Stomach cancer medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Parminder Dhingra, M.D. [3] Mohammed Abdelwahed M.D[4]

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Overview

The optimal therapy for stomach cancer depends on the stage at diagnosis and, in advanced disease, increasingly on molecular biomarkers. For patients with resectable disease, perioperative chemotherapy with the FLOT regimen (fluorouracil, leucovorin, oxaliplatin, and docetaxel) is the preferred standard for medically fit patients, having demonstrated superior Survival rate|overall survival compared with the older epirubicin-based ECF/ECX regimen (median Survival rate|overall survival 50 versus 35 months) in the phase 3 FLOT4-AIO trial.[1] The addition of perioperative immunotherapy with durvalumab to FLOT further improved event-free survival and overall survival in the phase 3 MATTERHORN trial.[2] Adjuvant chemoradiotherapy and adjuvant chemotherapy with S-1 or capecitabine plus oxaliplatin remain acceptable options, particularly where perioperative therapy was not given. Medical therapy is also indicated for patients with unresectable or recurrent disease, after non-curative R2 resection, unresectable T4b disease, extensive nodal disease, hepatic metastases, peritoneal dissemination, or other M1 disease. Response to treatment should be evaluated by examinations such as CT scan, endoscopy, and contrast radiography. For unresectable, recurrent, or metastatic disease, systemic therapy is guided by biomarker testing for HER2 overexpression, programmed death-ligand 1 (PD-L1) combined positive score (CPS), claudin 18.2 (CLDN18.2), and mismatch repair/microsatellite instability (MMR/MSI) status. First-line therapy uses a fluoropyrimidine plus platinum backbone, to which a PD-1 inhibitor (nivolumab or pembrolizumab) is added in HER2-negative disease, trastuzumab is added in HER2-positive disease (with pembrolizumab for PD-L1–positive HER2-positive tumors), and zolbetuximab is added for CLDN18.2-positive tumors. For locally advanced unresectable and metastatic tumors, the goals of chemotherapy include palliation of symptoms, improvement in quality of life, and prolongation of survival; later-line options include ramucirumab with or without paclitaxel, trastuzumab deruxtecan for HER2-positive disease, and trifluridine/tipiracil.

Medical Therapy

The goal of chemotherapy is to delay disease-related symptoms and to prolong survival. Some patients with advanced disease survive more than 5 years by chemotherapy alone. The median survival time of chemotherapy for recurrent gastric cancer is 6–13 months, and with modern immunotherapy-containing first-line regimens median Survival rate|overall survival now exceeds 12–14 months in biomarker-selected populations.

  • Indications:
    • Patients with unresectable or recurrent disease
    • After non-curative R2 resection (macroscopic removal of primary tumor margins)
    • Patients with unresectable T4b disease
    • Extensive nodal disease
    • Hepatic metastases
    • Peritoneal dissemination or other M1 disease (metastatic disease)

Response to the treatment should be evaluated by examinations such as CT scan, endoscopy and contrast radiography, followed by comparison with the baseline data. Tumor shrinkage should be evaluated by response criteria of the Japanese Classification of Gastric Carcinoma or Response Evaluation Criteria in Solid Tumors (RECIST) to decide whether to continue treatment.When continuation of the treatment is deemed oncologically feasible, the drug dosage and administration schedule should be reconsidered taking into account the adverse events observed in the previous cycle of treatment. Attention should also be paid to cumulative adverse events such as skin manifestations, taste disturbance and neurotoxicity. Chemotherapy for individuals exposed to or infected with hepatitis B virus should be screened, monitored, and treated. Before starting first-line systemic therapy for advanced disease, predictive biomarker testing for HER2, PD-L1 CPS, CLDN18.2, and MMR/MSI status is recommended, as each directs the choice of targeted or immunotherapeutic agents. These drugs are to be used alone or in combination, adhering to the dose and schedule employed when being evaluated in clinical trials.

Drugs used in chemotherapy for gastric cancer

The following drugs may be used as chemotherapy or targeted/immunotherapy for the treatment of gastric cancer:[3]

Postoperative Adjuvant Chemotherapy

Postoperative adjuvant chemotherapy is indicated to reduce recurrence by controlling residual tumor cells following curative resection. Adjuvant treatment would be recommended for any T stage with N1 disease. The AJCC staging system supports observation for T2N0 stage IB patients as long as they have undergone an adequate lymph node dissection. For medically fit patients with resectable disease, perioperative chemotherapy (FLOT), rather than postoperative chemotherapy alone, is the preferred approach in Western practice (see below). S-1 efficacy was proven in the ACTS-GC trial, which secured the place of postoperative chemotherapy with S-1 as a standard of care; five-year overall survival was 71.7% with S-1 versus 61.1% with surgery alone (hazard ratio 0.669).[4][5] The CLASSIC trial showed significant prolongation of disease-free survival with adjuvant capecitabine plus oxaliplatin after D2 gastrectomy; the estimated 5-year disease-free survival was 68% versus 53% with observation (hazard ratio 0.58), with 5-year overall survival of 78% versus 69% (hazard ratio 0.66).[6] Combination of S-1 and another cytotoxic drug has also been studied in the postoperative setting.[7] The patients eligible for the ACTS-GC trial were those with a tumor of pathological stage II, IIIA or IIIB, excluding those classified as stage II due to T1, N2, N3 status.

Perioperative immunotherapy (MATTERHORN)

In the phase 3 MATTERHORN trial, adding durvalumab to perioperative FLOT in resectable stage II–IVa gastric or gastroesophageal junction adenocarcinoma significantly improved event-free survival (hazard ratio 0.71; 95% CI 0.58–0.86; p<0.001; median event-free survival not reached versus 32.8 months) and overall survival (hazard ratio 0.78; 95% CI 0.63–0.96; p=0.021) versus FLOT plus placebo, without a major increase in high-grade adverse events.[2]

Patients Who Have Already Undergone Potentially Curative Resection

Adjuvant chemoradiotherapy, rather than surgery alone, was established as beneficial for patients who did not receive preoperative therapy.[8] For patients who received preoperative chemotherapy, continuing the same regimen postoperatively (e.g., completing perioperative FLOT) is generally preferred over adjuvant chemoradiotherapy. For patients with T2N0 disease, observation or adjuvant treatment is acceptable and the decision is based on the general condition of the patient and risk factors.

Preferred regimen (perioperative FLOT):

Docetaxel 50 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24-hour infusion, on day 1 every two weeks, for four preoperative and four postoperative cycles.[1]

Alternative regimen (adjuvant chemoradiotherapy, INT-0116):

One cycle of fluorouracil (425 mg/m2 of body surface area) + leucovorin calcium (20 mg/m2 of body surface area) for five days followed by radiation therapy for one month given with the same chemotherapy regimen on days 1 through 4 and the last three days of the month.[9] Two more five-day cycles of chemotherapy are given at monthly intervals beginning one month after completion of radiation.

Japanese S-1 approach:

S-1 is approved in Japan for adjuvant therapy of gastric cancer and in Europe for treatment of advanced gastric cancer.[10] S-1 is an oral fluoropyrimidine that includes three different agents:[5]

  • Ftorafur (tegafur)
  • Gimeracil
  • Oteracil (which reduces gastrointestinal toxicity such as diarrhea)

Most trials do not show increased benefit of radiotherapy over chemotherapy alone in the adjuvant setting.[11]

Patients With Potentially Resectable Disease Not yet Resected

For most patients with potentially resectable gastric cancer, perioperative therapy is preferred over initial surgery.

Neoadjuvant/perioperative chemotherapy

Neoadjuvant chemotherapy may be administered in locally advanced tumors before surgery. This approach has been applied to patients thought to have resectable disease as well as to those with apparently unresectable but non-metastatic disease. Another benefit of neoadjuvant chemotherapy is that patients who are at high risk of developing distant metastases may be spared the morbidity of unnecessary gastrectomy if evidence of distant metastases emerges after chemotherapy. Preoperative combined chemotherapy and radiation therapy is more commonly used for esophageal, esophagogastric junction cancers, and cancer affecting the gastric cardia rather than for potentially resectable adenocarcinomas. In historical multi-institutional experience, response rates of 20% to 30% were seen, with 70% to 78% of patients able to undergo an R0 resection after chemoradiotherapy.[12]

Choice of regimen and patient selection

The FLOT regimen is the preferred perioperative chemotherapy, rather than an epirubicin-containing regimen, based on the FLOT4-AIO trial.[1] For medically fit patients, the addition of perioperative durvalumab to FLOT may be considered based on the MATTERHORN trial.[2] Epirubicin-containing triplets (ECF/ECX) are now regarded as inferior alternatives reserved for patients unable to receive FLOT.

FLOT regimen

A docetaxel-based triplet with oxaliplatin, leucovorin, and short-term infusional fluorouracil, administered every two weeks. In the phase 2 portion of FLOT4-AIO, FLOT achieved higher rates of pathological complete or subtotal regression than ECF/ECX; in the phase 3 analysis it improved median overall survival to 50 months versus 35 months (hazard ratio 0.77; 95% CI 0.63–0.94; p=0.012), with better R0 resection and disease-free survival.[13][1]

Drug Dose (day 1, every 2 weeks)
Docetaxel 50 mg/m2 IV
Oxaliplatin 85 mg/m2 IV
Leucovorin 200 mg/m2 IV
Fluorouracil 2600 mg/m2 as a 24-hour infusion

ECF/ECX regimens (alternative)

One option is to administer three cycles prior to resection and then three cycles after surgery. These epirubicin-based triplets are now considered less favorable than FLOT and are reserved for patients who cannot tolerate docetaxel- or oxaliplatin-based therapy.[14]

Epirubicin, cisplatin, and capecitabine (ECX) regimen

Drug Dose
Epirubicin 50 mg/m2 IV
Cisplatin 60 mg/m2 IV
Capecitabine 625 mg/m2 per dose by mouth

Epirubicin, cisplatin, and fluorouracil (ECF) regimen

Drug Dose
Epirubicin 50 mg/m2 IV
Cisplatin 60 mg/m2 IV
Fluorouracil (FU) 200 mg/m2 per day IV

Patients monitoring

Locally Unresectable Metastatic Disease

Options for anticancer therapy include chemotherapy alone or chemoradiotherapy. Unresectable locally advanced gastric cancer is treated primarily with chemotherapy, using the same biomarker-directed regimens as are used for metastatic disease. Initial chemotherapy treatment may transform a previously unresectable tumor into a resectable tumor. A subset of patients with localized but initially unresectable gastric cancer can undergo potentially curative resection after preoperative chemotherapy for locally advanced disease without distant metastases.[15][16] Pathological complete response rates with conversion chemotherapy alone remain low, in the range of 5% to 15%.[17]

Locally Advanced Unresectable And Metastatic

Initial Management

Goals of chemotherapy include palliation of symptoms, improvement in quality of life, and prolongation of survival.[17] Combination chemotherapy regimens provide higher response rates than do single agents.[18] All patients should undergo predictive biomarker testing (HER2, PD-L1 CPS, CLDN18.2, MMR/MSI) before selecting first-line therapy. The chemotherapy backbone is a fluoropyrimidine (fluorouracil, capecitabine, or S-1) combined with a platinum agent (oxaliplatin or cisplatin); oxaliplatin-based doublets (FOLFOX, CAPOX) are generally preferred for tolerability.

Medical Therapy

First-line biomarker-directed therapy

Biomarker / subgroup Recommended first-line therapy Key evidence
HER2-negative, PD-L1 CPS ≥5 (and considered CPS ≥1) Fluoropyrimidine + oxaliplatin + nivolumab CheckMate 649: CPS ≥5 OS HR 0.71, PFS HR 0.68[19]
HER2-negative (all CPS, greatest benefit CPS ≥1/≥10) Fluoropyrimidine + platinum + pembrolizumab KEYNOTE-859: OS 12.9 vs 11.5 months, HR 0.78; CPS ≥10 15.7 vs 11.8 months, HR 0.65[20]
HER2-negative, CLDN18.2-positive (≥75% tumor cells moderate–strong membrane staining) Zolbetuximab + mFOLFOX6 or CAPOX SPOTLIGHT: PFS 10.61 vs 8.67 months, HR 0.751 (p=0.0066); GLOW: PFS 8.21 vs 6.80 months, HR 0.687; OS 14.39 vs 12.16 months, HR 0.771[21][22]
HER2-positive (IHC 3+, or IHC 2+/FISH-positive) Fluoropyrimidine + platinum + trastuzumab (add pembrolizumab if PD-L1 CPS ≥1) ToGA: OS 13.8 vs 11.1 months, HR 0.74; KEYNOTE-811: OS 20.0 vs 16.8 months, HR 0.80[23][24]
MSI-high / dMMR PD-1 inhibitor–containing therapy (pembrolizumab or nivolumab); immunotherapy alone may be considered Marked, durable benefit in MSI-high subgroups of first-line immunotherapy trials[19]

Trastuzumab (HER2-positive): In the ToGA trial, adding trastuzumab to cisplatin plus a fluoropyrimidine improved median overall survival to 13.8 months versus 11.1 months (hazard ratio 0.74; 95% CI 0.60–0.91; p=0.0046).[23] Pembrolizumab with trastuzumab (HER2-positive): In KEYNOTE-811, adding pembrolizumab to trastuzumab plus chemotherapy improved median overall survival to 20.0 months versus 16.8 months (hazard ratio 0.80; p=0.0040), with benefit concentrated in PD-L1 CPS ≥1 tumors.[24] Nivolumab (HER2-negative): In CheckMate 649, first-line nivolumab plus chemotherapy improved overall survival and progression-free survival in patients with PD-L1 CPS ≥5 (OS hazard ratio 0.71; PFS hazard ratio 0.68) and in the overall randomized population, with benefit maintained at 5-year follow-up.[19] Pembrolizumab (HER2-negative): In KEYNOTE-859, first-line pembrolizumab plus chemotherapy improved median overall survival to 12.9 months versus 11.5 months (hazard ratio 0.78; 95% CI 0.70–0.87; p<0.0001), with greater benefit at higher PD-L1 CPS (CPS ≥10: 15.7 vs 11.8 months; hazard ratio 0.65).[20] Zolbetuximab (CLDN18.2-positive): In SPOTLIGHT, zolbetuximab plus mFOLFOX6 improved median progression-free survival to 10.61 months versus 8.67 months (hazard ratio 0.751; p=0.0066) and overall survival (hazard ratio 0.750; p=0.0053).[21] In GLOW, zolbetuximab plus CAPOX improved median progression-free survival to 8.21 months versus 6.80 months (hazard ratio 0.687; p=0.0007) and median overall survival to 14.39 months versus 12.16 months (hazard ratio 0.771; p=0.0118).[22]

Second-line and subsequent therapy

Setting Preferred therapy Key evidence
Second-line, unselected Ramucirumab + paclitaxel RAINBOW: OS 9.6 vs 7.4 months, HR 0.807 (p=0.017)[25]
Second-line, patients unfit for combination Ramucirumab monotherapy REGARD: significant OS and PFS benefit vs placebo[26]
Second-line or later, HER2-positive (prior trastuzumab) Trastuzumab deruxtecan DESTINY-Gastric01: OS 12.5 vs 8.9 months, HR 0.59–0.60; DESTINY-Gastric04: superior OS vs ramucirumab + paclitaxel[27][28]
Third-line or later Trifluridine/tipiracil TAGS: OS 5.7 vs 3.6 months, HR 0.69[29]
MSI-high / dMMR (if not previously treated with immunotherapy) Pembrolizumab or nivolumab Durable responses in MSI-high tumors[19]

Ramucirumab + paclitaxel: In RAINBOW, this combination improved median overall survival to 9.6 months versus 7.4 months with paclitaxel alone (hazard ratio 0.807; 95% CI 0.678–0.962; p=0.017).[25] Ramucirumab monotherapy: In REGARD, ramucirumab improved overall survival and progression-free survival versus placebo in previously treated advanced disease and was the first anti-angiogenic agent approved in this setting.[26]Trastuzumab deruxtecan (HER2-positive): In DESTINY-Gastric01, this antibody-drug conjugate improved response and overall survival (12.5 vs 8.9 months) versus chemotherapy in patients progressing after trastuzumab.[27] In the confirmatory phase 3 DESTINY-Gastric04 trial, trastuzumab deruxtecan produced significantly longer overall survival than ramucirumab plus paclitaxel in the second-line HER2-positive setting.[28] Trifluridine/tipiracil: In TAGS, this oral agent improved median overall survival to 5.7 months versus 3.6 months with placebo in heavily pretreated metastatic disease (hazard ratio 0.69).[29]

Procedural / Surgical Therapy

Palliative surgery or endoscopic intervention may be indicated for bleeding, obstruction, or perforation, but systemic therapy remains the mainstay for metastatic disease. Radiation therapy may be used for palliation of bleeding, pain, or obstruction. Conversion gastrectomy may be considered in highly selected patients who achieve a marked response to systemic therapy, though evidence for routine use is limited.

Long-Term Management

Immunotherapy-containing regimens may be continued until disease progression or unacceptable toxicity, with checkpoint inhibitors often continued for a defined maximum duration (commonly up to two years). Ongoing monitoring for immune-related adverse events (e.g., thyroiditis, colitis, pneumonitis, hepatitis) is required during checkpoint inhibitor therapy. Nutritional support, management of anemia, and palliative care integration improve quality of life across the treatment course.

Special Populations

Elderly and frail patients: Reduced-intensity doublets or single-agent fluoropyrimidine may be preferred; oxaliplatin-based doublets are generally better tolerated than cisplatin-based regimens. HER2-positive disease: HER2 testing should be repeated on re-biopsy at progression when feasible, given the overall survival benefit of trastuzumab deruxtecan after prior trastuzumab. MSI-high / dMMR tumors: Derive substantial and durable benefit from PD-1 inhibitors and may be candidates for immunotherapy-based approaches, including in the perioperative setting under investigation. CLDN18.2-positive tumors: Should be identified on validated immunohistochemistry to select patients for zolbetuximab; nausea and vomiting are the most common toxicities and require prophylaxis. Hepatitis B virus carriers: Require screening and antiviral prophylaxis before and during chemotherapy to prevent reactivation.

References

  1. ↑ 1.0 1.1 1.2 1.3 Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Löhr C, Bernhard H, Schuch G, Rethwisch V, von Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Weniger J, Belle S, Gaiser T, Oduncu FS, Güntner M, Hozaeel W, Reichart A, Jäger E, Kraus T, Mönig S, Bechstein WO, Schuler M, Schmalenberg H, Hofheinz RD (May 2019). "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. 393 (10184): 1948–1957. doi:10.1016/S0140-6736(18)32557-1. PMID 30982686.
  2. ↑ 2.0 2.1 2.2 Janjigian YY, Al-Batran SE, Wainberg ZA, Muro K, Molena D, Van Cutsem E, Hyung WJ, Wyrwicz L, Oh DY, Guimbaud R, Yong WP, Ilson DH, Wang J, Kang N, Zander T, Bang YJ, Tabernero J (October 2025). "Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer". N Engl J Med. 393 (16): 1583–1595. doi:10.1056/NEJMoa2503701. PMID 40454643 Check |pmid= value (help).
  3. ↑ "Gastric Cancer Treatment (PDQ)–Patient Version". National Cancer Institute.
  4. ↑ Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A; et al. (2007). "Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine". N Engl J Med. 357 (18): 1810–20. doi:10.1056/NEJMoa072252. PMID 17978289.
  5. ↑ 5.0 5.1 Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T; et al. (2011). "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. 29 (33): 4387–93. doi:10.1200/JCO.2011.36.5908. PMID 22010012.
  6. ↑ Noh SH, Park SR, Yang HK, Chung HC, Chung IJ, Kim SW; et al. (2014). "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. 15 (12): 1389–96. doi:10.1016/S1470-2045(14)70473-5. PMID 25439693.
  7. ↑ Kodera Y, Ishiyama A, Yoshikawa T, Kinoshita T, Ito S, Yokoyama H; et al. (2010). "A feasibility study of postoperative chemotherapy with S-1 and cisplatin (CDDP) for gastric carcinoma (CCOG0703)". Gastric Cancer. 13 (3): 197–203. doi:10.1007/s10120-010-0559-y. PMID 20820990.
  8. ↑ Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN; et al. (2001). "Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction". N Engl J Med. 345 (10): 725–30. doi:10.1056/NEJMoa010187. PMID 11547741.
  9. ↑ O'Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG; et al. (1994). "Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery". N Engl J Med. 331 (8): 502–7. doi:10.1056/NEJM199408253310803. PMID 8041415.
  10. ↑ Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC; et al. (2017). "Chemotherapy for advanced gastric cancer". Cochrane Database Syst Rev. 8: CD004064. doi:10.1002/14651858.CD004064.pub4. PMID 28850174.
  11. ↑ Ilson DH (2017). "Current Progress in the Adjuvant Treatment of Gastric Cancer". Surg Oncol Clin N Am. 26 (2): 225–239. doi:10.1016/j.soc.2016.10.008. PMID 28279466.
  12. ↑ Ajani JA, Mansfield PF, Janjan N, Morris J, Pisters PW, Lynch PM; et al. (2004). "Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma". J Clin Oncol. 22 (14): 2774–80. doi:10.1200/JCO.2004.01.015. PMID 15254045.
  13. ↑ Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB; et al. (2016). "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. 17 (12): 1697–1708. doi:10.1016/S1470-2045(16)30531-9. PMID 27776843.
  14. ↑ Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH; et al. (2012). "Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial". Lancet. 379 (9813): 315–21. doi:10.1016/S0140-6736(11)61873-4. PMID 22226517.
  15. ↑ Gallardo-Rincón D, Oñate-Ocaña LF, Calderillo-Ruiz G (2000). "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. 7 (1): 45–50. PMID 10674448.
  16. ↑ Ajani JA, Mansfield PF, Janjan N, Morris J, Pisters PW, Lynch PM; et al. (2004). "Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma". J Clin Oncol. 22 (14): 2774–80. doi:10.1200/JCO.2004.01.015. PMID 15254045.
  17. ↑ 17.0 17.1 Yoshikawa T, Sasako M, Yamamoto S, Sano T, Imamura H, Fujitani K; et al. (2009). "Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer". Br J Surg. 96 (9): 1015–22. doi:10.1002/bjs.6665. PMID 19644974.
  18. ↑ Nakajima T, Ota K, Ishihara S, Oyama S, Nishi M, Ohashi Y, Yanagisawa A (1997). "Combined intensive chemotherapy and radical surgery for incurable gastric cancer". Ann. Surg. Oncol. 4 (3): 203–8. PMID 9142380.
  19. ↑ 19.0 19.1 19.2 19.3 Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Tsuji A, Ajani JA (July 2021). "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. 398 (10294): 27–40. doi:10.1016/S0140-6736(21)00797-2. PMID 34102137 Check |pmid= value (help).
  20. ↑ 20.0 20.1 Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, Rivera F, Alves GV, Garrido M, Shiu KK, Ferenc G, Shitara K, Kowalyszyn R, Benavides M, Bennouna J, Van Cutsem E, Metges JP, Wyrwicz L, Kang YK, Muro K, Bang YJ, Fuchs CS, Shih CS, Bhagia P, Tabernero J (November 2023). "Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial". Lancet Oncol. 24 (11): 1181–1195. doi:10.1016/S1470-2045(23)00515-6. PMID 37875143 Check |pmid= value (help).
  21. ↑ 21.0 21.1 Shitara K, Lordick F, Bang YJ, Enzinger P, Ilson D, Shah MA, Van Cutsem E, Xu RH, Aprile G, Xu J, Chao J, Pazo-Cid R, Kang YK, Yang J, Moran D, Bhattacharya P, Arozullah A, Park JW, Oh M, Ajani JA (May 2023). "Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial". Lancet. 401 (10389): 1655–1668. doi:10.1016/S0140-6736(23)00620-7. PMID 37068504 Check |pmid= value (help).
  22. ↑ 22.0 22.1 Shah MA, Shitara K, Ajani JA, Bang YJ, Enzinger P, Ilson D, Lordick F, Van Cutsem E, Gallego Plazas J, Huang J, Shen L, Oh SC, Sunpaweravong P, Soparattanapaisarn N, Moran D, Bhattacharya P, Arozullah A, Park JW, Oh M, Ryu MH (August 2023). "Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial". Nat Med. 29 (8): 2133–2141. doi:10.1038/s41591-023-02465-7. PMID 37524953 Check |pmid= value (help).
  23. ↑ 23.0 23.1 Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK (August 2010). "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. 376 (9742): 687–97. doi:10.1016/S0140-6736(10)61121-X. PMID 20728210.
  24. ↑ 24.0 24.1 Janjigian YY, Kawazoe A, Bai Y, Xu J, Lonardi S, Metges JP, Yanez P, Wyrwicz LS, Shen L, Ostapenko Y, Bilici M, Chung HC, Shitara K, Qin SK, Van Cutsem E, Tabernero J, Li K, Shih CS, Bhagia P, Rha SY (December 2023). "Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial". Lancet. 402 (10418): 2197–2208. doi:10.1016/S0140-6736(23)02033-0. PMID 37871604 Check |pmid= value (help).
  25. ↑ 25.0 25.1 Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A (October 2014). "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. 15 (11): 1224–35. doi:10.1016/S1470-2045(14)70420-6. PMID 25240821.
  26. ↑ 26.0 26.1 Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Koshiji M, Liang J, Schwartz JD, Marabotti C, Wang Y, Muro K (January 2014). "Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial". Lancet. 383 (9911): 31–39. doi:10.1016/S0140-6736(13)61719-5. PMID 24094768.
  27. ↑ 27.0 27.1 Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, Chung HC, Kawakami H, Yabusaki H, Lee J, Saito K, Kawaguchi Y, Kamio T, Kojima A, Sugihara M, Yamaguchi K (June 2020). "Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer". N Engl J Med. 382 (25): 2419–2430. doi:10.1056/NEJMoa2004413. PMID 32469182 Check |pmid= value (help).
  28. ↑ 28.0 28.1 Shitara K, Van Cutsem E, Gümüş M, Kim SS, Fatkhutdinov N, Barranco Sánchez A, Sung MW, Kang YK, Xu R, Elimova E, Doi T, Yamaguchi K, Sunakawa Y, Sacdalan D, Lee KW, Bai Y, Liu T, Zheng B, Zhu W, Wei J, Tabernero J (August 2025). "Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer". N Engl J Med. 393 (8): 759–771. doi:10.1056/NEJMoa2500892. PMID 40454632 Check |pmid= value (help).
  29. ↑ 29.0 29.1 Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalçın Ş, Fujitani K, Beretta GD, Cutsem EV, Winkler RE, Makris L, Ilson DH, Tabernero J (November 2018). "Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial". Lancet Oncol. 19 (11): 1437–1448. doi:10.1016/S1470-2045(18)30739-3. PMID 30355453.

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