Treatment Options for Patients With No Distant Metastases (M0)
Treatment Options for Patients With Distant Metastases (M1)
Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Standard treatment options:

1. Radical surgery. Curative resection procedures are confined to patients who at the time of surgical exploration do not have extensive nodal involvement.



2. Postoperative chemoradiation therapy.[1]



3. Perioperative chemotherapy.[2]

All patients with tumors that can be resected should undergo surgery. As many as 15% of selected stage IV patients can be cured by surgery alone, particularly if lymph node involvement is minimal (<7 lymph nodes).

Postoperative chemoradiation therapy may be considered for patients with stage IV gastric cancer. A prospective multi-institution phase III trial (INT-0116) evaluating postoperative combined chemoradiation therapy versus surgery alone in 556 patients with completely resected stage IB to stage IV (M0) adenocarcinoma of the stomach and gastroesophageal junction reported a significant survival benefit with adjuvant combined modality therapy.[1][Level of evidence: 1iiA] With a median follow-up of 5 years, median survival was 36 months for the adjuvant chemoradiation therapy group as compared to 27 months for the surgery-alone arm (P = .005). Three-year overall survival (OS) and relapse-free survival rates were 50% and 48%, respectively, with adjuvant chemoradiation therapy versus 41% and 31%, respectively, for surgery alone (P = .005). Because distant disease remains a significant concern, the aim of the current Cancer and Leukemia Group B study (CALGB-80101) is to augment the postoperative chemoradiation regimen used in the INT-0116trial, for example, and the preoperative chemotherapy and chemoradiation therapy regimen used in the RTOG-9904 trial.

Investigators in Europe evaluated the role of preoperative and postoperative chemotherapy without radiation therapy.[2] In the randomized phase III trial (MRC-ST02), patients with stage II or higher adenocarcinoma of the stomach or of the lower third of the esophagus were assigned to receive three cycles of epirubicin, cisplatin, and continuous infusion 5-fluorouracil (ECF) before and after surgery or to receive surgery alone. Compared with the surgery group, the perioperative chemotherapy group had a significantly higher likelihood of progression-free survival (hazard ratio [HR] for progression, 0.66; 95% confidence interval [CI], 0.53–0.81; P < .001) and of OS (HR for death, 0.75; 95% CI, 0.60–0.93; P = .009). Five-year OS was 36.3%; 95% CI, 29 to 43 for the perioperative chemotherapy group and 23%; 95% CI, 16.6 to 29.4 for the surgery group.[2][Level of evidence: 1iiA]

Treatment options under clinical evaluation:

1. Postoperative chemoradiation with ECF such as in the CALGB-80101 trial.[3].
2. Neoadjuvant chemoradiation therapy such as in the SWOG-S0425 and RTOG-9904 trials.[4]

All newly diagnosed patients with stage IV gastric cancer should be considered candidates for clinical trials.

Standard treatment options:

1. Palliative chemotherapy with:
   • Fluorouracil (5-FU).[5-7]
   • Epirubicin, cisplatin, and 5-FU (ECF).[8,9]
   • Cisplatin and 5-FU (CF).[10,7]
   • Etoposide, leucovorin, and 5-FU (ELF).[11]
   • 5-FU, doxorubicin, and methotrexate (FAMTX).[10]



2. Endoluminal laser therapy or endoluminal stent placement may be helpful to patients whose tumors have occluded the gastric inlet or outlet.[12]



3. Palliative radiation therapy may alleviate bleeding, pain, and obstruction.



4. Palliative resection should be reserved for patients with continued bleeding or obstruction.

Standard chemotherapy versus best supportive care for patients with metastatic gastric cancer has been tested in several clinical trials, and there is general agreement that patients who receive chemotherapy live for several months longer on average than patients who receive supportive care.[13-15][Level of evidence: 1iiA] During the last 20 years, multiple randomized studies evaluating different treatment regimens (monotherapy vs. combination chemotherapy) have been performed in patients with metastatic gastric cancer with no clear consensus emerging as to the best management approach. A meta-analysis of these studies demonstrated an HR of 0.83 for OS (95% CI, 0.74–0.93) in favor of combination chemotherapy.[16]

Of all the combination regimens, ECF is often considered the reference standard in the United States and Europe. In one European trial, 274 patients with metastatic esophagogastric cancer were randomly assigned to receive either ECF or FAMTX.[17] The group who received ECF had a significantly longer median survival (8.9 vs. 5.7 months, P = .0009) than the FAMTX group.[17][Level of evidence: 1iiA] In a second trial that compared ECF with mitomycin, cisplatin, and 5-FU (MCF), there was no statistically significant difference in median survival (9.4 vs. 8.7 months, P = .315).[9][Level of evidence: 1iiA]

An international collaboration of investigators randomly assigned 445 patients with metastatic gastric cancer to receive docetaxel, cisplatin, and 5-FU (DCF) or CF.[18] Time-to-treatment progression (TTP) was the primary endpoint. Patients who received DCF experienced a significantly longer TTP (5.6 months; 95% CI, 4.9–5.9; vs. 3.7 months; 95% CI, 3.4–4.5; HR, 1.47; 95% CI, 1.19–1.82; log-rank P < .001; risk reduction 32%). The median OS was significantly longer for patients who received DCF versus patients who received CF (9.2 months; 95% CI, 8.4–10.6; vs. 8.6 months; 95% CI, 7.2–9.5; HR, 1.29; 95% CI, 1.0–1.6; log-rank P = .02; risk reduction = 23%).[18][Level of evidence: 1iiA] There were high toxicity rates in both arms.[19] Febrile neutropenia was more common in patients who received DCF (29% vs. 12%), and the death rate on the study was 10.4% for patients on the DCF arm and 9.4% for patients on the CF arm.

Whether the CF regimen should be considered as an index regimen for the treatment of patients with metastatic gastric cancer is the subject of debate.[19] The results of a study that randomly assigned 245 patients with metastatic gastric cancer to receive CF, FAMTX, or ELF demonstrated no significant difference in response rate, progression-free survival, or OS between the arms.[10] Grades 3 and 4 neutropenia occurred in 35% to 43% of patients on all arms, but severe nausea and vomiting was more common in patients in the CF arm and occurred in 26% of those patients.[10][Level of evidence: 1iiDiv]

Treatment options under clinical evaluation:

• Palliative chemotherapy with:
  • Irinotecan and cisplatin.
  • Folic acid, 5-FU, and irinotecan (FOLFIRI).
  • Leucovorin, 5-FU, and oxaliplatin (FOLFOX).

Phase II studies evaluating irinotecan-based or oxaliplatin-based regimens demonstrate similar response rates and TTP to those found with ECF or CF, but the former may be less toxic.[20-25] There are conflicting data regarding relative efficacy of any one regimen for another. Ongoing studies are evaluating these newer regimens.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV gastric cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Macdonald JS, Smalley SR, Benedetti J, et al.: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345 (10): 725-30, 2001.  [PUBMED Abstract]
   
   
2. Cunningham D, Allum WH, Stenning SP, et al.: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355 (1): 11-20, 2006.  [PUBMED Abstract]
   
   
3. Fuchs C, Tepper JE, Niedwiecki D, et al.: Postoperative adjuvant chemoradiation for gastric or gastroesophageal adenocarcinoma using epirubicin, cisplatin, and infusional (CI) 5-FU (ECF) before and after CI 5-FU and radiotherapy (RT): interim toxicity results from Intergroup trial CALGB 80101. [Abstract] American Society of Clinical Oncology 2006 Gastrointestinal Cancers Symposium, 26-28 January 2006, San Francisco, California. A-61, 2006. 
   
   
4. 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 24 (24): 3953-8, 2006.  [PUBMED Abstract]
   
   
5. Comis RL, Carter SK: Integration of chemotherapy into combined modality treatment of solid tumors. III. Gastric cancer. Cancer Treat Rev 1 (3): 221-238, 1974. 
   
   
6. Cullinan SA, Moertel CG, Fleming TR, et al.: A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 253 (14): 2061-7, 1985.  [PUBMED Abstract]
   
   
7. 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 21 (1): 54-9, 2003.  [PUBMED Abstract]
   
   
8. Waters JS, Norman A, Cunningham D, et al.: Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer 80 (1-2): 269-72, 1999.  [PUBMED Abstract]
   
   
9. Ross P, Nicolson M, Cunningham D, et al.: Prospective randomized trial comparing mitomycin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) With epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20 (8): 1996-2004, 2002.  [PUBMED Abstract]
   
   
10. Vanhoefer U, Rougier P, Wilke H, et al.: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18 (14): 2648-57, 2000.  [PUBMED Abstract]
    
    
11. Ajani JA, Ota DM, Jackson DE: Current strategies in the management of locoregional and metastatic gastric carcinoma. Cancer 67 (1 Suppl): 260-5, 1991.  [PUBMED Abstract]
    
    
12. Ell C, Hochberger J, May A, et al.: Coated and uncoated self-expanding metal stents for malignant stenosis in the upper GI tract: preliminary clinical experiences with Wallstents. Am J Gastroenterol 89 (9): 1496-500, 1994.  [PUBMED Abstract]
    
    
13. Murad AM, Santiago FF, Petroianu A, et al.: Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 72 (1): 37-41, 1993.  [PUBMED Abstract]
    
    
14. Pyrhönen S, Kuitunen T, Nyandoto P, et al.: Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71 (3): 587-91, 1995.  [PUBMED Abstract]
    
    
15. Glimelius B, Ekström K, Hoffman K, et al.: Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8 (2): 163-8, 1997.  [PUBMED Abstract]
    
    
16. Wagner AD, Grothe W, Haerting J, et al.: Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol 24 (18): 2903-9, 2006.  [PUBMED Abstract]
    
    
17. Webb A, Cunningham D, Scarffe JH, et al.: Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15 (1): 261-7, 1997.  [PUBMED Abstract]
    
    
18. Ajani JA, Moiseyenko VM, Tjulandin S, et al.: Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group. J Clin Oncol 25 (22): 3205-9, 2007.  [PUBMED Abstract]
    
    
19. Ilson DH: Docetaxel, cisplatin, and fluorouracil in gastric cancer: does the punishment fit the crime? J Clin Oncol 25 (22): 3188-90, 2007.  [PUBMED Abstract]
    
    
20. Ilson DH, Saltz L, Enzinger P, et al.: Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol 17 (10): 3270-5, 1999.  [PUBMED Abstract]
    
    
21. Beretta E, Di Bartolomeo M, Buzzoni R, et al.: Irinotecan, fluorouracil and folinic acid (FOLFIRI) as effective treatment combination for patients with advanced gastric cancer in poor clinical condition. Tumori 92 (5): 379-83, 2006 Sep-Oct.  [PUBMED Abstract]
    
    
22. Pozzo C, Barone C, Szanto J, et al.: Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a randomized phase II study. Ann Oncol 15 (12): 1773-81, 2004.  [PUBMED Abstract]
    
    
23. 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 22 (21): 4319-28, 2004.  [PUBMED Abstract]
    
    
24. Ajani JA, Baker J, Pisters PW, et al.: CPT-11 plus cisplatin in patients with advanced, untreated gastric or gastroesophageal junction carcinoma: results of a phase II study. Cancer 94 (3): 641-6, 2002.  [PUBMED Abstract]
    
    
25. Cavanna L, Artioli F, Codignola C, et al.: Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic gastric cancer (MGC). Am J Clin Oncol 29 (4): 371-5, 2006.  [PUBMED Abstract]
    
    

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