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:
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Stage of disease
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Surgical fitness of the patient
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The patient’s preference
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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 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]
Preoperative Chemoradiotherapy Regimens
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] :
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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
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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
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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
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Cisplatin 30 mg/m2 IV on day 1 plus capecitabine 800 mg/m2 PO BID on days 1-5; weekly for 5wk [11] or
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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
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] :
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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:
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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 2 on 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
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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]
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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]
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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:
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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:
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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
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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]
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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]
First-Line Chemotherapy for Metastatic or Locally Advanced Cancer (Where Local Therapy Not Indicated)
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:
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Trastuzumab 8 mg/kg IV loading dose on day 1 of cycle one, then 6 mg/kg IV; every 21 d with chemotherapy [23] or
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Trastuzumab 6 mg/kg IV loading dose on day 1 of cycle one, then 4 mg/kg IV every 14 d with chemotherapy
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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 overexpression–positive adenocarcinoma, in combination with trastuzumab:
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Oxaliplatin 85 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 [24] or
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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
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Oxaliplatin 130 mg/m2 IV on day 1 plus capecitabine 1000 mg/m2 PO BID on days 1-14; every 21 d [19] or
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Oxaliplatin 85 mg/m2 IV on day 1 plus capecitabine 625 mg/m2 PO BID on days 1-14; every 21 d [25] or
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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 [26] or
For HER overexpression–negative adenocarcinoma:
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Fluorouracil or capecitabine plus oxaliplatin plus nivolumab (PDL1 CPS ≥ 5)
See the list below:
- Nivolumab 360 mg IV day 1 plus capecitabine 1000 mg/m2 PO BID on days 1-14 plus oxaliplatin 130 mg/m2 IV day 1; every 21 days
- Nivolumab 240 mg IV day 1 plus oxaliplatin 85 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
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Fluorouracil or capecitabine plus oxaliplatin
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Fluorouracil or capecitabine plus cisplatin
Other regimens [1] :
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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 [32]
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Paclitaxel 135-250 mg/m2 IV on day 1; every 21 d [33] or
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Paclitaxel 80 mg/m2 IV on day 1 weekly; every 28 d [34] or
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Paclitaxel 135-200 mg/m2 IV on day 1 plus cisplatin 75 mg/m2 IV on day 2; every 21 d [35] or
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Paclitaxel 90 mg/m2 IV on day 1 plus cisplatin 50 mg/m2 IV on day 1; every 14 d [36] or
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Paclitaxel 200 mg/m2 IV on day 1 plus carboplatin AUC 5 IV on day 1; every 21 d [37] or
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Docetaxel 75-100 mg/m2 IV on day 1; every 21 d [38] or
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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 [39]
See the list below:
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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 [40] or
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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 [41] or
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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 [42] or
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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 [27] or
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5-FU 800 mg/m2/day continuous IV infusion on days 1-5; every 28 d [46] or
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Capecitabine 1000-1250 mg/m2 PO BID daily on days 1-14; every 21 d [47]
Second-Line Chemotherapy for Metastatic or Locally Advanced Cancer (Where Local Therapy Not Indicated)
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. [48] The regimen is as follows:
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Trastuzumab deruxtecan 6.4 mg/kg IV every 3 weeks (21-day cycle); continue until disease progression or unacceptable toxicity
Preferred regimens [1] :
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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 [49] or
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Docetaxel 75-100 mg/m2 IV on day 1; every 21 d [38] or
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Paclitaxel 135-250 mg/m2 IV on day 1; every 21 d [33] or
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Paclitaxel 80 mg/m2 IV on day 1 weekly; every 28 d [34] or
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Paclitaxel 80 mg/m2 IV on days 1, 8, and 15; every 28 d [50] or
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Irinotecan 250-350 mg/m2 IV on day 1; every 21 d [51] or
For second-line or subsequent therapy for MSI-high or deficient MMR tumors OR third-line or subsequent therapy for gastric adenocarcinoma with PD-L1 expression by CPS ≥1 [54, 55] :
Other regimens [1] :
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Ramucirumab 8 mg/kg IV on day 1; every 14 d [59] or
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Irinotecan 250 mg/m2 IV on day 1 plus capecitabine 1000 mg/m2 PO BID daily on days 1-14; every 21 d [61] or
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Docetaxel 35 mg/m2 IV on days 1 and 8 plus irinotecan 50 mg/m2 IV on days 1 and 8; every 21 d [63]
For NTRK gene fusion-positive tumors
Useful in certain circumstances (advanced gastric and gastroesophageal junction adenocarcinoma, together gastroesophageal adenocarcinoma [GEA])
Ramucirumab 8 mg/kg IV on day 1 plus 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 [66]
For third-line or subsequent therapy:
Used for metastatic gastric or GEJ adenocarcinoma previously treated with at least 2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy. Only consider in patients with low-volume gastric cancer who have minimal or no symptoms and are able to swallow pills. [67]
Dose based on trifluridine component rounded to nearest 5-mg increment
35 mg/m2 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
Tables
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- 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