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Sections Gastric Cancer Treatment Protocols
General Treatment Recommendations
Preoperative Chemoradiotherapy Regimens
Perioperative Chemotherapy Regimens
Postoperative Chemoradiotherapy Regimens
First-Line Chemotherapy for Metastatic or Locally Advanced Cancer (Where Local Therapy Not Indicated)
Second-Line Chemotherapy for Metastatic or Locally Advanced Cancer (Where Local Therapy Not Indicated)
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References

General Treatment Recommendations

Tumors involving the esophagogastric junction (EGJ) with the 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.

Treatment decisions should be made with a multidisciplinary team^[1] and based on the following:

Stage of disease
Surgical fitness of the patient
Patient preference
Patient comorbidities

Stage 0 to IA

Surgery is the primary treatment for early-stage gastric cancer. Complete surgical resection offers the potential for long-term survival.

Laparoscopic resection is an emerging modality that may improve operative mortality, but requires additional investigation.^[2]Endoscopic mucosal resection and endoscopic submucosal dissection should be performed only in experienced medical centers.^[1]

Stage IB to IIIC, potentially resectable

For medically fit patients, perioperative neoadjuvant chemotherapy or chemoradiotherapy followed by surgery is appropriate. Perioperative therapy is common practice, with chemoradiotherapy after surgery showing a clear survival benefit in patients who did not receive preoperative chemotherapy^[3]. For patients who received preoperative chemotherapy, the addition of postoperative radiotherapy has not demonstrated additional benefit.^[4]

Medically unfit patients can be treated with chemoradiotherapy or chemotherapy.

Stage IV

Chemotherapy based around a doublet or triplet platinum/fluoropyrimidine combination is given for metastatic disease. Local therapy is not indicated. HER2 and programmed cell death ligand 1 (PD-L1) testing are recommended upon confirmation of metastatic disease.^{[1, 5]}

Trastuzumab should be added to first-line chemotherapy in HER2-NEU–overexpressing metastatic adenocarcinomas.^{[6, 5]}

Preferred regimens

A higher level of evidence supports use of the following regimens; clinical trials have shown strong benefit and there is consensus among experts (note: infusional fluorouracil can be replaced by capecitabine)^[1]:

Oxaliplatin 85 mg/m² IV on day 1 plus leucovorin 400 mg/m² IV on day 1 plus 5-fluorouracil (5-FU) 400 mg/m² IV push (IVP) on day 1 and 5-FU 800 mg/m² continuous IV infusion daily on days 1 and 2; every 14 d for three cycles with radiation^[7] or
Oxaliplatin 85 mg/m² IV on days 1, 15, and 29 for 3 doses plus capecitabine 625 mg/m² PO BID on days 1-5 weekly for 5 wk^[8] or
Cisplatin 75-100 mg/m² IV on day 1 and 29 plus 5-FU 750-1000 mg/m²/day IV continuous infusion on days 1-4 and 29-32; single 35-day cycle^[9] or
Cisplatin 15 mg/m² IV daily on days 1-5 plus 5-FU 800 mg/m²/day IV continuous infusion on days 1-5; 21-day cycle for two cycles^[10]or
Cisplatin 30 mg/m² IV on day 1 plus capecitabine 800 mg/m² PO BID on days 1-5; weekly for 5wk^[11] or
Paclitaxel 45-50 mg/m² IV on day 1 plus 5-FU 300 mg/m² continuous IV infusion daily on days 1-5; weekly for 5 wk^[12] or
Paclitaxel 45-50 mg/m² IV on day 1 plus capecitabine 625-825 mg/m² PO BID daily on days 1-5; weekly for 5 wk^{[12, 13]}

Other regimens

A lower level of evidence supports use of the following regimens; smaller studies show benefit of the therapy, and therapy may need to be used on the basis of the clinical situation (eg, limiting toxicities, patient comorbidity)^[1]:

Paclitaxel 50 mg/m² IV on day 1 plus carboplatin area under the curve (AUC) 2 IV on day 1; weekly for 5 wk^{[14, 15]}(see the Carboplatin AUC Dose Calculation [Calvert formula] calculator) or

Perioperative Chemotherapy Regimens

Note that in regimens that contain a fluoropyrimidine (5-FU or capecitabine), infusional fluorouracil can be replaced by capecitabine.

Preferred regimens

The FLOT (fluorouracil, oxaliplatin, docetaxel [Taxotere]) regimen is given for four preoperative cycles and then four postoperative cycles, as follows:

5-FU 2600 mg/m ² IV continuous infusion on day 1 plus leucovorin 200 mg/m ² IV on day 1 plus oxaliplatin 85 mg/m ²on day 1 plus docetaxel 50 mg/m ² on day 1, every 14 days ^[16]

The following fluoropyrimidine (5-FU or capecitabine) and oxaliplatin regimens are given in three preoperative cycles and then three postoperative cycles

Oxaliplatin 85 mg/m ² IV on day 1 plus leucovorin 400 mg/m ² IV on day 1 plus 5-FU 400 mg/m ² IVP on day 1 plus 5-FU 1200 mg/m ² continuous IV infusion daily on days 1 and 2; 14-day cycle ^[17]
Oxaliplatin 85 mg/m ² plus 5-FU 2600 mg/m ² IV continuous infusion on day 1 plus leucovorin 200 mg/m ² IV on day 1; 14-day cycle ^[18]
Capecitabine 1000 mg/m ² PO BID on Days 1-14 plus oxaliplatin 130 mg/m ² IV on day 1; 21-day cycle ^[19]

Other regimens

The following regimen is given in four preoperative cycles and then four postoperative cycles:

Cisplatin 50 mg/m ² IV on day 1 plus 5-FU 2000 mg/m ²/day IV continuous infusion daily on days 1-2; 14-day cycle

Postoperative Chemoradiotherapy Regimens

Compared with surgery alone, adjuvant chemotherapy leads to improved overall survival.^[20]Postoperative chemotherapy regimens for patients who underwent D2 lymph node dissection include the following:

Oxaliplatin 130 mg/m ² IV on day 1 plus capecitabine 1000 mg/m ² PO BID on days 1-14; every 21 d for eight cycles ^[21] or
Oxaliplatin 85 mg/m ² IV on day 1 plus leucovorin 400 mg/m ² IV on day 1 plus 5-FU 400 mg/m ² IVP on day 1 and 5-FU 1200 mg/m ² continuous IV infusion daily on days 1 and 2; 14-day cycle ^[18]
Oxaliplatin 85 mg/m ² plus 5-FU 2600 mg/m ² IV continuous infusion on day 1 plus leucovorin 200 mg/m ² IV on day 1; 14-day cycle ^[18]

In one trial of patients with D2-resected gastric cancer, the addition of radiotherapy to adjuvant chemotherapy (with capecitabine and cisplatin) improved disease-free survival in patients with node-positive disease and with intestinal-type gastric cancer. However, this finding requires further study.^[22]

Checkpoint inhibitors as adjuvant therapy

Nivolumab prolonged disease free survival in patients with resected (R0) stage II or III esophageal or gastroesophageal junction cancer who received neoadjuvant chemoradiotherapy and had residual pathological disease.^[23]

Nivolumab 240 mg IV over 30 minutes every 2 weeks for 16 weeks, followed by 480 mg over 30 minutes every 4 weeks beginning at week 17 ^[23]
The above therapy is continued until disease recurrence or unacceptable side effects occur, with max duration being 1 year in the randomized controlled trial of this regimen

Stage IV

Trastuzumab should be added to first-line chemotherapy for HER2-NEU overexpressing adenocarcinomas. Not recommended in regimens containing an anthracycline.^[1] Trastuzumab is used as follows:

Trastuzumab 8 mg/kg IV loading dose on day 1 of cycle one, then 6 mg/kg IV; every 21 d with chemotherapy^[24] or
Trastuzumab 6 mg/kg IV loading dose on day 1 of cycle one, then 4 mg/kg IV every 14 d with chemotherapy
An FDA-approved biosimilar may be substituted for trastuzumab

Preferred regimens

Two-drug regimens are preferred because of lower toxicity; reserve three-drug regimens for patients who are medically fit and have access to frequent follow-up. Oxaliplatin is generally preferred over cisplatin due to lower toxicity.^[1]

For HER2–positive adenocarcinoma, in combination with trastuzumab:

Oxaliplatin 85 mg/m² IV on day 1 plus leucovorin 400 mg/m² IV on day 1 plus 5-FU 400 mg/m² IV push (IVP) on day 1 plus 5-FU 1200 mg/m²/day continuous IV infusion on days 1 and 2; every 14 d^[25]or
Oxaliplatin 85 mg/m² IV on day 1 plus leucovorin 200 mg/m² IV on day 1 plus 5-FU 2600 mg/m²/day continuous IV infusion on day 1; every 14 d^[18] or
Oxaliplatin 130 mg/m² IV on day 1 plus capecitabine 1000 mg/m² PO BID on days 1-14; every 21 d ^[19] or
Oxaliplatin 85 mg/m² IV on day 1 plus capecitabine 625 mg/m² PO BID on days 1-14; every 21 d^[26] or
Cisplatin 75-100 mg/m² IV on day 1 plus 5-FU 750-1000 mg/m²/day continuous IV infusion over 24 h on days 1-4; every 28 d ^[27] or
Cisplatin 50 mg/m² IV on day 1 plus leucovorin 200 mg/m² IV on day 1 plus 5-FU 2000 mg/m²/day continuous IV infusion on day 1; every 14 d^{[18, 28]} or
Cisplatin 80 mg/m² IV on day 1 plus capecitabine 1000 mg/m² PO BID daily on days 1-14; every 21 d^{[24, 29]}

For HER2–negative adenocarcinoma:

5-FU or capecitabine plus oxaliplatin plus nivolumab (for cases with PD-L1 expression by Combined Positive Score [CPS] of 5 or greater) ^{[1, 30]}
5-FU or capecitabine plus oxaliplatin
5-FU or capecitabine plus cisplatin

Dosing options for regimens with nivolumab are as follows:

Nivolumab 360 mg IV day 1 plus capecitabine 1000 mg/m ² PO BID on days 1-14 plus oxaliplatin 130 mg/m ² IV day 1; every 21 days
Nivolumab 240 mg IV day 1 plus oxaliplatin 85 mg/m ² IV on day 1 plus leucovorin 400 mg/m ² IV on day 1 plus 5-FU 400 mg/m ² IVP on day 1 plus 5-FU 1200 mg/m ²/day continuous IV infusion on days 1 and 2; every 14 d

Other regimens^[1]:

Docetaxel 40 mg/m² IV on day 1 plus leucovorin 400 mg/m² IV on day 1 plus 5-FU 400 mg/m² IV on day 1 plus 5-FU 1000 mg/m²/day continuous IV infusion on days 1 and 2 plus cisplatin 40 mg/m² IV on day 3; every 14 d^[31] or

Irinotecan 80 mg/m² IV on day 1 plus leucovorin 500 mg/m² IV on day 1 plus 5-FU 2000 mg/m²/day continuous IV infusion on day 1; weekly for 6 wk followed by 1 wk off treatment^[32] or 2 wk off treatment^{[33, 34]} or
Irinotecan 180 mg/m² IV on day 1 plus leucovorin 400 mg/m² IV on day 1 plus 5-FU 400 mg/m² IVP on day 1 plus 5-FU 1200 mg/m² /day continuous IV infusion on days 1 and 2; every 14 d^[35]
Paclitaxel 135-250 mg/m² IV on day 1; every 21 d^[36] or
Paclitaxel 80 mg/m² IV on day 1 weekly; every 28 d^[37] or
Paclitaxel 135-200 mg/m² IV on day 1 plus cisplatin 75 mg/m² IV on day 2; every 21 d^[38] or
Paclitaxel 90 mg/m² IV on day 1 plus cisplatin 50 mg/m² IV on day 1; every 14 d^[39] or
Paclitaxel 200 mg/m² IV on day 1 plus carboplatin AUC 5 IV on day 1; every 21 d^[40] or
Docetaxel 75-100 mg/m² IV on day 1; every 21 d^[41] or
Docetaxel 75 mg/m² IV on day 1 plus cisplatin 75 mg/m² IV on day 1 plus 5-FU 1000 mg/m²/day continuous IV infusion on days 1-5; every 28 d^[42]
Docetaxel 50 mg/m² IV on day 1 plus oxaliplatin 85 mg/m² IV on day 1 plus 5-FU 1200 mg/m²/day continuous IV infusion on days 1 and 2; every 14 d^[43] or
Docetaxel 75 mg/m² IV on day 1 plus carboplatin AUC 6 IV on day 2 plus 5-FU 1200 mg/m²/day continuous IV infusion on days 1-3; every 21 d^[44] or
Docetaxel 70-85 mg/m² IV on day 1 plus cisplatin 70-75 mg/m² IV on day 1; every 21 d^{[45, 46, 47]} or
Leucovorin 400 mg/m² IV on day 1 plus 5-FU 400 mg/m² IVP on day 1 plus 5-FU 1200 mg/m²/day continuous IV infusion on days 1 and 2; every 14 d^[28] or
5-FU 800 mg/m²/day continuous IV infusion on days 1-5; every 28 d^[48] or
Capecitabine 1000-1250 mg/m² PO BID daily on days 1-14; every 21 d^[49]

Use of other monoclonal antibodies in first-line therapy:

For HER2-positive cancers, pembrolizumab provided a significant increase in progression free survival when combined with trastuzumab and first line chemotherapy:

Induction with IV pembrolizumab 200 mg q3 weeks plus 8mg/kg trastuzumab followed by subsequent cycles of first line chemotherapy plus IV pembrolizumab 200 mg, and 6 mg/kg of trastuzumab, administered on day 1 of each 3-week cycle. ^[50]

For ERBB2-negative and PDL-1 CPS ≥1 metastatic cancer, pembrolizumab alone or in combination with current first-line therapy has been shown to be noninferior to first-line chemotherapy and, when used alone, had fewer adverse events:

Pembrolizumab 200 mg q3 weeks ^[51]

Stage IV

For HER2-NEU overexpressing adenocarcinomas

Trastuzumab deruxtecan is approved for locally advanced and metastatic HER2-positive gastric and gastroesophageal junction adenocarcinoma in adults who have received a prior trastuzumab-based regimen.^[52] The regimen is as follows:

Trastuzumab deruxtecan 6.4 mg/kg IV every 3 weeks (21-day cycle); continue until disease progression or unacceptable toxicity

Preferred regimens^[1]:

Ramucirumab 8 mg/kg IV on days 1 and 15 plus paclitaxel IV 80 mg/m² on days 1, 8, and 15; every 28 d^[53] or
Docetaxel 75-100 mg/m² IV on day 1; every 21 d^[41] or
Paclitaxel 135-250 mg/m² IV on day 1; every 21 d^[36] or
Paclitaxel 80 mg/m² IV on day 1 weekly; every 28 d^[37] or
Paclitaxel 80 mg/m² IV on days 1, 8, and 15; every 28 d^[54] or
Irinotecan 250-350 mg/m² IV on day 1; every 21 d^[55] or
Irinotecan 150-180 mg/m² IV on day 1; every 14 d^{[56, 57, 54]} or
Irinotecan 125 mg/m² IV on days 1 and 8; every 21 d^{[56, 57]}

Other regimens^[1]:

Ramucirumab 8 mg/kg IV on day 1; every 14 d^[58] or
Irinotecan 65 mg/m² IV on days 1 and 8 plus cisplatin 25-30 mg/m² IV on days 1 and 8; every 21 d^{[25, 59]} or
Irinotecan 250 mg/m² IV on day 1 plus capecitabine 1000 mg/m² PO BID daily on days 1-14; every 21 d^[60] or
Irinotecan 180 mg/m² IV on day 1 plus leucovorin 400 mg/m² IV on day 1 plus 5-FU 400 mg/m² IVP on day 1 plus 5-FU 600-1200 mg/m²/day continuous IV infusion on days 1 and 2; every 14 d^{[61, 19]} or
Docetaxel 35 mg/m² IV on days 1 and 8 plus irinotecan 50 mg/m² IV on days 1 and 8; every 21 d^[62]

For patients with HER2 positive disease previously treated with trastuzumab plus 1 or more lines of chemotherapy, a recent phase 2 study showed significant complete and partial response rates with margetuximab plus pembrolizumab. The most benefit was seen in those with Her2-IHC_3-positive/PDL-1-positive tumors.

Margetuximab 15 mg/kg IV plus pembrolizumab 200mg q 3 weeks ^[63]

Second and third-line treatments with specific indications:

For NTRK gene fusion-positive tumors:

Entrectinib 600 mg PO daily ^[64]
Larotrectinib 100 mg PO BID ^[65]

For second-line or subsequent therapy for MSI-high or deficient MMR tumors or third-line therapy for PDL-1 expression CPS ≥1: ^{[66, 67]}:

Pembrolizumab 200mg IV q3wk or 400 mg IV q6wk^{[68, 69, 70]}

Useful in certain circumstances (advanced gastric and gastroesophageal junction adenocarcinoma, together with gastroesophageal adenocarcinoma [GEA])

Ramucirumab 8 mg/kg IV on day 1 plus irinotecan 180 mg/m ² IV on day 1 plus leucovorin 400 mg/m ² IV on day 1 plus 5-FU 400 mg/m ² IVP on day 1 plus 5-FU 1200 mg/m ²/day continuous IV infusion on days 1 and 2; every 14 d ^[71]

Patients who have been treated with fluoropyrimidines and cisplatin and taxanes or irinotecan, but no prior exposure to oxaliplatin:

Oxaliplatin (85 mg/m2 as a 2-h infusion on day 1) plus 5-FU bolus (400 mg/m2 on day 1) plus 46 h infusion of 5-FU (2400 mg/m2) concurrently with 200 mg/m2 Leucovorin. Repeat cycles at 2-week intervals until disease progression. ^[72]

Third-Line and subsequent treatment options

See the list below:

Trifluridine/tipiracil 35 mg/m ² PO BID with food on days 1-5 and days 8-12 of each 28-day cycle; not to exceed 80 mg/dose until disease progression or unacceptable toxicity ^[73] (Dose based on trifluridine component rounded to nearest 5-mg increment).
Trifluridine/tipiracil 35 mg/m ² PO BID with food on days 1-5 and days 8-12 of each 28-day cycle plus ramucirumab (8mg/kg ²) on day 1 and 15 ^[74]
Nivolumab 3 mg/kg q2 weeks for 6 weeks ^[75]

Other regimens that have shown encouraging antitumor activity or progression-free survival in phase Ib or phase II clinical trials but require further investigation include:

Regorafenib 80 mg qD for 21 days on followed by 7 days off with with nivolumab 3 mg/kg every 2 weeks ^[76]
In patients with positive CLDN18.2 expression, zolbetuximab (investigational) plus epirubicin/oxaliplatin/capecitabine (EOX): loading dose of 800 mg/m ²on cycle 1 day 1 (before EOX) followed by 600 mg/m ² on day 1 of subsequent cycles + EOX ( 21 day cycles of IV epirubicin 50 mg/m ² plus oxaliplatin 130 mg/m ² plus po capecitabine 625 mg/m ² BID x 21 days) for max of 8 cycles ^[77]

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Sections Gastric Cancer Treatment Protocols
General Treatment Recommendations
Preoperative Chemoradiotherapy Regimens
Perioperative Chemotherapy Regimens
Postoperative Chemoradiotherapy Regimens
First-Line Chemotherapy for Metastatic or Locally Advanced Cancer (Where Local Therapy Not Indicated)
Second-Line Chemotherapy for Metastatic or Locally Advanced Cancer (Where Local Therapy Not Indicated)
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References

Gastric Cancer Treatment Protocols

General Treatment Recommendations

Stage 0 to IA

Stage IB to IIIC, potentially resectable

Stage IV

Preoperative Chemoradiotherapy Regimens

Preferred regimens

Other regimens

Perioperative Chemotherapy Regimens

Preferred regimens

Other regimens

Postoperative Chemoradiotherapy Regimens

First-Line Chemotherapy for Metastatic or Locally Advanced Cancer (Where Local Therapy Not Indicated)

Stage IV

Second-Line Chemotherapy for Metastatic or Locally Advanced Cancer (Where Local Therapy Not Indicated)

Stage IV

Second and third-line treatments with specific indications:

Third-Line and subsequent treatment options

References

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