• Should be considered in patients with stage IV disease that can improve survival compared with best supportive care alone
  • Co-morbidities, organ function and performance status must always be taken into consideration
• Decision to offer palliative or best supportive care alone or in combination with systemic therapy is based on the patient's performance status

Chemoradiation

• May be an option for medically fit patients with locally unresectable tumors and have no previous therapy
• Preferred regimens include:
  • Cisplatin and Fluorouracil
  • Cisplatin and Capecitabine
  • FOLFOX
  • CAPOX
• Other recommended regimens include: Fluoropyrimidine (Fluorouracil or Capecitabine) and Paclitaxel

• Provides palliation of symptoms, enhances quality of life and improves survival of patients with locally advanced or metastatic gastric cancer

First-line Therapy

• Two-drug cytotoxic combination regimens are preferred due to lower toxicity
• Three-drug cytotoxic combination regimens are reserved for medically fit patients with good performance status
• Oxaliplatin is preferred over Cisplatin due to lower toxicity
• Preferred regimens for HER2 overexpression-positive adenocarcinoma include:
  • Fluoropyrimidine (5-FU or Capecitabine) and Cisplatin and Trastuzumab
  • Fluoropyrimidine (5-FU or Capecitabine) and Oxaliplatin and Trastuzumab
• Preferred regimens for HER2 overexpression-negative adenocarcinoma include:
  • Fluoropyrimidine (5-FU or Capecitabine) and Cisplatin
  • Fluoropyrimidine (5-FU or Capecitabine) and Oxaliplatin
  • Fluoropyrimidine (5-FU or Capecitabine) + Oxaliplatin + Nivolumab for tumors with PD-L1 expression levels by CPS¹ ≥5
• Other recommended regimens include:
  • Docetaxel
  • Docetaxel and Cisplatin
  • Docetaxel, Cisplatin and Fluorouracil (DCF)
    • Has been recommended as alternative treatment option for the treatment of patients with advanced gastric cancer, including EGJ cancers, in patients who have not received prior chemotherapy
    • However, it was associated with increased myelosuppression and infectious complications
  • Docetaxel, Carboplatin and Fluorouracil
  • Docetaxel, Oxaliplatin and Fluorouracil
  • Fluoropyrimidine (Fluorouracil or Capecitabine)
  • Fluoropyrimidine (5-FU or Capecitabine) + Cisplatin + Trastuzumab + Pembrolizumab
    • For HER2 overexpression-positive adenocarcinoma
  • Fluoropyrimidine (5-FU or Capecitabine) + Oxaliplatin + Trastuzumab + Pembrolizumab
    • For HER2 overexpression-positive adenocarcinoma
  • Fluorouracil and Irinotecan (FOLFIRI)
  • Paclitaxel
  • Paclitaxel and Cisplatin or Carboplatin
• Fluoropyrimidine (5-FU or Capecitabine) + Oxaliplatin + Nivolumab may be useful in HER2 overexpression-negative adenocarcinoma with PD-L1 expression levels by combined positive score (CPS)¹ <5

Second-line or Subsequent Therapy

• Choice of agents depends on previous therapy and performance status
• Preferred regimens include:
  • Docetaxel
  • Fam-trastuzumab deruxtecan-nxki
    • For patients with HER2 overexpression-positive adenocarcinoma and received prior Trastuzumab-based therapy
  • FOLFIRI
    • For patients who did not previously receive FOLFIRI
  • Irinotecan
  • Paclitaxel
  • Ramucirumab and Paclitaxel
  • Trifluridine and Tipiracil
    • Indicated as third-line or subsequent therapy for select patients with low-volume gastric cancer without or minimal symptoms and with the ability to swallow pills
• Other recommended regimens include:
  • Docetaxel and Irinotecan
  • FOLFIRI + Ramucirumab
  • Irinotecan and Cisplatin
  • Irinotecan and Ramucirumab
  • Ramucirumab
• Agents useful in certain circumstances include:
  • Dostarlimab-gxly is indicated for MSI-high (MSI-H) or MMR-deficient (dMMR) tumors
  • Entrectinib or Larotrectinib is used for NTRK gene fusion-positive tumors
  • Pembrolizumab is indicated for MSI-H or dMMR tumors or for TMB high (≥10 mutations/megabase) tumors
• In patients of adequate performance status, second-line chemotherapy is associated with proven improvements in overall survival and quality of life compared with best supportive care

Targeted Therapies

• HER2 testing is recommended for all patients with inoperable, locally advanced, recurrent and metastatic disease at the time of diagnosis
• In HER2-positive gastric cancer, addition of Trastuzumab to a Cisplatin-Fluoropyrimidine doublet showed clinically and statistically significant improvements in response rate, progression-free survival and overall survival
  • Trastuzumab in combination with Cisplatin and fluoropyrimidine (first-line) or with other chemotherapy agents (eg Capecitabine or 5-fluorouracil and Oxaliplatin) is the standard care regimen
  • Trastuzumab was limited only in patients with an IHC score of 3+ or 2+ and FISH positive
  • Trastuzumab is not recommended to be continued in second-line therapy
• Pembrolizumab is a PD-1 antibody
  • Other second-line or subsequent therapy for MSI-H or dMMR tumors or for TMB high (≥10 mutations/megabase) tumors
  • May be added to first-line fluoropyrimidine, platinum and Trastuzumab in the treatment of HER2 overexpression-positive adenocarcinoma
• Dostarlimab-gxly is a PD-1 antibody
  • Indicated for patients with progressive MSI-H or dMMR gastric cancer on or following prior therapy which did not include a checkpoint inhibitor such as PD-1i, PDL-1i, or CTLA4i, and without alternative therapy options
• Entrectinib or Larotrectinib is recommended as second-line or subsequent therapy for NTRK gene fusion-positive tumors
• Fam-trastuzumab deruxtecan-nxki is an antibody-conjugate composed of Trastuzumab and a cytotoxic topoisomerase I inhibitor which is connected by a cleavable tetrapeptide-based linker
  • Preferred second-line or subsequent therapy for patients with HER2 overexpression-positive adenocarcinoma and received prior Trastuzumab-based therapy
• Nivolumab is a monoclonal PD-1 antibody
  • In combination with fluoropyrimidine- and platinum-based chemotherapy is approved as first-line therapy for patients with HER2-negative advanced or metastatic gastric cancer with PD-L1 expression levels by CPS¹ of ≥5 and may be useful in tumors with a CPS¹ <5
    • Addition of Nivolumab to chemotherapy resulted in significant improvements in overall survival and progression-free survival in patients with a PD-L1 CPS¹ of ≥5
• Targeting vascular endothelial growth factor receptors (VEGFR) with the anti-VEGFR-2 monoclonal antibody Ramucirumab showed promising results in patients with advanced gastric or EGJ adenocarcinoma positive for disease progression despite treatment with platinum-/fluoropyrimidine-based doublet/triplet chemotherapy
  • Ramucirumab may be given alone or in combination with Paclitaxel

Palliative/Best Supportive Care

• Recommended for all patients with unresectable locally advanced, recurrent or metastatic gastric cancer
• Goal is to prevent, reduce and relieve suffering and improve the quality of life for patients and their families

Interventional Radiotherapy

• Angiographic embolization may be considered in patients with acute bleeding not relieved by endoscopy

Radiotherapy

• Hypofractionated radiotherapy is an effective and well-tolerated treatment modality which may palliate bleeding, obstructive symptoms or pain in patients with symptomatic locally advanced or recurrent disease
• External beam radiotherapy may be considered for patients with malignant obstruction causing pain, and acute or chronic gastrointestinal bleeding

Surgery

• Surgeries that will aid the patients with unresectable gastric cancer control the cancer or prevent or relieve symptoms or complications 
• Although resection of the primary tumor is not generally recommended in the palliative setting, a small number of advanced disease patients may be deemed to be operable following a good response in systemic therapy
• Gastric resections should be reserved for palliation of symptoms such as obstruction or uncontrollable bleeding in patients with incurable disease
  • Gastrojejunostomy or gastrectomy may be done to alleviate or bypass obstruction
    • Gastrojejunostomy is preferred for gastric outlet obstruction over endoluminal stenting for patients fit for surgery and with a more prolonged prognosis 
  • Lymph node dissection is not required

• Subtotal gastrectomy can help in problems of bleeding, pain or blockage in the stomach
• Limited gastric resection, even with positive margins, is acceptable for unresectable tumors for symptomatic palliation of bleeding
  • Presence of peritoneal involvement, distant metastases, or locally advanced disease (eg invasion or encasement of major blood vessels) are contraindications for resection

• Routine or prophylactic splenectomy should be avoided if possible
• Gastric bypass (gastrojejunostomy) can treat or prevent large tumors that block food from leaving the stomach
  • For selected patients who will be receiving postoperative chemoradiation, placement of a venting gastrostomy or jejunostomy feeding tube may be considered

• Endoscopic tumor ablation helps to stop bleeding or help relieve blockage without surgery
  • For short-term control of bleeding

• Stent placement helps keep the opening at the beginning and end of the stomach open and allows food to pass through it
  • Endoscopic insertion of self-expanding metal stents (SEMS) has been shown to be effective for the long-term relief of tumor obstruction at the gastric outlet or EGJ
    • Preferred over gastrojejunostomy for patients with luminal obstruction secondary to advanced gastric cancer and with relatively short life expectancy
• Venting gastrostomy may be performed to reduce symptoms of obstruction when bypass or alleviation is not possible
• Feeding tube placement is done to help in the liquid nutrition that can be put directly into the tube