Adjuvant FOLFOX-4 in patients with radically resected gastric cancer: Tolerability and prognostic factors

Carlomagno,Chiara; Matano,Elide; Bianco,Roberto; Cimminiello,Carolina; Prudente,Antonella; Pagliarulo,Clorindo; Crispo,Anna; Cannella,Lucia; De Stefano,Alfonso; D'Armiento,Francesco Paolo; De Placido,Sabino

doi:10.3892/etm_00000096

Adjuvant FOLFOX-4 in patients with radically resected gastric cancer: Tolerability and prognostic factors

Authors:
- Chiara Carlomagno
- Elide Matano
- Roberto Bianco
- Carolina Cimminiello
- Antonella Prudente
- Clorindo Pagliarulo
- Anna Crispo
- Lucia Cannella
- Alfonso De Stefano
- Francesco Paolo D'Armiento
- Sabino De Placido
View Affiliations

Affiliations: Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università Federico II, 80131 Naples, Italy. chiara.carlomagno@unina.it
Published online on: July 1, 2010 https://doi.org/10.3892/etm_00000096
Pages: 611-617

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to evaluate the toxicity and efficacy of the FOLFOX-4 regimen as adjuvant chemotherapy in patients with gastric cancer after radical surgery. Fifty-four patients (1 stage Ib, 6 stage II, 22 stage IIIa, 14 stage IIIb and 11 stage IV) received 8-12 cycles of FOLFOX-4 (oxaliplatin 85 mg/m2, Day 1; leucovorin 100 mg/m2 i.v., Days 1 and 2; 5-fluorouracil 400 mg/m2 i.v. bolus, Days 1 and 2 and 600 mg/m2 in 22 h i.v. continuous infusion, Days 1 and 2; every 14 days). Toxicity was recorded at each cycle according to the National Cancer Institute Common Toxicity Criteria. Disease-free (DFS) and overall survival (OS) were calculated according to the Kaplan-Meier method. Thirty-eight patients (70.4%) completed the prescribed number of cycles of chemotherapy. The toxicity was mild. Grade 3-4 neutropenia occurred in 57% of patients, thrombocytopenia and anemia in 2% of cases. Peripheral neuropathy was experienced by 46% of the patients (grade 4 in 2% of cases). Five patients experienced grade 3 gastrointestinal toxicity. After a median follow-up of 33.1 months, 17 patients relapsed and 17 succumbed to the disease. The mean observed DFS and OS were 49.7 months (range 40.7-58.8) and 57.9 months (range 49.6-66.2), respectively. At univariate analysis, females and patients who had received <8 cycles of chemotherapy had a significantly worse probability of DFS and OS. The Cox model showed gender to be independent of the factors affecting DFS. Adjuvant FOLFOX-4 is feasible and well-tolerated in patients radically resected for gastric cancer. Receiving <4 months of adjuvant FOLFOX-4 could be detrimental to prognosis.

View Figures

View References

1.	Kamangar F, Dores GM and Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 24:2137–2150. 2006. View Article : Google Scholar
2.	Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar
3.	Kajitani T: The general rules for the gastric cancer study in surgery and pathology. Part I. Clinical classification. Jpn J Surg. 11:127–139. 1981. View Article : Google Scholar : PubMed/NCBI
4.	Dent DM, Madden MV and Price SK: Randomized comparison of R1 and R2 gastrectomy for gastric carcinoma. Br J Surg. 75:110–112. 1988. View Article : Google Scholar : PubMed/NCBI
5.	Robertson CS, Chung SC, Woods SD, Griffin SM, Raimes SA, Lau JT and Li AK: A prospective randomized trial comparing R1 subtotal gastrectomy with R3 total gastrectomy for antral cancer. Ann Surg. 220:176–182. 1994. View Article : Google Scholar : PubMed/NCBI
6.	Cuschieri A, Weeden S, Fielding J, et al: Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Co-operative Group. Br J Cancer. 79:1522–1530. 1999. View Article : Google Scholar : PubMed/NCBI
7.	Bonenkamp JJ, Hermans J, Sasako M, et al: Extended lymph-node dissection for gastric cancer. N Engl J Med. 340:908–914. 1999. View Article : Google Scholar : PubMed/NCBI
8.	The Gastrointestinal Tumor Study Group: Controlled trial of adjuvant chemotherapy following curative resection for gastric cancer. Cancer. 49:1116–1122. 1982. View Article : Google Scholar : PubMed/NCBI
9.	Higgins GA, Amadeo JH, Smith DE, Humphrey EW and Keehn RJ: Efficacy of prolonged intermittent therapy with combined 5-FU and methyl-CCNU following resection for gastric carcinoma. A Veterans Administration Surgical Oncology, Group report. Cancer. 52:1105–1112. 1983. View Article : Google Scholar
10.	Engstrom PF, Lavin PT, Douglass HO Jr and Brunner KW: Postoperative adjuvant 5-fluorouracil plus methyl-CCNU therapy for gastric cancer patients. Eastern Cooperative Oncology Group study (EST 3275). Cancer. 55:1868–1873. 1985. View Article : Google Scholar : PubMed/NCBI
11.	Allum WH, Hallissey MT and Kelly KA: Adjuvant chemo-therapy in operable gastric cancer. 5 year follow-up of first British Stomach Cancer Group trial. Lancet. 1:571–574. 1989.PubMed/NCBI
12.	Coombes RC, Schein PS, Chilvers CE, et al: A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer. International Collaborative Cancer Group. J Clin Oncol. 8:1362–1369. 1990.
13.	Krook JE, O’Connell MJ, Wieand HS, et al: A prospective, randomized evaluation of intensive-course 5-fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancer. Cancer. 67:2454–2458. 1991. View Article : Google Scholar : PubMed/NCBI
14.	Grau JJ, Estape J, Alcobendas F, Pera C, Daniels M and Teres J: Positive results of adjuvant mitomycin-C in resected gastric cancer: a randomised trial on 134 patients. Eur J Cancer. 29A:340–342. 1993. View Article : Google Scholar : PubMed/NCBI
15.	Lise M, Nitti D, Marchet A, et al: Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin and mitomycin regimen in resectable gastric cancer. J Clin Oncol. 13:2757–2763. 1995.PubMed/NCBI
16.	Macdonald JS, Fleming TR, Peterson RF, et al: Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A Southwest Oncology Group study. Ann Surg Oncol. 2:488–494. 1995. View Article : Google Scholar
17.	Neri B, de Leonardis V, Romano S, et al: Adjuvant chemotherapy after gastric resection in node-positive cancer patients: a multicentre randomised study. Br J Cancer. 73:549–552. 1996. View Article : Google Scholar : PubMed/NCBI
18.	Cirera L, Balil A, Batiste-Alentorn E, et al: Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer. J Clin Oncol. 17:3810–3815. 1999.PubMed/NCBI
19.	Bajetta E, Buzzoni R, Mariani L, et al: Adjuvant chemotherapy in gastric cancer: 5-year results of a randomised study by the Italian Trials in Medical Oncology (ITMO) Group. Ann Oncol. 13:299–307. 2002.PubMed/NCBI
20.	De Vita F, Giuliani F, Orditura M, et al: Adjuvant chemotherapy with epirubicin, leucovorin, 5-fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study). Ann Oncol. 18:1354–1358. 2007.
21.	Di Costanzo F, Gasperoni S, Manzione L, et al: Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC. J Natl Cancer Inst. 100:388–398. 2008.PubMed/NCBI
22.	Hermans J, Bonenkamp JJ, Boon MC, Bunt AM, Ohyama S, Sasako M and van de Velde CJ: Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. J Clin Oncol. 11:1441–1447. 1993.PubMed/NCBI
23.	Hermans J and Benekamp K: In replay. J Clin Oncol. 12:879–880. 1994.
24.	Earle CC and Maroun JA: Adjuvant chemotherapy after curative resection for gastric cancer in non-Asian patients: revisiting a meta-analysis of randomised trials. Eur J Cancer. 35:1059–1064. 1999. View Article : Google Scholar
25.	Mari E, Floriani I, Tinazzi A, et al: Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’ Apparato Digerente). Ann Oncol. 11:837–843. 2000.
26.	Gianni L, Panzini I, Tassinari D, Mianulli AM, Desiderio F and Ravaioli A: Meta-analyses of randomized trials of adjuvant chemotherapy in gastric cancer. Ann Oncol. 12:1178–1180. 2001.PubMed/NCBI
27.	Panzini I, Gianni L, Fattori PP, et al: Adjuvant chemotherapy in gastric cancer: a meta-analysis of randomized trials and a comparison with previous meta-analyses. Tumori. 88:21–27. 2002.PubMed/NCBI
28.	Hu JK, Chen ZX, Zhou ZG, et al: Intravenous chemotherapy for resected gastric cancer: meta-analysis of randomized controlled trials. World J Gastroenterol. 8:1023–1028. 2002.PubMed/NCBI
29.	Janunger KG, Hafstrom L and Glimelius B: Chemotherapy in gastric cancer: a review and updated meta-analysis. Eur J Surg. 168:597–608. 2002. View Article : Google Scholar : PubMed/NCBI
30.	Liu TS, Wang Y, Chen SY and Sun YH: An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancer. Eur J Surg Oncol. 34:1208–1216. 2008. View Article : Google Scholar : PubMed/NCBI
31.	Zhao SL and Fang JY: The role of postoperative adjuvant chemotherapy following curative resection for gastric cancer: a meta-analysis. Cancer Invest. 26:317–325. 2008. View Article : Google Scholar : PubMed/NCBI
32.	Sun P, Xiang JB and Chen ZY: Meta-analysis of adjuvant chemotherapy after radical surgery for advanced gastric cancer. Br J Surg. 96:26–33. 2009. View Article : Google Scholar : PubMed/NCBI
33.	Oba K: Efficacy of adjuvant chemotherapy using tegafur-based regimen for curatively resected gastric cancer: update of a meta-analysis. Int J Clin Oncol. 14:85–89. 2009. View Article : Google Scholar : PubMed/NCBI
34.	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. 345:725–730. 2001. View Article : Google Scholar
35.	Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 355:11–20. 2006. View Article : Google Scholar : PubMed/NCBI
36.	Sakuramoto S, Sasako M, Yamaguchi T, et al: Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 357:1810–1820. 2007. View Article : Google Scholar : PubMed/NCBI
37.	Cunningham D, Starling N, Rao S, et al: Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 358:36–46. 2008. View Article : Google Scholar : PubMed/NCBI
38.	Andre T, Boni C, Navarro M, et al: Improved overall survival with oxaliplatin, fluorouracil and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 27:3109–3116. 2009. View Article : Google Scholar : PubMed/NCBI
39.	Kuebler JP, Wieand HS, O’Connell MJ, et al: Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 25:2198–2204. 2007. View Article : Google Scholar
40.	Kaplan EL and Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc. 53:457–481. 1958. View Article : Google Scholar
41.	Peto R and Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc. 135A:185–206. 1972.
42.	Cox DR: Regression models and life tables (with discussion). J R Stat Soc. 4B:187–220. 1972.
43.	Qiu MZ, Teng KY, Ruan DY, et al: Impact of adjuvant chemotherapy duration on 3-year disease-free survival of colorectal carcinoma patients after radical resection. Chin J Cancer. 28:743–748. 2009.PubMed/NCBI
44.	Neugut AI, Matasar M, Wang X, et al: Duration of adjuvant chemotherapy for colon cancer and survival among the elderly. J Clin Oncol. 24:2368–2375. 2006. View Article : Google Scholar : PubMed/NCBI
45.	Yen MS, Twu NF, Lai CR, Horng HC, Chao KC and Juang CM: Importance of delivered cycles and nomogram for intraperitoneal chemotherapy in ovarian cancer. Gynecol Oncol. 114:415–419. 2009. View Article : Google Scholar : PubMed/NCBI
46.	Arkenau HT, Bermann A, Rettig K, Strohmeyer G and Porschen R: 5-Fluorouracil plus leucovorin is an effective adjuvant chemotherapy in curatively resected stage III colon cancer: long-term follow-up results of the adjCCA-01 trial. Ann Oncol. 14:395–399. 2003. View Article : Google Scholar : PubMed/NCBI
47.	Chau I, Norman AR, Cunningham D, et al: A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer. Ann Oncol. 16:549–557. 2005. View Article : Google Scholar
48.	Hershman D, Hall MJ, Wang X, Jacobson JS, McBride R, Grann VR and Neugut AI: Timing of adjuvant chemotherapy initiation after surgery for stage III colon cancer. Cancer. 107:2581–2588. 2006. View Article : Google Scholar : PubMed/NCBI
49.	Cold S, During M, Ewertz M, Knoop A and Moller S: Does timing of adjuvant chemotherapy influence the prognosis after early breast cancer? Results of the Danish Breast Cancer Cooperative Group (DBCG). Br J Cancer. 93:627–632. 2005. View Article : Google Scholar : PubMed/NCBI
50.	Jara SC, Ruiz A, Martin M, et al: Influence of timing of initiation of adjuvant chemotherapy over survival in breast cancer: a negative outcome study by the Spanish Breast Cancer Research Group (GEICAM). Breast Cancer Res Treat. 101:215–223. 2007. View Article : Google Scholar : PubMed/NCBI
51.	Colleoni M, Bonetti M, Coates AS, et al: Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors. The International Breast Cancer Study Group. J Clin Oncol. 18:584–590. 2000.
52.	Box B, Lindsey I, Wheeler JM, et al: Neoadjuvant therapy for rectal cancer: improved tumor response, local recurrence, and overall survival in nonanemic patients. Dis Colon Rectum. 48:1153–1160. 2005. View Article : Google Scholar : PubMed/NCBI
53.	Lee SD, Park JW, Park KS, et al: Influence of anemia on tumor response to preoperative chemoradiotherapy for locally advanced rectal cancer. Int J Colorectal Dis. 24:1451–1458. 2009. View Article : Google Scholar : PubMed/NCBI
54.	Ferrandina G, Distefano M, Smaniotto D, et al: Anemia in patients with locally advanced cervical carcinoma administered preoperative radiochemotherapy: association with pathological response to treatment and clinical outcome. Gynecol Oncol. 103:500–505. 2006. View Article : Google Scholar
55.	Shen JG, Cheong JH, Hyung WJ, Kim J, Choi SH and Noh SH: Pretreatment anemia is associated with poorer survival in patients with stage I and II gastric cancer. J Surg Oncol. 91:126–130. 2005. View Article : Google Scholar : PubMed/NCBI
56.	Park SH, Lee J, Lee SH, et al: Anemia is the strongest prognostic factor for outcomes of 5-fluorouracil-based first-line chemotherapy in patients with advanced gastric cancer. Cancer Chemother Pharmacol. 57:91–96. 2006. View Article : Google Scholar : PubMed/NCBI
57.	De Vita F, Orditura M, Matano E, et al: A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients. Br J Cancer. 92:1644–1649. 2005.PubMed/NCBI
58.	Fang Y, Wang YJ, Li F and Li J: Oxaliplatin in combination with calcium folinate and fluorouracil as neoadjuvant chemotherapy in the treatment of advanced gastric cancer. Zhonghua Wei Chang Wai Ke Za Zhi. 9:510–512. 2006.PubMed/NCBI
59.	Zhao L, Li XY, Bai CM and Chen SC: Post-operative adjuvant treatment with oxaliplatin, fluorouracil, and leucovorin for local advanced gastric cancer. Zhonghua Yi Xue Za Zhi. 88:1264–1266. 2008.PubMed/NCBI
60.	Matsui M, Kojima O, Kawakami S, Uehara Y and Takahashi T: The prognosis of patients with gastric cancer possessing sex hormone receptors. Surg Today. 22:421–425. 1992. View Article : Google Scholar : PubMed/NCBI
61.	Harrison JD, Morris DL, Ellis IO, Jones JA and Jackson I: The effect of tamoxifen and estrogen receptor status on survival in gastric carcinoma. Cancer. 64:1007–1010. 1989. View Article : Google Scholar : PubMed/NCBI
62.	Koullias GJ, Kouraklis GP, Raftopoulos IS, Davaris PS, Papadopoulos SA and Golematis BC: Increased estrogen receptor and epidermal growth factor receptor gene product co-expression in surgically resected gastric adenocarcinomas. J Surg Oncol. 63:166–171. 1996. View Article : Google Scholar : PubMed/NCBI