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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]

[Guideline] National Comprehensive Cancer Network. Gastric Cancer. Version 2.2021. NCCN Clinical Practice Guidelines in Oncology. Available at https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. 2021 Mar 09; Accessed: April 19, 2021.
Huscher CG, Mingoli A, Sgarzini G, Sansonetti A, Di Paola M, Recher A, et al. Laparoscopic versus open subtotal gastrectomy for distal gastric cancer: five-year results of a randomized prospective trial. Ann Surg. 2005 Feb. 241 (2):232-7. [QxMD MEDLINE Link].
Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6. 355(1):11-20. [QxMD MEDLINE Link].
[Guideline] Smyth EC, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep. 27 (suppl 5):v38-v49. [QxMD MEDLINE Link].
[Guideline] Bartley AN, Washington MK, Colasacco C, et al. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017 Feb. 35 (4):446-464. [QxMD MEDLINE Link].
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. 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. 2010 Aug 28. 376 (9742):687-97. [QxMD MEDLINE Link].
Conroy T, Viret F, François E, et al. Phase I trial of oxaliplatin with fluorouracil, folinic acid and concurrent radiotherapy for oesophageal cancer. Br J Cancer. 2008 Nov 4. 99(9):1395-401. [QxMD MEDLINE Link].
Javle MM, Yang G, Nwogu CE, et al. Capecitabine, oxaliplatin and radiotherapy: a phase IB neoadjuvant study for esophageal cancer with gene expression analysis. Cancer Invest. 2009 Feb. 27(2):193-200. [QxMD MEDLINE Link].
Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008 Mar 1. 26(7):1086-92. [QxMD MEDLINE Link].
Bedenne L, Michel P, Bouché O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007 Apr 1. 25(10):1160-8. [QxMD MEDLINE Link].
Lee SS, Kim SB, Park SI, et al. Capecitabine and cisplatin chemotherapy (XP) alone or sequentially combined chemoradiotherapy containing XP regimen in patients with three different settings of stage IV esophageal cancer. Jpn J Clin Oncol. 2007 Nov. 37(11):829-35. [QxMD MEDLINE Link].
Ajani JA, Winter K, Okawara GS, et al. Phase II trial of preoperative chemoradiation in patients with localized gastric adenocarcinoma (RTOG 9904): quality of combined modality therapy and pathologic response. J Clin Oncol. 2006 Aug 20. 24(24):3953-8. [QxMD MEDLINE Link].
Czito BG, Kelsey CR, Hurwitz HI, et al. A Phase I study of capecitabine, carboplatin, and paclitaxel with external beam radiation therapy for esophageal carcinoma. Int J Radiat Oncol Biol Phys. 2007 Mar 15. 67(4):1002-7. [QxMD MEDLINE Link].
van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31. 366(22):2074-84. [QxMD MEDLINE Link]. [Full Text].
van Meerten E, Muller K, Tilanus HW, et al. Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study. Br J Cancer. 2006 May 22. 94(10):1389-94. [QxMD MEDLINE Link].
Al-Batran SE, Homann N, Pauligk C, Goetze TO, et al. 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. 2019 May 11. 393 (10184):1948-1957. [QxMD MEDLINE Link]. [Full Text].
Enzinger PC, Burtness BA, Niedzwiecki D, Ye X, Douglas K, Ilson DH, et al. CALGB 80403 (Alliance)/E1206: A Randomized Phase II Study of Three Chemotherapy Regimens Plus Cetuximab in Metastatic Esophageal and Gastroesophageal Junction Cancers. J Clin Oncol. 2016 Aug 10. 34 (23):2736-42. [QxMD MEDLINE Link]. [Full Text].
Al-Batran SE, Hartmann JT, Probst S, et al. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20. 26(9):1435-42. [QxMD MEDLINE Link].
Kim GM, Jeung HC, Rha SY, Kim HS, Jung I, Nam BH, et al. A randomized phase II trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer. Eur J Cancer. 2012 Mar. 48(4):518-26. [QxMD MEDLINE Link].
Sasako M, Sakuramoto S, Katai H, et al. 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. 2011 Nov 20. 29 (33):4387-93. [QxMD MEDLINE Link].
Chua YJ, Barbachano Y, Cunningham D, Oates JR, Brown G, Wotherspoon A, et al. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. Lancet Oncol. 2010 Mar. 11(3):241-8. [QxMD MEDLINE Link].
Park SH, Sohn TS, Lee J, et al. Phase III Trial to Compare Adjuvant Chemotherapy With Capecitabine and Cisplatin Versus Concurrent Chemoradiotherapy in Gastric Cancer: Final Report of the Adjuvant Chemoradiotherapy in Stomach Tumors Trial, Including Survival and Subset Analyses. J Clin Oncol. 2015 Oct 1. 33 (28):3130-6. [QxMD MEDLINE Link].
Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. New England Journal of Medicine. 2021 Apr. 01. 384:1191-1203.
Bang YJ, Van Cutsem E, Feyereislova A, et al. 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. 2010 Aug 28. 376(9742):687-97. [QxMD MEDLINE Link].
Enzinger PC, Burtness BA, Niedzwiecki D, Ye X, et al. CALGB 80403 (Alliance)/E1206: A Randomized Phase II Study of Three Chemotherapy Regimens Plus Cetuximab in Metastatic Esophageal and Gastroesophageal Junction Cancers. J Clin Oncol. 2016 Aug 10. 34 (23):2736-42. [QxMD MEDLINE Link]. [Full Text].
Hall PS, Swinson D, Waters JS, et al. Optimizing chemotherapy for frail and elderly patients (pts) with advanced gastroesophageal cancer (aGOAC): The GO2 phase III trial. J Clin Oncol. 2019. 37:suppl; abstr 4006. [Full Text].
Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, et al. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009 Oct. 20(10):1667-73. [QxMD MEDLINE Link].
Bouché O, Raoul JL, Bonnetain F, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803. J Clin Oncol. 2004 Nov 1. 22(21):4319-28. [QxMD MEDLINE Link].
Kang YK, Kang WK, Shin DB, et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann Oncol. 2009 Apr. 20(4):666-73. [QxMD MEDLINE Link].
Moehler M, Shitara K, Garrido M, Salman P, Shen L, Wyriwicz L, et al. Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): First results of the CheckMate 649 study (abstract). Presented at the European Society of Medical Oncology Virtual Congress; September 21, 2020. Ann Oncol. 2020. 31 (suppl 4):S1142-S1215. [Full Text].
Shah MA, Shibata S, Stroller RG. Random assignment multicenter phase II study of modified docetaxel, cisplatin, fluorouracil (mDCF) versus DCF with growth factor support (GCSF) in metastatic gastroesophageal adenocarcinoma (GE). J Clin Oncol (Meeting Abstracts). 2010. 28:4014.
Dank M, Zaluski J, Barone C, et al. Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol. 2008 Aug. 19(8):1450-7. [QxMD MEDLINE Link].
Wolff K, Wein A, Reulbach U, et al. Weekly high-dose 5-fluorouracil as a 24-h infusion and sodium folinic acid (AIO regimen) plus irinotecan in patients with locally advanced nonresectable and metastatic adenocarcinoma or squamous cell carcinoma of the oesophagus: a phase II trial. Anticancer Drugs. 2009 Mar. 20(3):165-73. [QxMD MEDLINE Link].
Wolff K, Wein A, Reulbach U, Männlein G, Brückl V, Meier C, et al. Weekly high-dose 5-fluorouracil as a 24-h infusion and sodium folinic acid (AIO regimen) plus irinotecan in patients with locally advanced nonresectable and metastatic adenocarcinoma or squamous cell carcinoma of the oesophagus: a phase II trial. Anticancer Drugs. 2009 Mar. 20(3):165-73. [QxMD MEDLINE Link].
Sym SJ, Hong J, Park J, Cho EK, Lee JH, Park YH, et al. A randomized phase II study of biweekly irinotecan monotherapy or a combination of irinotecan plus 5-fluorouracil/leucovorin (mFOLFIRI) in patients with metastatic gastric adenocarcinoma refractory to or progressive after first-line chemotherapy. Cancer Chemother Pharmacol. 2013 Feb. 71(2):481-8. [QxMD MEDLINE Link].
Ajani JA, Ilson DH, Daugherty K, et al. Activity of taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst. 1994 Jul 20. 86(14):1086-91. [QxMD MEDLINE Link].
Ilson DH, Wadleigh RG, Leichman LP, et al. Paclitaxel given by a weekly 1-h infusion in advanced esophageal cancer. Ann Oncol. 2007 May. 18(5):898-902. [QxMD MEDLINE Link].
Ilson DH, Forastiere A, Arquette M, et al. A phase II trial of paclitaxel and cisplatin in patients with advanced carcinoma of the esophagus. Cancer J. 2000 Sep-Oct. 6(5):316-23. [QxMD MEDLINE Link].
Petrasch S, Welt A, Reinacher A, et al. Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer. Br J Cancer. 1998 Aug. 78(4):511-4. [QxMD MEDLINE Link].
Gadgeel SM, Shields AF, Heilbrun LK, et al. Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol. 2003 Feb. 26(1):37-41. [QxMD MEDLINE Link].
Albertsson M, Johansson B, Friesland S, et al. Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer. Med Oncol. 2007. 24(4):407-12. [QxMD MEDLINE Link].
Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006. 24:4991-7.
Shankaran V, Mulcahy MF, Hochster HS. Docetaxel, oxaliplatin, and 5-fluorouracil for the treatment of metastatic or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinomas: Preliminary results of a phase II study. 2009.
Elkerm YM, Elsaid A, Al-Batran SE, et al. Final results of a phase II trial of docetaxel-carboplatin-FU in locally advanced gastric carcinoma. 2008.
Roth AD, Fazio N, Stupp R, et al. Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research. J Clin Oncol. 2007 Aug 1. 25(22):3217-23. [QxMD MEDLINE Link].
Ajani JA, Fodor MB, Tjulandin SA, et al. Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol. 2005 Aug 20. 23(24):5660-7. [QxMD MEDLINE Link].
Kim JY, Do YR, Park KU, et al. A multi-center phase II study of docetaxel plus cisplatin as first-line therapy in patients with metastatic squamous cell esophageal cancer. Cancer Chemother Pharmacol. 2010 May. 66(1):31-6. [QxMD MEDLINE Link].
Ohtsu A, Shimada Y, Shirao K, et al. Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The Japan Clinical Oncology Group Study (JCOG9205). J Clin Oncol. 2003 Jan 1. 21(1):54-9. [QxMD MEDLINE Link].
Hong YS, Song SY, Lee SI, et al. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004 Sep. 15(9):1344-7. [QxMD MEDLINE Link].
Janjigian YY, Maron SB, Chatila WK, et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2020 Jun. 21 (6):821-831. [QxMD MEDLINE Link]. [Full Text].
Shitara K, Van Cutsem E, Bang YJ, et al. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Oct 1. 6 (10):1571-1580. [QxMD MEDLINE Link]. [Full Text].
Shitara K, Bang YJ, Iwasa S, Sugimoto N, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020 Jun 18. 382 (25):2419-2430. [QxMD MEDLINE Link]. [Full Text].
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. 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. 2014 Oct. 15 (11):1224-35. [QxMD MEDLINE Link].
André T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer. 1999 Sep. 35(9):1343-7. [QxMD MEDLINE Link].
Thuss-Patience PC, Kretzschmar A, Deist T, et al. Irinotecan versus best supportive care (BSC) as second-line therapy in gastric cancer: A randomized phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). J Clin Oncol. 2009. 27:15s (suppl; abstr 4540).
Fuchs CS, Moore MR, Harker G, et al. Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003 Mar 1. 21(5):807-14. [QxMD MEDLINE Link].
Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22. 351(4):337-45. [QxMD MEDLINE Link].
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014 Jan 4. 383(9911):31-9. [QxMD MEDLINE Link].
Ilson DH. Phase II trial of weekly irinotecan/cisplatin in advanced esophageal cancer. Oncology (Williston Park). 2004 Dec. 18(14 Suppl 14):22-5. [QxMD MEDLINE Link].
Leary A, Assersohn L, Cunningham D, et al. A phase II trial evaluating capecitabine and irinotecan as second line treatment in patients with oesophago-gastric cancer who have progressed on, or within 3 months of platinum-based chemotherapy. Cancer Chemother Pharmacol. 2009 Aug. 64(3):455-62. [QxMD MEDLINE Link].
Di Lauro L, Fattoruso SI, Giacinti L, et al. Second-line chemotherapy with FOLFIRI in patients with metastatic gastric cancer (MGC) not previously treated with fluoropyrimidines. J Clin Oncol. 2009. 27:15s (suppl; abstr 4549).
Burtness B, Gibson M, Egleston B, et al. Phase II trial of docetaxel-irinotecan combination in advanced esophageal cancer. Ann Oncol. 2009 Jul. 20(7):1242-8. [QxMD MEDLINE Link].
Catenacci DVT, Kang YK, Park H, et al. Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial. Lancet Oncol. 2020 Aug. 21 (8):1066-1076. [QxMD MEDLINE Link]. [Full Text].
Doebele RC, Drilon A, Paz-Ares L, Siena S, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020 Feb. 21 (2):271-282. [QxMD MEDLINE Link]. [Full Text].
Drilon A, Laetsch TW, Kummar S, DuBois SG, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018 Feb 22. 378 (8):731-739. [QxMD MEDLINE Link]. [Full Text].
FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. U.S. Food and Drug Administration. Available at https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm560040.htm. May 30, 2017; Accessed: January 30, 2021.
FDA grants accelerated approval to pembrolizumab for advanced gastric cancer. United States Food and Drug Administration. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm577093.htm. 2017 Sep 22; Accessed: January 30, 2021.
Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28. 357 (6349):409-413. [QxMD MEDLINE Link].
Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25. 372 (26):2509-20. [QxMD MEDLINE Link].
Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc. April 2020. Available at [Full Text].
Tabernero J, Yoshino T, Cohn AL, Obermannova R, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015 May. 16 (5):499-508. [QxMD MEDLINE Link]. [Full Text].
Mitani S, Kadowaki S, Komori A, Kondoh C, Oze I, Kato K, et al. A Phase II Study of Modified FOLFOX6 for Advanced Gastric Cancer Refractory to Standard Therapies. Adv Ther. 2020 Jun. 37 (6):2853-2864. [QxMD MEDLINE Link]. [Full Text].
Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Nov. 19 (11):1437-1448. [QxMD MEDLINE Link].
Kawazoe A, Ando T, Hosaka H, Fujita J, Koeda K, Nishikawa K, et al. Safety and activity of trifluridine/tipiracil and ramucirumab in previously treated advanced gastric cancer: an open-label, single-arm, phase 2 trial. Lancet Gastroenterol Hepatol. 2021 Mar. 6 (3):209-217. [QxMD MEDLINE Link]. [Full Text].
Chen LT, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, et al. A phase 3 study of nivolumab in previously treated advanced gastric or gastroesophageal junction cancer (ATTRACTION-2): 2-year update data. Gastric Cancer. 2020 May. 23 (3):510-519. [QxMD MEDLINE Link]. [Full Text].
Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, et al. Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603). J Clin Oncol. 2020 Jun 20. 38 (18):2053-2061. [QxMD MEDLINE Link]. [Full Text].
U. Sahin, O. Tureci, G. Manikhas, et. al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gatric and gastro-oesophageal adenocarcinoma. Annals of Oncology. 2021 May. Vol 32:609-619. [Full Text].