Uitgangsvraag 4a: Welke eerstelijns behandeling -systeem therapie (chemo- en/of targeted therapie) of standaard chemotherapie- zorgt voor de beste uitkomst bij patiënten met een gemetastaseerd maagcarcinoom, of een voortgeschreden niet resectabel maagcarcinoom, of een recidief maagcarcinoom, in termen van kwaliteit van leven en (progressievrije) overleving ?

P

Patiënten met een gemetastaseerd maagcarcinoom of een voortgeschreden, niet resectabel maagcarcinoom of een recidief maagcarcinoom

I

Systeem therapie (chemo- en/of targeted therapie)

C

Standaard chemotherapie (i.e. een platinum verbinding met een fluopyrimidine (e.g. cisplatin + fluoropyrimidine) +/- epirubicine of alleen fluopyrimidine)

O

Kwaliteit van leven, progressievrije overleving, overall survival

(Bewijs voor westerse subgroepen in evidence tabel)

Uitgangsvraag 4b: Welke tweedelijns behandeling - best supportive care of systeem therapie (chemo- en/of targeted therapie)- zorgt voor de beste uitkomst bij patiënten met een  gemetastaseerd maagcarcinoom, of een voortgeschreden niet resectabel maagcarcinoom, of een recidief maagcarcinoom, in termen van kwaliteit van leven en (progressievrije) overleving ?

P

Patiënten met een gemetastaseerd maagcarcinoom of een voortgeschreden, niet resectabel maagcarcinoom of een recidief maagcarcinoom

I

Systeem therapie (chemo- en/of targeted therapie)

C

Best supportive care, chemotherapie en/of targeted therapie

O

Kwaliteit van leven, progressievrije overleving, overall survival

(Bewijs voor westerse subgroepen in evidence tabel)

Studies

• (1) meta-analyses, systematische reviews, (2) randomised controlled trials (RCT), controlled clinical trials (CCT)

Periode (vanaf tot):

2008-nu

Databases:

Medline, Embase, Cochrane (CDSR)

Taal:

Eng. Ned.

• 1. Bang et al, 2010. Trastuzumab in combination with chemotherapy versus chemotherapy alone for the treatment of Her2 Neu positive advanced gastric or gstric-oesophageal junction cancer (ToGA): a phanse 3 open-label, randomised controlled trial, Lancet 2010; 376(9742) 687-97.
• 2. Wilke H, Muro K, 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. doi: 10.1016/S1470-2045(14)70420-6. Epub 2014 Sep 17.

•3.        Fuchs CS Tomasek J. 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.

1.

Bevacizumab (Avastin) for metastatic gastric cancer - first line in combination with capecitabine and cisplatin (Structured abstract). Health Technology Assessment Database, 2008(1).

Ex

Unavailable

2.

Capecitabine for the treatment of advanced gastric cancer (Structured abstract). Health Technology Assessment Database, 2010(1).

Ex

Unavailable

3.

Everolimus (Afinitor) for advanced gastric cancer - second line (Structured abstract). Health Technology Assessment Database, 2011(1).

Ex

Unavailable

4.

Bang, Y.J., A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer (AGC) in Asian population: Tytan study. J Clin Oncol, 2013. 31(4 SUPPL. 1).

Ex

Satoh 2014 is full text article

5.

Bi, Y., D. Zeng, and Y. Ling, The clinical research of elemene emulsion combined with FOLFOX4 regimen in the treatment of advanced gastric carcinoma. Chinese-German Journal of Clinical Oncology, 2012. 11(6): p. 336-9.

Ex

Other intervention

6.

Chau, I., et al., Tolerability and quality-of-life (QoL) results from the phase 3 REGARD study: Ramucirumab versus placebo in patients with previously treated gastric or gastroesophageal junction (GEJ) adenocarcinoma. Eur J Cancer, 2013. 49: p. S615.

Ex

Full report = Fuchs 2014

7.

Chi, Y., et al., Phase II clinical study on the modified DCF regimen for treatment of advanced gastric carcinoma. Chinese Medical Journal, 2011. 124(19): p. 2997-3002.

Ex

Other study type (uncontrolled study)

8.

Cui, Y., et al., Combination of low-dose docetaxel and standard-dose S-1 for the treatment of advanced gastric cancer: Efficacy, toxicity, and potential predictive factor. Cancer chemotherapy and pharmacology, 2013. 71(1): p. 145-52.

Ex

Other study type (uncontrolled study)

9.

Cutsem, E., et al., Randomized phase II study (GATE study) of docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer. J Clin Oncol, 2011. 29(15 SUPPL. 1).

Ex

Full report = van Cutsem 2015

10.

Doshi, S., et al., Modeling the combined efficacy of rilotumumab (R; AMG 102) plus epirubicin/cisplatin/capecitabine (ECX) for the treatment of locally advanced or metastatic gastric or esophagogastric junction (G/EGJ) cancer. J Clin Oncol, 2012. 30(15 SUPPL. 1).

Ex

Iveson = full report

11.

Higuchi, K., et al., Biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer: a randomised phase III trial (TCOG GI-0801/BIRIP trial). Eur J Cancer, 2014. 50(8): p. 1437-45.

In

Second-line

12.

Janjigian, Y.Y., et al., A multicenter random assignment phase II study of irinotecan and flavopiridol versus irinotecan alone for patients with p53 wild-type gastric adenocarcinoma (NCI 8060). J Clin Oncol, 2012. 30(15 SUPPL. 1).

Ex

Other study type (likely interim report)

13.

Kim, G.M., et al., A randomized phase II trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer. Eur J Cancer, 2012. 48(4): p. 518-26.

Ex

Other comparator first-line (S-1 + oxaliplatin vs. capecitabine + oxaliplatin)

14.

Koizumi, W., et al., S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol, 2008. 9(3): p. 215-21.

Ex

Included in Liu 2014

15.

Lee, K.H., et al., Randomized, multicenter, phase III trial of heptaplatin 1-hour infusion and 5-fluorouracil combination chemotherapy comparing with cisplatin and 5-fluorouracil combination chemotherapy in patients with advanced gastric cancer. Cancer Res, 2009. 41(1): p. 12-8.

Ex

Other comparator first-line (heptaplatin + 5FU vs. cisplatin + 5FU)

16.

Lin, R.B., et al., A phase II study of 5-fluorouracil/leucovorin in combination with paclitaxel and oxaliplatin as first-line treatment for patients with advanced gastric cancer. Journal of chemotherapy (Florence, Italy), 2008. 20(6): p. 744-8.

Ex

Other study type (uncontrolled study)

17.

Liu, G.-F., et al., S-1-based combination therapy vs S-1 monotherapy in advanced gastric cancer: a meta-analysis. World J Gastroenterol, 2014. 20(1): p. 310-8.

In

First-line, S1-based combination vs. S1 monotherapy

18.

Lu, Y., Z. Liu, and J. Zhang, S-1 plus oxaliplatin vs. S-1 as first-line treatment in patients with previously untreated advanced gastric cancer: a randomized phase II study. J Chemother, 2014. 26(3): p. 159-64.

In

First-line, S1-based combination vs. S1 monotherapy

19.

Nihr, H.S.C., Ramucirumab monotherapy for advanced gastric cancer and gastro-oesophageal junction adenocarcinoma ? after prior chemotherapy (Structured abstract). Health Technology Assessment Database, 2013(1).

Ex

Other study type (narrative review: no systematic search and selection)

20.

Nihr, H.S.C., Ramucirumab in combination with paclitaxel for advanced gastric cancer and gastro-oesophageal junction adenocarcinoma after prior chemotherapy (Structured abstract). Health Technology Assessment Database, 2014(1).

Ex

Unavailable

21.

Norman, G., et al., Capecitabine for the treatment of advanced gastric cancer. Health Technol Assess, 2010. 14(Suppl. 2): p. 11-7.

Ex

Other comparator first-line (capecitabine vs. 5-fluorouracil)

22.

Ocvirk, J., et al., Randomized prospective phase II study to compare the combination chemotherapy regimen epirubicin, cisplatin, and 5-fluorouracil with epirubicin, cisplatin, and capecitabine in patients with advanced or metastatic gastric cancer. Am J Clin Oncol, 2012. 35(3): p. 237-41.

Ex

Other comparator first-line (epirubicin + cisplatin +

5-fluorouracil vs. epirubicin, + cisplatin + capecitabine)

23.

Qi W.-X, et al., The role of anti-VEGF agents in the treatment of advanced gastric cancer: a meta-analysis of randomized controlled trials. Tumor Biol., 2014. 35(8): p. 7675-7683.

Ex

Other patients (first- and second-line patients mixed in meta-analysis, used for reference tracking)

24.

Randolph, H.J., et al., Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO-013/LOGiC Trial. J Clin Oncol, 2013. 31(18 SUPPL. 1).

Ex

Other population (oesophagus tumour patients included, unclear which proportion. Available as abstract only)

25.

Roth, A., et al., Lapatinib in combination with ECF/x in EGFR1 or HER2-overexpressing first-line metastatic gastric cancer (GC): A phase II randomized placebo controlled trial (EORTC 40071) abstract no.TPS205. J Clin Oncol, 2010. 28(Suppl 15): p. 32.

Ex

Other study type (protocol)

26.

Roy, A., et al., Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study. Br J Cancer, 2012. 107(3): p. 435-41.

Ex

Other comparator first-line (docetaxel + irinotecan vs. docetaxel vs. fluorouracil)

27.

Shah, M.A., et al., Survival analysis according to disease subtype in AVAGAST: First-line capecitabine and cisplatin plus bevacizumab (bev) or placebo in patients (pts) with advanced gastric cancer. J Clin Oncol, 2012. 30(4 SUPPL. 1).

Ex

Subgroup analysis of an included study with no additional relevant data

28.

Shen, L., et al., Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer, 2015. 18(1): p. 168-76.

In

First-line

29.

Starling N and Cunningham D, REAL-2 study: Capecitabine and oxaliplatin for the treatment of advanced esophagogastric cancer. Am. J. Hematol. Oncol., 2008. 7(5).

Ex

Other comparator first-line (epirubicin + cisplatin + either fluorouracil or capecitabine vs. epirubicin + oxaliplatin + either fluorouracil or capecitabine)

30.

Sun, X.C., J. Lin, and A.H. Ju, Treatment of Borrmann type IV gastric cancer with a neoadjuvant chemotherapy combination of docetaxel, cisplatin and 5-fluorouracil/leucovorin. Journal of International Medical Research, 2011. 39(6): p. 2096-102.

Ex

Other population (operable patients)

31.

Van Cutsem, E., et al., Docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer: a randomized phase II study. Ann Oncol, 2015. 26(1): p. 149-56.

Ex

Other intervention first-line (docetaxel/oxaliplatin vs. docetaxel/oxaliplatin/5-FU vs.  docetaxel/oxaliplatin/capecitabine)

32.

Wu, J.-R., et al., S-1-based therapy versus S-1 monotherapy in advanced gastric cancer: a meta-analysis. Tumour Biol, 2014. 35(4): p. 3283-93.

Ex

Other study type (includes 1 retrospective study in M-A)

33.

Yamaguchi, K., et al., Randomized phase II study of S-1/CDDP plus TSU-68 versus S-1/CDDP in patients with advanced gastric cancer. J Clin Oncol, 2013. 31(4 SUPPL. 1).

Ex

Koizumi 2013 is full report

Reference

In/Ex

Reason for exclusion

1

Cetuximab (Erbitux) in combination with capecitabine and cisplatin for advanced or metastatic gastric cancer - first line (Structured abstract). Health Technology Assessment Database, 2011(4).

Ex

Other study type (narrative review: no systematic search and selection)

Lapatinib in combination with capecitabine and oxaliplatin for advanced gastric, oesophageal or gastro-oesophageal cancer - first line (Structured abstract). Health Technology Assessment Database, 2012(4).

Ex

Other study type (narrative review: no systematic search and selection)

Overall Survival of Inoperable Gastric/GastroOesophageal Cancer Subjects on Treating With LMWH + Chemotherapy(CT) vs Standard CT (GASTRANOX). ClinicalTrials.gov, 2010.

Ex

Other study type (trial registration)

Trastuzumab for the treatment of HER2-positive metastatic gastric cancer (Structured abstract). Health Technology Assessment Database, 2010(4).

Ex

Not available

5

Trastuzumab (Herceptin) for gastric cancer - metastatic HER2 positive, first line: horizon scanning technology briefing (Project record). Health Technology Assessment Database, 2009(4).

Ex

Not available

Abdel-Rahman O and Fouad M, Risk of mucocutaneous toxicities in patients with solid tumors treated with everolimus; A systematic review and meta-analysis. Expert Rev. Anticancer Ther., 2014. 14(12): p. 1529-1536.

Ex

Other outcome (used for reference tracking)

Al-Batran, S.-E., Ajani, J.A., Impact of chemotherapy on quality of life in patients with metastatic esophagogastric cancer. Cancer, 2010. 116(11): p. 2511-8.

Ex

Other study type (review without quality assessment of included trials; narrative presentation of results; actual data not reported for all included trials. In addition, many other comparisons included)

Al-Batran S.-E, et al., The feasibility of triple-drug chemotherapy combination in older adult patients with oesophagogastric cancer: A randomised trial of the Arbeitsgemeinschaft Internistische Onkologie (FLOT65+). Eur J Cancer, 2013. 49(4): p. 835-842.

Ex

Other comparator first-line (5-FU + leucovorin + oxaliplatin

+ docetaxel vs. 5-FU + leucovorin + oxaliplatin)

Amit L, et al., The impact of bevacizumab (Avastin) on survival in metastatic solid tumors - a meta-analysis and systematic review. PLoS ONE [Electronic Resource], 2013. 8(1).

Ex

Other population (majority non-gastric carcinoma patients. Used for reference tracking)

10

Bang Y.-J, 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. 376(9742): p. 687-697.

In

Satoh 2014 QoL data

Boku, N., Yamamoto, S., et al., Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol, 2009. 10(11): p. 1063-9.

In

fluorouracil + irinotecan + cisplatin vs. S-1

Cao Y, et al., Meta-analysis of incidence and risk of Hypomagnesemia with Cetuximab for advanced cancer. Chemotherapy, 2010. 56(6): p. 459-465.

Ex

Other outcome (hypokalemia, used for reference tracking)

Cao Y, et al., Meta-analysis of incidence and risk of hypokalemia with cetuximab-based therapy for advanced cancer. Cancer Chemother. Pharmacol., 2010. 66(1): p. 37-42.

Ex

Other outcome (hypokalemia, used for reference tracking)

Chau, I., et al., REAL3: A multicenter randomized phase II/III trial of epirubicin, oxaliplatin, and capecitabine (EOC) versus modified (m) EOC plus panitumumab (P) in advanced oesophagogastric (OG) cancer-Response rate (RR), toxicity, and molecular analysis from phase II. J Clin Oncol, 2011. 29(15 SUPPL. 1).

Ex

Other outcomes

15

Chen W-W, Wang, F. and R.-H. Xu, Platinum-based versus non-platinum-based chemotherapy as first line treatment of inoperable, advanced gastric adenocarcinoma: a meta-analysis. PLoS ONE [Electronic Resource], 2013. 8(7): p. e68974.

Ex

Other comparator first-line (many different chemotherapy regimens in one meta-analysis, platinum vs. non-platinum)

Chen X.-L, et al., Docetaxel, Cisplatin and Fluorouracil (DCF) Regimen Compared with Non-Taxane-Containing Palliative Chemotherapy for Gastric Carcinoma: A Systematic Review and Meta-Analysis. PLoS ONE [Electronic Resource], 2013. 8(4).

Ex

No distinction between first and second line treatment

Cohen, D.J., et al., Vismodegib (V), a hedgehog (HH) pathway inhibitor, combined with FOLFOX for first-line therapy of patients (pts) with advanced gastric and gastroesophageal junction (GEJ) carcinoma: A New York Cancer Consortium led phase II randomized study. J Clin Oncol, 2013. 31(15 SUPPL. 1).

Ex

Other comparator first-line (FOLFOX + vismodegib vs. placebo)

Cohen, D.J., et al., A randomized phase II study of vismodegib (V), a hedgehog (HH) pathway inhibitor, combined with FOLFOX in patients (pts) with advanced gastric and gastroesophageal junction (GEJ) carcinoma: A New York Cancer Consortium led study. J Clin Oncol, 2013. 31(4 SUPPL. 1).

Ex

Other comparator first-line (FOLFOX + vismodegib vs. placebo)

Curran, D., Pozzo, C., et al., Quality of life of palliative chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction treated with irinotecan combined with 5-fluorouracil and folinic acid: results of a randomised phase III trial. Qual Life Res, 2009. 18(7): p. 853-61.

In

QoL data of Dank 2008

20

Cutsem, E.V., et al., Phase III trial of everolimus (EVE) in previously treated patients with advanced gastric cancer (AGC): GRANITE-1. J Clin Oncol, 2012. 30(4 SUPPL. 1).

Ex

Ohtsu 2013 is the full article of this study

Dank, M., 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. Annals of Oncology, 2008. 19(8): p. 1450-7.

In

QoL data in Curran 2009

Dong, L., et al., Comparison of short-term efficacy and safety of TIROX and DCF regimens for advanced gastric cancer. Journal of international medical research, 2014. 42(3): p. 737-43.

Ex

Other outcomes

Eatock, M.M., et al., Phase II randomized, double-blind, placebo-controlled study of AMG 386 (trebananib) in combination with cisplatin and capecitabine in patients with metastatic gastro-oesophageal cancer. Annals of Oncology, 2013. 24(3): p. 710-8.

In

RCT - trebananib

Ford, HER. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol, 2014. 15(1): p. 78-86.

In

Included in SR Kim 2013 and in Iacovelli 2014

RCT - Docetaxel vs. best supportive care: subgroup analyses excluding oesophageal cancer

25

Fuchs C.S, 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. 383(9911): p. 31-39.

In

Included in Iacovelli 2014

Fuji M. Chemotherapy for advanced gastric cancer: ongoing phase III study of S-1 alone versus S-1 and docetaxel combination (JACCRO GC03 study). Int J Clin Oncol, 2008. 13(3): p. 201-5.

Ex

Koizumi 2014 is full article

Fujii, M., et al., Randomized phase III study of S-1 alone versus S-1 plus docetaxel (DOC) in the treatment for advanced gastric cancer (AGC): The START trial update. J Clin Oncol, 2011. 29(15 SUPPL. 1).

Ex

Koizumi 2014 is full article

Glenjen, N., et al., FLOX regimen (5-FU, folinic acid, oxaliplatin) and FLIRI regimen (5-FU, folinic acid, irinotecan) as first-line treatment in metastatic and locally advanced gastric cancer: A randomized phase II study. J Clin Oncol, 2012. 30(4 SUPPL. 1).

Ex

Other comparator first-line (FLOX vs. FLIRI)

Guimbaud R, et al., Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: A French intergroup (Federation Francophone de Cancerologie Digestive, Federation Nationale des Centres de Lutte Contre le Cancer, and Groupe Cooperateur Multidisciplinaire en Oncologie) study. J. Clin. Oncol., 2014. 32(31): p. 3520-3526.

In

RCT - fluorouracil, leucovorin, and

irinotecan vs. epirubicin, cisplatin, and capecitabine

30

Guimbaud, R., et al., Planned interim analysis of the intergroup FFCD-GERCOR-FNCLCC-AERO phase III study comparing two sequences of chemotherapy in locally advanced or metastatic gastric cancers abstract no. 4533. J Clin Oncol, 2009. 27(15S Part I): p. 210 210.

Ex

Interim analysis of Guimbaud 2014

Heiss, M.M., Murawa, P., et al., The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int J Cancer, 2010. 127(9): p. 2209-21.

Ex

Other intervention (intraperitoneal chemotherapy)

Hironaka, S., Ueda, S., et al., Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol, 2013. 31(35): p. 4438-44.

In

Second-line

Iacovelli, R. Chemotherapy or targeted therapy as second-line treatment of advanced gastric cancer. A systematic review and meta-analysis of published studies. PLoS ONE [Electronic Resource], 2014. 9(9): p. e108940.

Ex

Does not include Thuss-patience in meta-analysis for unclear reasons, which Kim 2013 does

Iveson T, et al., Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: An open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study. Lancet Oncol., 2014. 15(9): p. 1007-1018.

In

RCT - rilotumumab + epirubicin + cisplatin + capecitabine vs. placebo + epirubicin + cisplatin + capecitabine

35

Jatoi, A., Foster, N.R., et al., Older versus younger patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction, and stomach: a pooled analysis of eight consecutive North Central Cancer Treatment Group (NCCTG) trials. Int J Oncol, 2010. 36(3): p. 601-6.

Ex

Other comparator (older vs. younger patients)

Kang J.H, et al., Salvage chemotherapy for pretreated gastric cancer: A randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J. Clin. Oncol., 2012. 30(13): p. 1513-1518.

In

RCT - Chemotherapy vs. BSC, not on relapsed patients

Kataoka H, et al., Lentinan with S-i and paclitaxel for gastric cancer chemotherapy improve patient quality of life. Hepatogastroenterology, 2009. 56(90): p. 547-550.

Ex

Other study type (uncontrolled study)

Kawakami, H., Okamoto, I., et al., Postprogression survival for first-line chemotherapy in patients with advanced gastric cancer. Eur J Cancer, 2013. 49(14): p. 3003-9.

Ex

Other outcome (post-progression survival)

Kim, H.J., et al., Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis. Ann Oncol, 2013. 24(11): p. 2850-4.

In

Includes:

- Kang 2012 = included here, right population

- Cook 2013 (not included here: relapsed patients, full study article = Ford 2014,  included here)

- Thuss-Patience 2011 = included here, correct population

See also Iacovelli

40

Kim, Y.H., et al., Randomized phase III study of S-1 alone versus S-1 plus docetaxel (DOC) in the treatment for advanced gastric cancer (AGC): The START trial. J Clin Oncol, 2011. 29(4 SUPPL. 1).

Ex

Koizumi 2014 is full article

Kim, S.T. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study. Eur J Cancer, 2014. 50(16): p. 2822-30.

Ex

Other intervention (simvastatin)

Koizumi, W., Yamaguchi, K., et al., Randomised phase II study of S-1/cisplatin plus TSU-68 vs S-1/cisplatin in patients with advanced gastric cancer. Br J Cancer, 2013. 109(8): p. 2079-86.

In

RCT - S-1/cisplatin +  TSU-68 vs. S-1/cisplatin

Koizumi, W., Kim, Y.H., et al., Addition of docetaxel to S-1 without platinum prolongs survival of patients with advanced gastric cancer: a randomized study (START). J Cancer Res Clin Oncol, 2014. 140(2): p. 319-28.

In

First-line

Komatsu, Y, Takahashi, Y., et al., Randomized phase II trial of first-line treatment with tailored irinotecan and S-1 therapy versus S-1 monotherapy for advanced or recurrent gastric carcinoma (JFMC31-0301). Anticancer Drugs, 2011. 22(6): p. 576-83.

Ex

Included in Liu 2014 and Qi 2013

45

Konings, I.R.H.M., van der Gaast, A., et al., The addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II trial. Eur J Cancer, 2010. 46(18): p. 3200-4.

Ex

Other intervention (pravastatin)

Kripp M, et al., Quality of life of older adult patients receiving docetaxel-based chemotherapy triplets for esophagogastric adenocarcinoma: A randomized study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Gastric Cancer, 2014. 17(1): p. 181-187.

Ex

Other comparator first-line (oxiplatin + 5-FU + folinic acid (leukovorin)  vs. oxiplatin + 5-FU + folinic acid + docetaxel) part of the Al-Batran 2013 RCT

Kulig, J. Kolodziejczyk, P., et al., Adjuvant chemotherapy with etoposide, adriamycin and cisplatin compared with surgery alone in the treatment of gastric cancer: a phase III randomized, multicenter, clinical trial. Oncology, 2010. 78(1): p. 54-61.

Ex

Other population (patients with a potentially curative resection)

Lee, S.S., et al., A pilot study of S-1 plus cisplatin versus 5-fluorouracil plus cisplatin for postoperative chemotherapy in histological stage IIIB-IV (M0) gastric cancer. Investigational new drugs, 2012. 30(1): p. 357-63.

Ex

Other population (curative resections)

Lee, H.J., et al., The ATP-based doublet chemotherapy response assay for un-resectable advanced gastric cancer; a single center, prospective, randomized controlled study. Gastrointestinal endoscopy, 2012. 75(4 SUPPL. 1): p. AB236.

Ex

Other intervention (ATP-based doublet chemotherapy response assay)

50

Lee, S., et al., Combined analysis of randomized controlled trial (RCT) and patient-preference trial (PPT) evaluating second-line chemotherapy (SLC) in advanced gastric cancer (AGC). J Clin Oncol, 2012. 30(15 SUPPL. 1).

Ex

Other study type (comparing results of RCT to results of patient preference trial)

Li, X-D., Shen, H., et al., Paclitaxel based vs oxaliplatin based regimens for advanced gastric cancer. World J Gastroenterol, 2011. 17(8): p. 1082-7.

Ex

Other comparator first-line (paclitaxel

+ fluorouracil + cisplatin vs. oxaliplatin + fluorouracil + leucovorin)

Li, J., et al., A randomized, double-blind, multicenter, phase II, three-arm, placebo-control study of apatinib as third-line treatment in patients with metastatic gastric carcinoma. J Clin Oncol, 2011. 29(15 SUPPL. 1).

Ex

Li 2013 full report

Li, J., Qin, S., et al., Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol, 2013. 31(26): p. 3219-25.

Ex

Third-line

Lordick, F., Kang, Y.-K., et al., Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol, 2013. 14(6): p. 490-9.

In

RCT - capecitabine-cisplatin + cetuximab vs. capecitabine-cisplatin

55

Luo, H.Q., L. Han, and Y. Jiang, Meta-analysis of six randomized control trials of chemotherapy plus anti-HER monoclonal antibody for advanced gastric and gastroesophageal cancer (Provisional abstract). Database of Abstracts of Reviews of Effects, 2014(1): p. 5343-5348.

Ex

Other population (RCT with 60% of patients having oesophagus carcinoma included (Rao 2010); in addition, 3/6 included RCTs are untraceable)

Maiello, E., et al., Epirubicin (E) in combination with cisplatin (CDDP) and capecitabine (C) versus docetaxel (D) combined with 5-fluorouracil (5-FU) by continuous infusion as front-line therapy in patients with advanced gastric cancer (AGC): Preliminary results of a randomized phase II trial of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol, 2011. 29(4 SUPPL. 1).

Ex

Other comparator first-line (epirubicin + cisplatin + capecitabine vs. docetaxel + 5FU)

Malka, D., et al., Met or EGFR Inhibition in Gastroesophageal Adenocarcinoma (MEGA): FOLFOX alone or in combination with AMG 102 or panitumumab as first-line treatment in patients with advanced gastroesophageal adenocarcinoma: FNCLCC-FFCD-AGEO-GERCOR PRODIGE 17-ACCORD 20 randomized phase II trial. J Clin Oncol, 2011. 29(15 SUPPL. 1).

Ex

Other study type (ongoing study)

Miyashiro I, et al., Randomized clinical trial of adjuvant chemotherapy with intraperitoneal and intravenous cisplatin followed by oral fluorouracil (UFT) in serosa-positive gastric cancer versus curative resection alone: Final results of the Japan Clinical Oncology Group trial JCOG9206-2. Gastric cancer, 2011. 14(3): p. 212-218.

Ex

Other population (curative resection)

Mochiki, E., Ogata, K., et al., Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer. Br J Cancer, 2012. 107(1): p. 31-6.

In

60

Moehler, M., Kanzler, S., et al., A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction. Ann Oncol, 2010. 21(1): p. 71-7.

In

Narahara, H, Iishi, H., et al., Randomized phase III study comparing the efficacy and safety of irinotecan plus S-1 with S-1 alone as first-line treatment for advanced gastric cancer (study GC0301/TOP-002). Gastric Cancer, 2011. 14(1): p. 72-80.

Ex

Included in Liu 2014, Qi 2013

Nihr, H.S.C., Trastuzumab emtansine (Kadcyla) for patients with HER2 positive locally advanced or metastatic relapsed gastric cancers (Structured abstract). Health Technology Assessment Database, 2013(4).

Ex

Other study type (narrative review: no systematic search and selection)

Nihr, H.S.C., Onartuzumab for metastatic Met positive gastric or gastro-oesophageal junction cancer (Structured abstract). Health Technology Assessment Database, 2014(4).

Ex

Other study type (narrative review: no systematic search and selection)

Norman, G., Rice, S., et al., Trastuzumab for the treatment of HER2-positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Health Technology Assessment, 2011. 1: p. 33-42.

Ex

Other study type (re-appraisal of clinical and cost-effectiveness analyses)

65

Oba, K., Kobayashi, M., et al., Individual patient based meta-analysis of lentinan for unresectable/recurrent gastric cancer. Anticancer Res, 2009. 29(7): p. 2739-45.

Ex

Unclear whether intervention was first- or second-line

Oba, K., et al., Role of chemotherapy for advanced/recurrent gastric cancer: an individual-patient-data meta-analysis. Eur J Cancer, 2013. 49(7): p. 1565-77.

Ex

Other comparator (wide variety of chemotherapeutic regimens included, seems first-line population though this is not stated explicitly)

Ohtsu A, et al., Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: A randomized, double-blind, placebo-controlled phase III study. J. Clin. Oncol., 2011. 29(30): p. 3968-3976.

In

RCT - bevacizumab

Ohtsu, A., Ajani, J.A., et al., Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol, 2013. 31(31): p. 3935-43.

In

Included in Iacovelli 2014

Okines, AFC. Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials. Eur J Cancer, 2013. 49(9): p. 2116-25.

Ex

Other intervention (biomarker analysis)

70

Pang, L.N., et al., Neoadjuvant chemotherapy for locally advanced gastric cancer: a meta analysis (Provisional abstract). Database of Abstracts of Reviews of Effects, 2014(1): p. 169-174.

Ex

Chinese

Park, S.H., Nam, E., et al., Randomized phase II study of irinotecan, leucovorin and 5-fluorouracil (ILF) versus cisplatin plus ILF (PILF) combination chemotherapy for advanced gastric cancer. Ann Oncol, 2008. 19(4): p. 729-33.

Ex

Other comparator  first-line (irinotecan

+ leucovorin + 5-FU vs.

irinotecan + leucovorin + 5-FU + cisplatin)

Park, S.H., et al., A multicenter, randomized phase III trial comparing second-line chemotherapy (SLC) plus best supportive care (BSC) with BSC alone for pretreated advanced gastric cancer (AGC). J Clin Oncol, 2011. 29(15 SUPPL. 1).

Ex

Kang 2012 =full report

Petrelli, F. Cisplatin or not in advanced gastric cancer: a systematic review and meta-analysis. PLoS ONE [Electronic Resource], 2013. 8(12): p. e83022.

Ex

Other study type (review with no quality appraisal)

Popov, I.P., Jelic, S.B., et al., Bimonthly 24 h infusion of high-dose 5-fluorouracil vs EAP regimen in patients with advanced gastric cancer. A randomized phase II study. Medical Oncology, 2008. 25(1): p. 73-80.

Ex

Other outcomes (survival only reported in median months without 95%CI)

75

Qi, W-X., Shen, Z., et al., Overall survival benefits for irinotecan-containing regimens as first-line treatment for advanced gastric cancer: an updated meta-analysis of ten randomized controlled trials. Int J Cancer, 2013. 132(2): p. E66-73.

Ex

Other population (unclear whether advanced carcinoma was inoperable)

Rao, S., Starling, N., et al., Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with epirubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: a randomised, multicentre open-label phase II study. Ann Oncol, 2010. 21(11): p. 2213-9.

Ex

Other population (around 60% of patients had carcinoma of the lower oesophagus or gastro-esophageal junction)

Richards, D, Kocs, D.M., et al., Results of docetaxel plus oxaliplatin (DOCOX) +/- cetuximab in patients with metastatic gastric and/or gastroesophageal junction adenocarcinoma: results of a randomised Phase 2 study. Eur J Cancer, 2013. 49(13): p. 2823-31.

Ex

Other comparator first-line (docetaxel + oxaliplatin  + cetuximab vs. docetaxel + oxaliplatin)

Roy, A.C., Park, S.R., et al., A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Ann Oncol, 2013. 24(6): p. 1567-73.

In

Second-line

Sakamoto, J., Matsui, T. and Y. Kodera, Paclitaxel chemotherapy for the treatment of gastric cancer. Gastric Cancer, 2009. 12(2): p. 69-78.

Ex

Other study type (narrative review of non-comparative studies)

80

Sakuramoto, S., 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. 29(33): p. 4387-93.

Ex

Other intervention (adjuvant therapy)

Satoh, T., Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study. J Clin Oncol, 2014. 32(19): p. 2039-49.

In

Second-line

Satoh T, et al., Quality of life in the trastuzumab for gastric cancer trial. Oncologist, 2014. 19(7): p. 712-719.

In

QoL data, primary data in Bang 2010

Sawaki, A., et al., The use of trastuzumab in Japanese patients with HER2-positive advanced or metastatic gastric cancer. J Clin Oncol, 2011. 29(4 SUPPL. 1).

Ex

Other study type (subgroup analysis of TOGA trial)

Schott, G., Trastuzumab (Herceptin) in addition to standard chemotherapy as first-line therapy for advanced gastric cancer (Structured abstract). Health Technology Assessment Database, 2010(4).

Ex

Unavailable

85

Shen, L., et al., Efficacy and tolerability of bevacizumab (BEV) plus capecitabine and cisplatin (XP) in Chinese patients (pts) with locally advanced or metastatic gastric/gastroesophageal junction cancer (AGC): Results from the AVATAR study. J Clin Oncol, 2012. 30(4 SUPPL. 1).

Ex

Other population (Chinese subgroup from the Avatar study)

Shirao, K, Boku, N., et al., Randomized Phase III study of 5-fluorouracil continuous infusion vs. sequential methotrexate and 5-fluorouracil therapy in far advanced gastric cancer with peritoneal metastasis (JCOG0106). Jpn J Clin Oncol, 2013. 43(10): p. 972-80.

In

First-line

Spackman, E., Rice, S., et al., Trastuzumab for the treatment of HER2-positive metastatic gastric cancer : a NICE single technology appraisal. Pharmacoeconomics, 2013. 31(3): p. 185-94.

Ex

Other study type (review of a cost-effectiveness study)

Sun, W. and W. Chen, Efficacy, safety and cost-effectiveness of trastuzumab in metastatic gastric cancer treatment in china. Value in health, 2014. 17(3): p. A97-A98.

Ex

Other study type (cost-effectiveness study; primary data not suited to our research question)

Sym, S., et al., A randomized phase II study of biweekly irinotecan versus irinotecan plus 5-fluorouracil/leucovorin as a salvage chemotherapy in previously treated patients with advanced gastric cancer. Annals of Oncology, 2010. 21(Suppl 6): p. 25.

Ex

Sym 2013 is full report

90

Sym, S.J., Hong, J., 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. 71(2): p. 481-8.

In

Second-line

Tabernero, J., et al., Pertuzumab (P) with trastuzumab (T) and chemotherapy (CTX) in patients (pts) with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer: An international phase III study (JACOB). J Clin Oncol, 2013. 31(15 SUPPL. 1).

Ex

Other study type (protocol)

Takashima, A., Boku, N., et al., Survival prolongation after treatment failure of first-line chemotherapy in patients with advanced gastric cancer: combined analysis of the Japan Clinical Oncology group trials JCOG9205 and JCOG9912. Gastric Cancer, 2014. 17(3): p. 522-8.

Ex

Other study type (non-comparative re-analysis of two trials)

Takagi, K., et al., Efficacy of paclitaxel for S-1-refractory gastric cancer (Japan). Japanese journal of clinical oncology, 2011. 41(3): p. i15.

Ex

Other study type (retrospective analysis)

Thuss-Patience, P.C., et al., Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). European journal of cancer (Oxford, England : 1990), 2011. 47(15): p. 2306-14.

In

RCT - irinotecan vs. BSC

Included in Kim 2013 & Iacovelli 2014

95

Waddell, T., Chau, I., et al., Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.[Erratum appears in Lancet Oncol. 2013 Jun;14(7):e254 Note: Frances, Alicia [corrected to Okines, Alicia Frances Clare]]. Lancet Oncol, 2013. 14(6): p. 481-9.

In

RCT - panitumumab

Wagner, A.D., et al., Chemotherapy for advanced gastric cancer. Cochrane Database of Systematic Reviews, 2010(3).

Ex

Other comparator first-line (chemotherapy is compared to different chemotherapeutic interventions than standard chemotherapy or fluoropyrimidine alone, or when these comparators are included they are mixed with trials with other comparators)

Wang, D-L., Gu, D.-Y., et al., Irinotecan-involved regimens for advanced gastric cancer: a pooled-analysis of clinical trials. World J Gastroenterol, 2010. 16(46): p. 5889-94.

Ex

Other study type (review with no quality appraisal. In addition, comparisons and study population were not described in detail)

Wang, X., Wang, M.L., et al., Randomized phase II study comparing paclitaxel with S-1 vs. S-1 as first-line treatment in patients with advanced gastric cancer. Clin Transl Oncol, 2013. 15(10): p. 836-42.

Ex

Included in Liu 2014

Wilke, H., et al., A randomized, multicenter, double-blind, placebo (PBO)-controlled phase III study of paclitaxel (PTX) with or without ramucirumab (IMC-1121B; RAM) in patients (pts) with metastatic gastric adenocarcinoma, refractory to or progressive after first-line therapy with platinum (PLT) and fluoropyrimidine (FP). J Clin Oncol, 2012. 30(15 SUPPL. 1).

Ex

Other study type (abstract of the full report Wilke 2014)

100

Wilke, H., 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. 15(11): p. 1224-35.

In

Second-line

Xu R, et al., Results of a randomized and controlled clinical trial evaluating the efficacy and safety of combination therapy with Endostar and S-1 combined with oxaliplatin in advanced gastric cancer. Onco Target Ther., 2013. 6: p. 925-929.

Ex

Other comparator first-line (docetaxel + fluorouracil + cisplatin)

Xu, C-D. Clinical study of nimotuzumab combined with chemotherapy in the treatment of late stage gastric cancer. Asian Pacific Journal of Cancer Prevention: Apjcp, 2014. 15(23): p. 10273-6.

Ex

Other population (both first- and second-line)

Yang, J. S-1-based vs non-S-1-based chemotherapy in advanced gastric cancer: a meta-analysis. World J Gastroenterol, 2014. 20(33): p. 11886-93.

Ex

Other comparator first-line (mainly S-1 vs. 5FU)

Yi, J.H., Lee, J., et al., Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum. Br J Cancer, 2012. 106(9): p. 1469-74.

In

Second-line

105

Zeng, C. Chemotherapy with or without irinotecan in patients with advanced or recurrent gastric cancer: a meta-analysis of randomized controlled trials. Chinese Medical Journal, 2014. 127(5): p. 951-6.

Ex

Other population (mixes first- and second-line treatment)

106

Zhang Z.-D, et al., Clinical evaluation of cetuximab combined with an S-1 and oxaliplatin regimen for Chinese patients with advanced gastric cancer. World J. Surg. Oncol., 2014. 12(1).

In

First-line