article summarises the main strategies for treating patients presenting with significant asthenia, Revised 9 April 2019 patients with GC. Correct assessment of patients with GC Accepted 13 April 2019 requires a multidisciplinary evaluation and close follow- difficulty for tolerating normal food (nausea, up. For patients with resectable tumours, perioperative vomiting and early satiety), anaemia and Published online chemotherapy should be always considered, especially non-depreciable weight loss. Correct evalua- 5 July 2019 in the neoadjuvant setting given its capacity for tumour tion of patients with GC requires particular downstaging and eradication of micro-metastases. In the consideration of supportive care and nutri- metastatic setting, first-line and second-line treatment tional assessment. improve survival and quality of life in patients with GC. Diagnosis of GC should be made from a In this setting, only trastuzumab as first-line therapy in gastroscopy with a biopsy, including histology patients with human epidermal growth factor receptor 2 reported according to the WHO criteria,4 positive tumours and ramucirumab as second-line therapy together with human epidermal growth have demonstrated a clear survival improvement. The factor receptor 2 (HER-2) receptor status (at lack of adequate biomarker selection and the intrinsic least in metastatic cases). Staging is normally heterogeneity of these tumours have jeopardised the possible usefulness of many other targeted agents. assessed by a thoracoabdominal CT scan. Finally, when considering GC carcinogenesis as a multiple However, a positron emission tomography-CT stepwise process from initial inflammation starting scan might be necessary in cases with suspi- in the gastric epithelia, immune checkpoint inhibitors cious metastatic spread, while an exploratory may improve the survival of these patients, although laparoscopy may rule out peritoneal spread the optimal setting for their activity has yet to be fully in cases considered upfront to be potentially elucidated. resectable, and an endoscopic ultrasound may improve the accuracy of staging in locally advanced cases. The TNM stage should be Introduction reported according to the latest edition of Gastric and gastro-oesophageal junction the American Joint Committee on Cancer/ cancers (GC) are the third cause of cancer-re- Union for International Cancer Control lated deaths,1 representing an international guidelines and staging manual.5 The evalu- problem which needs precise individualised ation of each patient with GC should always © Author (s) (or their treatment. While the incidence of gastric include a precise anamnesis and physical employer(s)) 2019. Re-use cancer is globally decreasing, the contrary examination including weight, a differential permitted under CC BY-NC. No is occurring for proximal and junctional commercial re-use. Published blood count, as well as liver and renal func- tumours.2 These epidemiological distinc- tion tests. Testing for tumour markers (CEA, by BMJ on behalf of the European Society for Medical tions are sustained by various associated CA19.9 and CA72.4), although not manda- Oncology. risk factors which ultimately potentiate the tory, may be helpful especially for detecting 1 Medical Oncology, VHIO (Vall occurrence of different molecularly driven recurrences during follow-up, and antici- d’Hebron Institute of Oncology), tumours within the stomach. According to pating progression in the metastatic setting. University Hospital Vall d’Hebron, the Cancer Genome Atlas,3 four molecular A thorough approach would ideally include a Barcelona, Spain 2 subtypes of GC have been identified, with multidisciplinary tumour board, especially in Facultat de Medicina, Universitat Autonoma de inherent genetic features. Also important is locally advanced and resectable cases. Barcelona, Bellaterra, Spain the particular need for recognition of GC 3 Surgery, Vall d’Hebron Hospital, heterogeneity, not only to understand the Barcelona, Spain failure of multiple phase III studies with Management of local/locoregional Correspondence to targeted agents carried out over the last disease Dr Maria Alsina; ​malsina@​ few years but also to provide physicians with Surgery represents the cornerstone of cura- vhio.​net adequate guided strategies. tive treatment, although recurrences occur in Alsina M, et al. ESMO Open 2019;4:e000521. doi:10.1136/esmoopen-2019-000521 1 Open access more than 50% of cases.6 Indeed, GC should be consid- surgery requirement (when debuting with initial refrac- ered a systemic disease from the start of care, such that tory bleeding or highly occlusive tumours). In this treatment with systemic perioperative chemotherapy setting, adjuvant treatment after surgery either with potentiates the downstaging and eradication of micro- chemoradiotherapy or with chemotherapy alone can be scopic metastases. Endoscopic resection (if cT1a, clearly considered. The North American Intergroup-0116 trial confined to the mucosa, well differentiated, ≤2 cm and demonstrated an OS benefit in patients who received non-ulcerated) or surgery alone can only be recom- postoperative 5-FU-based chemoradiotherapy,10 although mended for stage I disease. For stages Ib–III, periopera- most of the patients had been treated with inadequate tive treatment is mandatory. lymphadenectomy (less than D1). The results of the study The type of the surgery depends on the location of the suggested that postoperative treatment might compen- tumour. Subtotal gastrectomies may only be carried out if sate suboptimal surgery. Similar findings in the Dutch a macroscopic proximal margin of at least 5 cm between D1D2 trial corroborated this, demonstrating a greater the tumour and the gastro-oesophageal junction can be survival benefit in patients who had undergone D1 (not achieved (otherwise a total gastrectomy is mandatory). D2) lymphadenectomies or R1 resections.11 12 More- A D2 lymph node dissection is recommended, with the over, the phase III ChemoRadiotherapy after Induction removal of perigastric lymph nodes plus those along the chemoTherapy In Cancer of the Stomach (CRITICS) left gastric, common hepatic and splenic arteries and the trial,13 which evaluated adjuvant chemoradiotherapy coeliac axis, with a minimum of 15 lymph nodes removed. versus chemotherapy alone in patients who had received Only specialised, high-volume institutions with appro- preoperative chemotherapy and surgery, confirmed the priate surgical expertise and postoperative care should limited benefit of adjuvant radiotherapy. Finally, an Asian be considered for performing these complex resections. study reinforced the benefit of the adjuvancy with chemo- Perioperative (preoperative and postoperative) chemo- therapy alone, demonstrating a benefit of performing 6 therapy with a platinum and a fluoropyrimidine combi- months of capecitabine–oxaliplatin after radical surgery nation is recommended for patients with stage >Ib. The in patients who had undergone R0 resection with an phase III UK Medical Research Council Adjuvant Gastric adequate lymphadenectomy but without having received Infusional Chemotherapy (MAGIC) trial6 demonstrated preoperative chemotherapy.14 an improvement in 5year overall survival (OS) from 23% to 36% with six cycles of perioperative epirubicin, cisplatin and 5-fluorouracil (5-FU) (ECF) chemotherapy, Management of advanced/metastatic disease compared with surgery alone in patients with stages II and (chemotherapy, targeted agents, immunotherapy) III GC. A French study7 demonstrated similar results with First-line treatment perioperative cisplatin plus 5-FU in a 28-day regimen, Patients with locally advanced unresectable and/or meta- although it included a greater proportion of patients static disease should be considered for systemic treatment with proximal tumours, compared with the MAGIC trial. (chemotherapy), which has consistently demonstrated a Finally, an European Organisation for Research and Treat- benefit in both OS and quality of life.15 The standard of ment of Cancer study with a weekly schema of cisplatin and care is based on a platinum (cisplatin or oxaliplatin) and 5-FU demonstrated an increase in R0 resection rates in a fluoropyrimidine doublet (5-FU, capecitabine, tegafur/ patients receiving chemotherapy plus surgery compared gimeracil/oteracil (S-1)). Patients with HER-2 overex- with those with surgery alone.8 This study was closed early pression (immunohistochemistry (IHC) 3+ or IHC 2+ due to poor accrual and consequently was not powered and in situ hybridisation positive) should also receive tras- to show differences in OS. These three phase III trials tuzumab (table 1a). established perioperative treatment as the gold standard The addition of epirubicin to a chemotherapy doublet in European patients, with the schema from the MAGIC has not definitively demonstrated an OS advantage and trial being the most widely accepted. Nevertheless, this slightly increases toxicity. In contrast, the addition of paradigm radically changed in 2017 when the OS results docetaxel offers a small benefit in OS but with consid- from the German AIO study group demonstrated greater erable toxicity with the original docetaxel, cisplatin and benefit with the addition of taxanes to the platinum-5-FU 5-FU (DCF) regimen assessed in the V325 phase III doublet.9 This study compared the fluorouracil, leucov- study.16 This latter fact together with the fact that taxanes orin, oxaliplatin, docetaxel (FLOT) regimen versus can be given in the second line makes the use of this drug ECF/X. Patients treated with FLOT presented a higher in the first-line setting rare. The original DCF regimen, pathological response rate and a large improvement in or better the analogous and less toxic FLOT regimen,9 survival (HR 0.77, p=0.012). Global toxicity rates were should only be considered in young/fit patients and if a similar in both groups, although patients treated with very quick response is needed. FLOT presented more leucopenia/neutropenia and To date, no other targeted agents have demonstrated peripheral neuropathy. an OS benefit in this setting. The lack of biomarkei Unfortunately, some patients with GC with stage >Ib stratification and the intrinsic GC heterogeneity have are not eligible for perioperative treatment, mainly due likely contributed to the failure to demonstrate a to age and/or comorbidities or because of an urgent benefit when using multiple targeted therapies against 2 Alsina M, et al. ESMO Open 2019;4:e000521. doi:10.1136/esmoopen-2019-000521 Open access Table 1 Main phase III clinical trials with chemotherapy (A and B) and targeted therapies (C). Clinical trial N Treatment OS PFS ORR P value (A) First-line chemotherapy treatment The V325 Trial 445 DPF 9.2 m HR 1.29 5.6 m* HR 1.47 37% 0.01 Van Cutsem PF 8.6 m p=0.02 3.7 m p<0.01 25% J Clin Oncol 2006 The Randomized ECF for Advanced 1002 EPF 9.9 m Non-inferiority 6.2 m 40.7% and Locally Advanced Esophagogastric EPC 9.9 m meet 6.7 m 46.4% Cancer 2 (REAL-2) Trial EOF 9.3 m 6.5 m 42.4% Cunningham EOC 11.2 m 7m 47.9% NEJM 2008 The ML17302 Trial 316 CP 10.5 m HR 0.85 5.6 m HR 0.81 46% 0.020 Kang FP 9.3 m p=0.008 5.0 m p<0.01 32% Ann Oncol 2009 The FLAGS Trial 1053 P-S1 8.6 m HR 0.92 4.8 m HR 0.99 29.1% 0.40 Ajani P-F 7.9 m p=0.2 5.5 m p=0.92 31.9% J Clin Oncol 2010 The French Intergroup Trial 416 EPC 9.49 m HR 1.01 5.29 m HR 0.99 39.2% Guimbaud FOLFIRI 9.72 m p=0.95 5.75 m p=0.96 37.8% J Clin Oncol 2014 (B) Second-line treatment and beyond The Arbeitsgemeinschaft Internistische 40 CPT-11 4.0 m HR 0.48 2.6 m 0% Onkologie (AIO) Trial BSC 2.4 m p=0.012 – – Thuss-Patience Eur J Can 2011 The Salvage Chemo Trial 188 D/CPT-11 5.3 m HR 0.65 – 13% Kang BSC 3.8 m p=0.007 – J Clin Oncol 2012 The COUGAR-02 Trial 168 D 5.2 m HR 0.67 7% Ford BSC 3.6 m p=0.01 – Lancet Oncol 2014 The West Japan Oncology Group (WJOG) 223 Pac 9.5 m HR 1.13 3.6 m HR 1.14 20.9% 0.24 Trial 4007 (WJOG 4007) CPT-11 8.4 m p=0.38 2.3 m p=0.33 13.6% Hironaka J Clin Oncol 2013 The KEYNOTE 061 Trial 592 Pem 9.1 m HR 0.82 1.5 m HR 1.27 16% – Shitara Pac 8.3 m p=0.042 4.1 m – 14% Lancet 2018 The TAGS Trial 507 TAS-102 5.7 m HR 0.69 2.0 m HR 0.57 4% 0.28 Shitara PB 3.6 m p<0.01 1.8 m p<0.01 2% Lancet Oncol 2018 The JAVELIN 300 Trial 371 Ave 4.6 m HR: 1.1 1.4 m HR: 1.73 2.2% – Bang CPT-11/ 5.0 m p=0.81 2.7 m p>0.99 4.3% Ann Oncol 2018 Pac (C) Targeted agents The TOGA Trial 594 CP/FP-T 13.8 m HR 0.74 6.7 m HR 0.71 47% <0.01 Bang CP/FP 11.1 m p<0.01 5.5 m p<0.01 35% Lancet 2010 The TRIO-013/LOGIC Trial 545 OC+L 12.2 m HR 0.91 6.0 m HR 0.82 53% <0.01 Hecht OC 10.5 m p=0.34 5.4 m p=0.038 39% J Clin Oncol 2016 The JACOB Trial 780 CP/FP-T- 17.5 m HR 0.84 8.5 m HR 0.73 56.7% 0.026 Tabernero Per 14.2 m p=0.057 7.0 m p<0.01 48.3% Lancet Oncol 2018 CP/FP-T Continued Alsina M, et al. ESMO Open 2019;4:e000521. doi:10.1136/esmoopen-2019-000521 3 Open access Table 1 Continued Clinical trial N Treatment OS PFS ORR P value The TyTAN (Tykerb With Taxol in Asian 261 Pac +L 11.0 m HR 0.84 5.4 m HR 0.85 27% <0.01 HER2-Positive Gastric Cancer) Trial Pac 8.9 m p=0.104 4.4 m p=0.244 9% Satoh J Clin Oncol 2014 The GATSBY Trial 345 T-DM1 7.9 m HR 1.15 2.7 m HR 1.13 20.6% 0.840 Tuss-Patience D/Pac 8.6 m p=0.86 2.9 m p=0.31 19.6% Lancet Oncol 2017 The Erbitux (cetuximab) in combination 904 CP-Cet 9.4 m HR 1.00 4.4 m HR 1.09 30% 0.77 with Xeloda (capecitabine) and cisplatin CP 10.7 m p=0.95 5.6 m p=0.32 29% in advanced esophago-gastric cancer (EXPAND) Trial Lordick Lancet Oncol 2013 The REAL3 Trial 553 EOC-Pan 8.8 m HR 1.37 6.0 m HR 1.22 46% 0.42 Waddell EOC 11.3 m p=0.013 7.4 m p=0.068 42% Lancet Oncol 2013 The Avastin in Gastric cancer (AVAGAST) 774 CP-Bev 12.1 m HR 0.87 6.7 m HR 0.80 46% 0.031 Trial CP 10.1 m p=0.100 5.3 m p=0.003 37.4% Ohtsu J Clin Oncol 2011 The RAINFALL Trial 645 CP-Ram 11.2 m HR 0.96 5.7 m† HR 0.75 41.1% 0.17 Fuchs CP 10.7 m p=0.68 5.4 m p=0.011 36.4% Lancet Oncol 2019 The REGARD Trial 355 Ram 5.2 m HR 0.77 2.1 m HR 0.48 3% 0.76 Fuchs PB 3.8 m p=0.047 1.3 m p<0.01 3% Lancet 2014 The RAINBOW Trial 665 Pac-Ram 9.6 m HR 0.80 4.4 m HR 0.63 28% <0.01 Wilke Pac 7.4 m p=0.017 2.9 m p<0.01 16% Lancet Oncol 2014 The Apatinib Trial 267 Apa 6.5 m HR 0.70 2.6 m HR 0.44 2.84% 0.169 Li PB 4.7 m p=0.015 1.8 m p<0.01 0% J Clin Oncol 2016 The RILOMET-1 Trial 609 EPC-Rilo 8.8 m HR 1.34 5.6 m HR 1.26 29.8% <0.01 Catenacci EPC 10.7 m p=0.003 6.0 m p=0.016 44.6% Lancet Oncol 2017 The METGASTRIC Trial 562 FOLFOX- 11.0 m HR 0.82 6.7 m HR 0.90 46.1% 0.25 Shah Ona 11.3 m p=0.24 6.8 m p=0.43 40.6% Jama Oncol 2016 FOLFOX The GOLD Trial 643 Pac-O 8.8 m HR 0.79 3.7 m HR: 0.84 17% 0.055 Bang Pac 6.9 m p=0.026 3.2 m p=0.065 11% Lancet Oncol 2017 The GRANITE-1 Trial 656 Eve 5.4 m HR 0.90 1.7 m HR 0.66 4.5% – Othsu PB 4.3 m p=0.124 1.4 m p<0.001 2.1% J Clin Oncol 2013 List of phase III clinical trials in (A) first-line treatment, (B) second-line treatment and beyond and (C) targeted agents. In green, those trials with statistically positive results. *Time to progression (not PFS). †Not confirmed by central independent review. –, not reported; Apa, apatinib; Ave, avelumab; BSC, best supportive care; Bev, bevacizumab; C, capecitabin; CPT-11, irinotecan; Cet, cetuximab; D, docetaxel; E, epirrubicin; Eve, everolimus; FOLFIRI, irinotecan, leucovorin, 5-fluorouracil; FOLFOX, oxaliplatin, leucovorin, 5-fluorouracil; 5-FU, 5-fluorouracil; L, lapatinib; O, olaparib;OS, overall survival; OX, oxaliplatin; Ona, onartuzumab; P, cisplatin; PB, placebo; PFS, progression-free survival; Pac, paclitaxel; Pan, panitumumab; Pem, pembrolizumab; Per, pertuzumab; Ram, ramucirumab; Rilo, rilotumumab;T, trastuzumab; TAS-102, trifluridine/tipiracil; m, months. 4 Alsina M, et al. ESMO Open 2019;4:e000521. doi:10.1136/esmoopen-2019-000521 Open access the second line) are acceptable, despite a lack of clear evidence. Trifluridine/tipiracil will likely be considered in the near future due to the benefit shown in a phase III clinical trial.17 Innovative strategies The GC treatment paradigm may change in the near future. Recognition of the historic failure in molecular selection due to GC heterogeneity was an important first step. Liquid biopsies should help us to acquire impor- tant biomarker information.18 Moreover, and taking into account the underlying gastritis that normally precedes GC tumorigenesis, the encouraging results showed by immune checkpoint inhibitors in the refractory setting19 will hopefully be translated into the clinical setting from the ongoing phase III clinical trials, with a consequent significant improvement in the prognosis of patients with GC. In GC tumours with microsatellite instability, pembroli- zumab, although not approved by the Europena Medicines Agency, may be recommended, as well as in refractory programmed death-ligand 1-positive (combined positive score) patients.19 In the Asian population, nivolumab has shown OS benefit in this refractory setting.20 Conclusions Patients with GC should be discussed in multidisciplinary tumour boards. The particular fragility of these patients Figure 1 Algorithm for the treatment of GC. ECOG, Eastern Cooperative Oncology Group; FLOT, fluorouracil, requires close monitoring by multiple specialists including leucovorin, oxaliplatin, docetaxel; GC, gastric and gastro- nutritionists and supportive care professionals. Moreover, oesophageal junction cancer; HER-2, human epidermal given the molecular complexity of these tumours, careful growth factor receptor 2; PS, performance status. hierarchy when selecting a targeted treatment should be considered. Having established the standard practice in the clinic (figure 1), physicians should always consider a HER2, epidermal growth factor receptor, MET, the tyro- clinical trial as the first option to offer. sine kinase receptor activated by the hepatocyte growth Funding The authors have not declared a specific grant for this research from any factor, fibroblast growth factor receptor 2, phosphati- funding agency in the public, commercial or not-for-profit sectors. dylinositol 3-kinase-mammalian target of rapamycin, Competing interests MA reports personal financial interest in form of scientific vascular endothelial growth factor (first line) and consultancy role for BMS, Servier and MSD. She has received honorarium for poly(ADP-ribose) polymerase-1 (table 1b). speaking issues from MSD, BMS, Lilly, Roche and Amgen; and has had travel Finally, comorbidities, organ function and performance expenses partially covered by Roche, Amgen and Lilly. JMM does not report personal financial interest. MD has received travel expenses partially covered by status (PS) must always be taken into consideration when Ipsen, Lilly and Servier. SC reports personal financial interest in form of honorarium choosing a regimen. for speaking issues or travel expenses from Johnson&Johnson, Wyeth, Covidien and Roche. JT reports personal financial interest in form of scientific consultancy role Second-line treatment for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Second-line treatment based at a minimum on chemo- Genentech, Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences therapy (paclitaxel, docetaxel or irinotecan) should be Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign considered in patients with PS 0–1, with the most robust SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle evidence demonstrated for combined paclitaxel and Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation ramucirumab (table 1c). This combination has demon- Medicine, HalioDX SAS and Roche Diagnostics. strated a benefit in both survival and also in quality of Patient consent for publication Not required. life. Provenance and peer review Commissioned; internally peer reviewed. Open access This is an open access article distributed in accordance with the Further lines Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which Further lines can be considered in fit patients (PS 0–1). permits others to distribute, remix, adapt, build upon this work non-commercially, Third lines with taxanes or irinotecan (depending on and license their derivative works on different terms, provided the original work is Alsina M, et al. 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