Gastric Cancer Treatment Protocols
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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:
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]
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.
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]
A higher level of evidence supports use of the following regimens; clinical trials have shown strong benefit and there is consensus among experts [1] :
Paclitaxel 50 mg/m2 IV on day 1 plus carboplatin AUC 2 IV on day 1; weekly for 5 wk [7, 8] (see the Carboplatin AUC Dose Calculation [Calvert formula] calculator)or
Cisplatin 75-100 mg/m2 IV on day 1 plus 5-fluorouracil (5-FU) 750-1000 mg/m2/day IV continuous infusion on days 1-4 and 29-32; single 35-day cycle [9] or
Cisplatin 30 mg/m2 IV on day 1 plus capecitabine 800 mg/m2 PO BID on days 1-5; weekly for 5wk [10] or
Cisplatin 15 mg/m2 IV daily on days 1-5 and days 22-26 plus 5-FU 800 mg/m2/day IV continuous infusion on days 1-5 and days 22-26; single 35-day cycle [11] or
Oxaliplatin 85 mg/m2 IV on days 1, 15, and 29 plus capecitabine 625 mg/m2 PO BID on days 1-5, 8-12, 15-19, 22-26, and 29-33; single 35-day cycle [12] or
Oxaliplatin 85 mg/m2 on days 1, 15, and 29 plus 5-FU 180 mg/m2 continuous IV infusion daily on days 1-33 [13] or
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 and 5-FU 800 mg/m2 continuous IV infusion daily on days 1 and 2; every 14 d for three cycles with radiation and three cycles after radiation [14]
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] :
Oxaliplatin 45-50 mg/m2 IV on day 1 weekly for 5 wk plus 5-FU 225 mg/m2 IV daily on days 1-33; single 35-day cycle [15] or
Carboplatin AUC 6 IV on days 1 and 22 plus 5-FU 200 mg/m2 IV daily on days 1-42 [16] or
Irinotecan 65 mg/m2 IV on days 1, 8, 22, and 29 plus cisplatin 30 mg/m2 IV on days 1, 8, 22, and 29 [17] 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 [18] 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 [18, 19]
The following regimens consist of three cycles before surgery and three cycles after surgery; the following regimens are used only for adenocarcinoma of the distal esophagus or gastroesophageal junction [1] (“ECF” regimen and variants):
Epirubicin 50 mg/m2 IV on day 1 plus cisplatin 60 mg/m2 IV on day 1 plus 5-FU 200 mg/m2/day IV continuous infusion daily for days 1-21; every 21 d for six cycles—three preoperatively and three postoperatively [3] or
Epirubicin 50 mg/m2 IV on day 1 plus oxaliplatin 130 mg/m2 IV on day 1 plus 5-FU 200 mg/m2/day IV continuous infusion daily for days 1-21; every 21 d for six cycles—three preoperatively and three postoperatively [20] or
Epirubicin 50 mg/m2 IV on day 1 plus cisplatin 60 mg/m2 IV on day 1 plus capecitabine 625 mg/m2 PO BID daily for days 1-21; every 21 d for six cycles—three preoperatively and three postoperatively [20] or
Epirubicin 50 mg/m2 IV on day 1 plus oxaliplatin 130 mg/m2 IV on day 1 plus capecitabine 625 mg/m2 PO BID daily for days 1-21; every 21 d for six cycles—three preoperatively and three postoperativelyy [20] or
See the list below:
The following regimen consists of four 14-day cycles preoperatively and then adjuvant therapy with the same regimen (“FLOT” regimen):
Uses of the following postoperative chemoradiotherapy regimens include cancers of the gastroesophageal junction:
Leucovorin 20 mg/m2 IVP on days 1-5 plus 5-FU 425 mg/m2 IVP daily on days 1-5, every 28 d (cycles 1, 3, and 4 given before and after radiation); for cycle 2, give leucovorin 20 mg/m2 IVP on days 1-4 and 31-33 plus 5-FU 400 mg/m2 IVP daily on days 1-4, every 35 d (cycle 2 given with radiation) [23]
Note: The National Comprehensive Cancer Network (NCCN) panel does not recommend the above specified doses or schedule, because of concerns regarding toxicity; instead, the panel recommends using one of the following modified regimens. [1]
One cycle before and two cycles after chemoradiation:
Capecitabine 750-1000 mg/m2 PO BID on days 1-14; every 28 d (one cycle before and two cycles after chemoradiation)
Leucovorin 400 mg/m2 IV on days 1 and 15 or days 1, 2, 15, and 16 plus 5-FU 400 mg/m2 IVP on days 1 and 15 or days 1, 2, 15, and 16 and 5-FU 1200 mg/m2 continuous IV infusion over 24 h daily on days 1, 2, 15 and 16, every 14 d (one cycle before radiation and two cycles after radiation) [24]
With radiation:
5-FU 200-250 mg/m2/day continuous IV infusion on days 1-5 or 1-7; weekly for 5 wk [25] or
Capecitabine 625-825 mg/m2 PO BID daily for days 1-5 or 1-7; weekly for 5 wk [26]
Postoperative chemotherapy regimens for patients who underwent D2 lymph node dissection include the following:
Oxaliplatin 130 mg/m2 IV on day 1 plus capecitabine 1000 mg/m2 PO BID on days 1-14; every 21 d for eight cycles [27] or
Cisplatin 60 mg/m2 IV on day 1 plus capecitabine 1000 mg/m2 PO BID on days 1-14; every 21 d for six cycles [28]
In one trial, postoperative adjuvant chemotherapy with capecitabine and cisplatin compared with postoperative chemoradiotherapy showed inferior disease-free survival, which may suggest that in patients who have undergone D2 lymph node dissection, chemoradiotherapy may be superior. However, this requires further study. [29]
Compared with adjuvant chemotherapy, observation postoperatively leads to decreased overall survival. [30]
For HER2-NEU overexpressing adenocarcinomas, trastuzumab should be added to first-line chemotherapy consisting of cisplatin plus a fluoropyrimidine (eg, 5-FU, capecitabine) but is 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 [31] or
Trastuzumab 6 mg/kg IV loading dose on day 1 of cycle one, then 4 mg/kg IV every 14 d with chemotherapy
Preferred regimens [1]
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:
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 [32]
Note that the NCCN panel does not recommend the above specified doses or schedule because of concerns regarding toxicity, and instead suggests using one of the following modified regimens:
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 [33] or
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 [34] 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 [35] or
Epirubicin 50 mg/m2 IV on day 1 plus cisplatin 60 mg/m2 IV on day 1 plus 5-FU 200 mg/m2/day continuous IV infusion on days 1-21; every 21 d [36, 37] or
Epirubicin 50 mg/m2 IV on day 1 plus oxaliplatin 130 mg/m2 on day 1 plus 5-FU 200 mg/m2/day continuous IV infusion on days 1-21; every 21 d [37] or
Epirubicin 50 mg/m2 IV on day 1 plus cisplatin 60 mg/m2 IV on day 1 plus capecitabine 625 mg/m2 PO BID daily on days 1-21; every 21 d [37] or
Epirubicin 50 mg/m2 IV on day 1 plus oxaliplatin 130 mg/m2 IV on day 1 plus capecitabine 625 mg/m2 PO BID daily on days 1-21; every 21 d [37] 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 [38] 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 [39, 40] or
Cisplatin 80 mg/m2 IV on day 1 plus capecitabine 1000 mg/m2 PO BID daily on days 1-14; every 21 d [31, 41]
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 [42] 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 [39] or
Oxaliplatin 130 mg/m2 IV on day 1 plus capecitabine 1000 mg/m2 PO BID on days 1-14; every 21 d [43]
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 [44] or 2 wk off treatment [45, 46] or
Irinotecan 150 mg/m2 IV on day 1 plus leucovorin 20 mg/m2 IV on day 1 plus 5-FU 1000 mg/m2 /day continuous IV infusion on days 1 and 2; every 14 d [47]
Other regimens [1]
Paclitaxel 135-200 mg/m2 IV on day 1 plus cisplatin 75 mg/m2 IV on day 2; every 21 d [48] or
Paclitaxel 90 mg/m2 IV on day 1 plus cisplatin 50 mg/m2 IV on day 1; every 14 d [49] or
Paclitaxel 200 mg/m2 IV on day 1 plus carboplatin AUC 5 IV on day 1; every 21 d [50] or
Docetaxel 70-85 mg/m2 IV on day 1 plus cisplatin 70-75 mg/m2 IV on day 1; every 21 d [51, 52, 53] 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 [54] 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 [40] or
5-FU 800 mg/m2/day continuous IV infusion on days 1-5; every 28 d [55] or
Capecitabine 1000-1250 mg/m2 PO BID daily on days 1-14; every 21 d [56] or
Docetaxel 75-100 mg/m2 IV on day 1; every 21 d [57] or
Paclitaxel 135-250 mg/m2 IV on day 1; every 21 d [58] or
Paclitaxel 80 mg/m2 IV on day 1 weekly; every 28 d [59]
For HER2-NEU overexpressing adenocarcinomas, trastuzumab should be added to first-line chemotherapy consisting of cisplatin plus a fluoropyrimidine (eg, 5-FU, capecitabine) but is not recommended in regimens containing an anthracycline. [1] Trastuzumab is used as follows:
Trastuzumab 8 mg/m2 IV loading dose on day 1 of cycle one, then 6 mg/m2 IV; every 21 d with chemotherapy [31] or
Preferred regimens [1] :
Ramucirumab 8 mg/kg IV on day 1; every 14 d [60] or
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 [61] or
Docetaxel 75-100 mg/m2 IV on day 1; every 21 d [57] or
Paclitaxel 135-250 mg/m2 IV on day 1; every 21 d [58] or
Paclitaxel 80 mg/m2 IV on day 1 weekly; every 28 d [59] or
Paclitaxel 80 mg/m2 IV on days 1, 8, and 15; every 28 d [62] or
Irinotecan 250-350 mg/m2 IV on day 1; every 21 d [63] or
Irinotecan 150-180 mg/m2 IV on day 1; every 14 d [64, 65, 62] or
Irinotecan 125 mg/m2 IV on days 1 and 8; every 21 d [64, 65]
For MSI-high or deficient MMR tumors that have progressed despite fluoropyrimidine- and platinum-containing chemotherapy [66] :
Pembrolizumab 200mg IV on day 1; every 21 d [67, 68]
Metastatic gastric or gastroesophageal junction adenocarcinoma tumors expressing PD-L1 ≥ 1 (or third line or subsequent therapy) [69] :
Pembrolizumab 200mg IV on day 1; every 21 d [70]
Other regimens [1] :
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 [42, 71] or
Irinotecan 250 mg/m2 IV on day 1 plus capecitabine 1000 mg/m2 PO BID daily on days 1-14; every 21 d [72] 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 [73, 74] 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 [54]
Alternative regimens to consider:
Mitomycin 6 mg/m2 IV on day 1 plus irinotecan 125 mg/m2 on days 2 and 9; every 28 d [75] or
Irinotecan 150 mg/m2 IV on days 1 and 15 plus mitomycin 8 mg/m2 IV on day 1; every 28 d [76] or
Irinotecan 125 mg/m2 IV on day 1 plus mitomycin 5 mg/m2 IV on day 1; every 14 d [77] or
Mitomycin 10 mg/m2 IV on days 1 and 22 plus leucovorin 500 mg/m2 IV on day 1 plus 5-FU 2600 mg/m2/day continuous IV infusion on day 1; weekly for 6 wk, followed by 2 wk off treatment [78] or
Nivolumab 3 mg/kg IV on day 1; every 14 d [80]
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Mohammad Muhsin Chisti, MD, FACP Assistant Professor of Hematology and Oncology, Medical Director of Research, Karmanos Cancer Institute, Wayne State University School of Medicine
Mohammad Muhsin Chisti, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Medical Society of the State of New York
Disclosure: Nothing to disclose.
Christopher A Willner, II, DO Resident Physician, Department of Internal Medicine, William Beaumont Hospital
Christopher A Willner, II, DO is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, American Thoracic Society, Gold Humanism Honor Society
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee
Christopher D Braden, DO is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology
Disclosure: Nothing to disclose.
N Joseph Espat, MD, MS, FACS Harold J Wanebo Professor of Surgery, Assistant Dean of Clinical Affairs, Boston University School of Medicine; Chairman, Department of Surgery, Director, Adele R Decof Cancer Center, Roger Williams Medical Center
N Joseph Espat, MD, MS, FACS is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Surgeons, American Medical Association, American Society for Parenteral and Enteral Nutrition, American Society of Clinical Oncology, Americas Hepato-Pancreato-Biliary Association, Association for Academic Surgery, Central Surgical Association, Chicago Medical Society, International Hepato-Pancreato-Biliary Association, Pancreas Club, Sigma Xi, Society for Leukocyte Biology, Society for Surgery of the Alimentary Tract, Society of American Gastrointestinal and Endoscopic Surgeons, Society of Surgical Oncology, Society of University Surgeons, Southeastern Surgical Congress, Southern Medical Association, Surgical Infection Society
Disclosure: Nothing to disclose.
Terence D Rhodes, MD, PhD Medical Oncologist, Intermountain Medical Group
Terence D Rhodes, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology
Disclosure: Nothing to disclose.
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