Modified FOLFIRI as Second-Line Chemotherapy after Failure of Modified FOLFOX-4 in Advanced Gastric Cancer

Eun Kyoung Jeon; Sook Hee Hong; Tae Hee Kim; Seung Eun Jung; Ji Chan Park; Hye-Sung Won; Yoon-Ho Ko; Sang Young Rho; Young Seon Hong

doi:10.4143/crt.2011.43.3.148

Articles

Page Path: HOME > Cancer Res Treat > Volume 43(3); 2011 > Article

Original Article Modified FOLFIRI as Second-Line Chemotherapy after Failure of Modified FOLFOX-4 in Advanced Gastric Cancer: Eun Kyoung Jeon, MD¹, Sook Hee Hong, MD¹, Tae Hee Kim, MD¹, Seung Eun Jung, MD, PhD², Ji Chan Park, MD¹, Hye-Sung Won, MD¹, Yoon-Ho Ko, MD¹, Sang Young Rho, MD¹, Young Seon Hong, MD, PhD¹; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2011;43(3):148-153.
DOI: https://doi.org/10.4143/crt.2011.43.3.148
Published online: September 30, 2011

¹Division of Oncology, Department of Internal Medicine, The Catholic University of Korea School of Medicine, Seoul, Korea.

²Department of Radiology, The Catholic University of Korea School of Medicine, Seoul, Korea.

Correspondence: Young Seon Hong, MD, PhD. Division of Oncology, Department of Internal Medicine, The Catholic University of Korea School of Medicine, 505 Banpo-dong, Seocho-gu, Seoul 137-701, Korea.
Tel: 82-2-2258-6042, Fax: 82-2-535-1682, y331@catholic.ac.kr

• Received: June 20, 2010 • Accepted: November 5, 2010

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

11,978 Views
83 Download
12 Crossref
10 Scopus

prev next

Full Article

Download PDF

Abstract

Purpose
The purpose of this study was to evaluate efficacy and toxicity of irinotecan, leucovorin and 5-fluorouracil (FOLFIRI) as second-line treatment after failure of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) for advanced gastric cancer.
Materials and Methods
Patients who received modified FOLFOX-4 as first-line treatment and then received sequential modified FOLFIRI for disease progression were included in this study. The modified FOLFIRI regimen consisted of irinotecan 150 mg/m² in a 90-minute intravenous infusion on day 1, leucovorin (LV) 20 mg/m² and 5-fluorouracil (5-FU) 400 mg/m² as a bolus followed by 600 mg/m² as a 22-hour infusion on days 1 and 2 with the same dose of 5-FU/LV of modified FOLFOX-4 every 2 weeks.
Results
A total of 32 patients received 126 courses of FOLFIRI chemotherapy. No complete response was achieved. Three patients (9.4%; 95% confidence interval [CI], 0 to 20.1%) achieved partial response, whereas 11 (34.4%; 95% CI, 17.0 to 51.8%) patients showed stable disease. Disease control rate (complete response, partial responses and stable diseases) was 43.8% (95% CI, 25.6 to 61.9%) and median follow up duration was 11.3 months (range, 2.23 to 37.9 months). Median time to progression was 2 months (95% CI, 1.49 to 2.51 months), and median overall survival from the start of FOLFIRI was 5.84 months (95% CI, 4.34 to 7.34 months). Toxicities were tolerable.
Conclusion
Modified FOLFIRI as second-line chemotherapy after failure of the modified FOLFOX-4 in advanced gastric cancer was tolerable but showed a lower response rate. Further study about retrying 5-FU/LV with irinotecan after failure of the 5-FU/LV combined regimen is necessary in advanced gastric cancer.
Key words: Stomach neoplasms, Chemotherapy, FOLFIRI

Introduction

Gastric cancer is the most common cancer in Korea and is the second leading cause of cancer-related deaths [1]. Approximately 20-60% of patients who have undergone curative surgery for gastric cancer develop recurrent diseases [2], and they undergo palliative chemotherapy.

Palliative chemotherapy has been shown to improve quality of life and overall survival (OS) compared to the best supportive care [3]. Different first-line treatments for advanced gastric cancer have response rates (RR) that range from 12-56%, with the median OS not exceeding 12 months [4,5]. There is no standard first-line treatment for advanced gastric cancer, yet a 5-fluorouracil (5-FU) and platinum-based regimen is usually administered.

Half of the patients receiving chemotherapy are unresponsive, and the majority of patients who initially responded eventually become unresponsive to the chemotherapy. These patients are candidates for second-line chemotherapy. However, the efficacy and benefit of second-line chemotherapy for advanced gastric cancer has not been proven, and there is no currently established second-line regimen or treatment options. Nevertheless, most patients want to receive chemotherapy if they are able to.

New agents such as docetaxel and irinotecan are under study as second-line chemotherapy for gastric cancer. Irinotecan is a camptothecan analog that is converted in vivo to SN-38, which binds to the topoisomerase I-DNA complex and thereby disrupts DNA replication and cell division [6]. The mechanism of action of irinotecan is different from that of fluoropyrimidine, platinum and taxane, and irinotecan has no cross-resistance with these agents [7,8]. The objective RR of irinotecan is 13% for gastric cancer patients as a single agent [9]. In combination with 5-FU and leucovorin (LV), the overall RR was 22-42%, and the median OS was 7.6-14.0 months for patients with untreated gastric cancer [10-13]. As second-line chemotherapy, the overall RR of the modified irinotecan, LV and 5-fluorouracil (FOLFIRI) regimen was 10-29%, with the median time to progression (TTP) being 2.3-4 months and the median OS being 5-10.9 months [14-18].

We treated patients with advanced gastric cancer with the modified oxaliplatin, LV and 5-fluorouracil (FOLFOX) regimen as first-line therapy and then with the modified FOLFIRI regimen as second-line therapy. Our goal in this study was to evaluate the efficacy and toxicity of the modified FOLFIRI regimen following the modified FOLFOX regimen for patients with metastatic gastric cancer.

Materials and Methods

1. Patient eligibility

We retrospectively reviewed all patients with gastric or gastroesophageal junction adenocarcinoma who received the modified FOLFOX-4 regimen as first-line treatment and the modified FOLFIRI regimen as second-line treatment for disease progression between January 2003 and August 2008 at Seoul St. Mary's Hospital. Patients with histologically confirmed and locally advanced, metastatic, or recurrent gastric cancer were eligible. Other eligibility criteria included the age range of 18 to 75 years, an Eastern Clinical Oncology Group (ECOG) performance status of 2 or less, adequate bone marrow and organ functions (an absolute neutrophil count≥1,500/µL, platelets≥75,000/µL, creatinine<2.0 mg/dL, serum bilirubin<2.0 mg/dL and serum transaminase levels<2 times the upper normal limit), no past or concurrent history of malignancy other than stomach cancer, except for curatively treated nonmelanoma skin cancer or in situ carcinoma of the cervix uteri. This study was reviewed and approved by Catholic Medical Center Institutional Review Board.

2. Treatment schedule

All patients received the modified FOLFOX-4 regimen, and this consisted of intravenous oxaliplatin 100 mg/m² in a 2-hour intravenous infusion on day 1, LV 20 mg/m² and 5-FU 400 mg/m² as a bolus followed by 600 mg/m² as a 22-hour infusion on days 1 and 2, every 2 weeks. As a second-line chemotherapy, the modified FOLFIRI regimen included irinotecan 150 mg/m² in a 90-minute intravenous infusion on day 1, LV 20 mg/m² and 5-FU 400 mg/m² as a bolus followed by 600 mg/m² as a 22-hour infusion on days 1 and 2, every 2 weeks. Atropine was not routinely used. All patients received adequate anti-emetic therapy prior to chemotherapy. Loperamide was prescribed prophylactically and the patients were instructed to take loperamide in case of developing diarrhea. Treatment was continued until documented disease progression, unacceptable toxicity or patient refusal.

3. Dose modifications

Chemotherapy was delayed if the patient s granulocyte count was <1,500/mm³ or the platelet count did not return to a minimum of 75,000/mm³ on the day of infusion. Other toxicities (except alopecia) were required to be either grade 0 or 1 before another cycle was started. The 5-FU dosage was reduced by 20% in the next cycle if a related grade 3 or worse toxicity (mucositis and hand-foot syndrome) occurred. The dose of irinotecan was not reduced by the occurrence of mucositis or hand-foot syndrome. The dose of irinotecan and 5-FU were reduced by 20% for grade 4 neutropenia lasting 7 days or more, neutropenic fever, grade 4 thrombocytopenia, grade 3 thrombocytopenia with bleeding requiring platelet transfusion, and grade 3/4 non-hematologic toxicities other than nausea and vomiting.

4. Assessment of efficacy and toxicity

Physical examination, chest X-rays, complete blood counts and biochemical tests were performed before each chemotherapy cycle. Computed tomography (CT) scans were performed every three cycles or when disease progression was suspected. The tumor response was classified according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. If there was no measurable lesion, the evaluable lesion was assessed. The presence or absence of each lesion was noted throughout follow-up. The CT scans were reviewed by a single experienced radiologist (SEJ). The toxicity was evaluated according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTC, ver. 3.0) at each cycle.

5. Statistics

Descriptive statistics were reported as proportions and medians. The TTP was measured from the first day of FOLFIRI treatment until the date of disease progression, the date of the last follow-up, or the date of the decision to receive palliative care when no further imaging study had been performed. The OS was measured from the first day of FOLFIRI chemotherapy until death or the date of the last follow up. The TTP and OS were estimated by the Kaplan-Meier method. All the statistical analyses were performed using SPSS ver. 13.0 (SPSS Inc., Chicago, IL).

Results

1. Patient characteristics

A total of 104 patients received modified FOLFOX-4 as first line chemotherapy for advanced or recurrent gastric cancer between January 2003 and August 2008 at Seoul St. Mary s Hospital. A total of 37 patients received modified FOLFIRI as second-line chemotherapy and 32 of these patients were eligible.

Patient characteristics are summarized in Table 1. The median age of the patients was 59 years (range, 33 to 72 years). The male to female ratio was 22 : 10. Thirteen (40.6%) of the patients had an ECOG performance status of 2. Thirty (93.8%) patients had metastatic disease and only 2 (6.2%) patients had locally advanced disease. Four patients (12.5%) had gastroesopheal junction adenocarcinoma. Ten (31.25%) patients had metastases in more than 3 organs, and the most common metastatic organ was peritoneum. The median hemoglobin level was 10.8 g/dL (range, 7.5 to 14.2 g/dL).

2. Treatment administration and toxicity

Patients received a total of 126 cycles of FOLFIRI chemotherapy, with a median of three cycles (range, 1 to 10 cycles) per patient. Dose reduction was applied in 29 cycles (23.0%) and the chemotherapy schedule was delayed in 20 cycles (15.9%), primarily due to hematological toxicity. The toxicities are listed in Table 2. No deaths due to toxicity occurred and the toxicities were tolerable. The most common toxicity was anemia in 27 (84.4%) patients. Grade 3 or 4 anemia occurred in 2 (6.2%) patients. Grade 3 or 4 neutropenia was observed in 7 (21.9%) patients. The non-hematologic toxicities consisted primarily of nausea and vomiting. Grade 1 or 2 diarrhea occurred in 2 (6.2%) patients.

3. Efficacy and survival

With the intent-to-treat analysis, the overall RR was 9.4% (Table 3). No patient had a complete response (CR), whereas 3 (9.4%; 95% confidence interval [CI], 0 to 20.1%) patients achieved partial responses (PR), and stable diseases (SD) were documented in 11 (34.4%; 95% CI, 17.0 to 51.8%) patients. The disease control rate (CR, PR and SD) was 43.8% (95% CI, 25.6 to 61.9%). Ten (31.2%; 95% CI, 14.3 to 48.2%) patients had progressive diseases (PD). The tumor responses were not evaluated in 8 (25%) patients; 6 patients showed clinical progression with aggravation of their performance status, while 2 patients were lost to follow-up. Nineteen (59.4%) patients received third line chemotherapy after failure of FOLFIRI regimen.

The median follow up duration was 11.3 months (range, 2.23 to 37.9 months). The median TTP for the FOLFIRI regimen was 2 months (95% CI, 1.49 to 2.51 months) (Fig. 1). The median OS was 5.84 months (95% CI, 4.34 to 7.34 months) (Fig. 2).

Discussion

This study assessed the efficacy and toxicity of the FOLFIRI regimen as second-line treatment after failure of the modified FOLFOX-4 regimen. The treatment was well-tolerated. The most predominant grade 3 or 4 toxicity was neutropenia. Febrile neutropenia was not seen. There was no grade 3 or 4 diarrhea, and only 3 patients (8.1%) had grade 1 or 2 diarrhea. This low rate of diarrhea, as compared with that of other irinotecan based studies, could be explained by the low dose of irinotecan and the ethnic differences of uridine diphosphate glucuronosyltransferase 1 (UGT1A1). Irinotecan is biotransformed into its active metabolite SN-38, and SN-38 is inactivated by UGT1A1 through glucuronidation. Depending on the number of TA insertions in the TATAA element of the 5' promoter region, the genotype of the UGT1A1*28 allele is named as the wild-type (6/6), the heterozygous genotype (6/7) and the homozygous genotype (7/7). The patients carrying the heterozygous or homozygous genotype experienced a decreased expression of the UGT1A1 enzyme, resulting in a lower rate of SN-38 glucuronidation. The association between the UGT1A1 gene polymorphism and increased toxicity in patients who received irinotecan-based chemotherapy is well known [6]. Liu et al. [19] showed the predominance of the UGT1A1 (6/6) genotype in Asians (76%) compared with 46% in Caucasians [19]. A high rate of grade 3 or 4 toxic diarrhea (48.9%) was reported at 180 mg/m² irinotecan in French patients [11], but this was 10% at 125 mg/m² in American patients [10], and 6% at 180 mg/m² in Korean patients [15].

There is no standard first-line treatment for advanced gastric cancer, yet a 5-FU and platinum based regimen is usually administered and a modified FOLFOX-4 regimen is one of the commonly used regimens. Several phase II studies have reported the efficacy of the modified FOLFIRI regimen as a second-line or salvage regimen after failure of a 5-FU combined regimen (Table 4), for which the response rate was 10-29%. The TTP was 2.3-4 months and the OS was 5-10.9 months. Our study showed a lower overall RR but had similar disease control rate (CR, PR and SD) and similar OS with the other studies. This study included 10 (31.3%) patients without measurable lesions. These patients only had evaluable lesions and were evaluated for only SD or PD responses, resulting in a low RR.

Based on the results of the phase III study [20], we used a low dose of LV. Jäger et al. [20] compared the therapeutic effects and toxicity of high-dose LV/5-FU versus low-dose LV/5-FU for treating colon cancer. The high dose LV/5-FU was not superior to the low-dose LV/5-FU, yet the RR and OS were comparable, but the treatment-related toxicity was higher in the high dose LV/5-FU group.

A low dose of irinotecan and the same dose of the prior failed regimen (5-FU/LV) with same infusion-method could also be reasons for the low RR and shorter TTP. Also, a synergistic effect of irinotecan and 5-FU/LV is controversial. In some studies, combining irinotecan with 5-FU/LV showed synergistic effects after failure of 5-FU/LV [21-23]. However, the FOLFIRI regimen as the second-line therapy had a lower response rate than the RR of second-line FOLFOX with the same dose of 5-FU/LV in advanced colon cancer [24]. In addition, the efficacy of irinotecan alone was comparable to that of 5-FU/LV and irinotecan after failure of 5-FU/LV [25]. Therefore, after failure of FOLFOX, irinotecan single chemotherapy, combination of irinotecan with other doses of 5-FU/LV can be considered.

Conclusion

The modified FOLFIRI regimen as second-line therapy after failure of the modified FOLFOX-4 regimen in patients with advanced gastric cancer was tolerable, but our study showed a lower response rate than that of other studies on second-line FOLFIRI after failure with various first-line chemotherapy strategies. Re-administration of failed 5-FU/LV with the same dose and with the same infusion method in the modified FOLFIRI regimen could be one of the reasons for this. Further study on retrying 5-FU/LV with irinotecan after failure of the 5-FU/LV combined regimen in advanced gastric cancer patients is necessary.

NOTES

Conflict of interest relevant to this article was not reported.

REFERENCES

1. Yaich L, Dupont WD, Cavener DR, Parl FF. Analysis of the PvuII restriction fragment-length polymorphism and exon structure of the estrogen receptor gene in breast cancer and peripheral blood. Cancer Res. 1992;52:77–83. PMID: 1345763PubMed
2. Yoo CH, Noh SH, Shin DW, Choi SH, Min JS. Recurrence following curative resection for gastric carcinoma. Br J Surg. 2000;87:236–242. PMID: 10671934Article PubMed
3. Glimelius B, Ekström K, Hoffman K, Graf W, Sjödén PO, Haglund U, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol. 1997;8:163–168. PMID: 9093725Article
4. Vanhoefer U, Rougier P, Wilke H, Ducreux MP, Lacave AJ, Van Cutsem E, 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. 2000;18:2648–2657. PMID: 10894863Article PubMed
5. Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, 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. 2002;20:1996–2004. PMID: 11956258Article PubMed
6. Schulz C, Boeck S, Heinemann V, Stemmler HJ. UGT1A1 genotyping: a predictor of irinotecan-associated side effects and drug efficacy? Anticancer Drugs. 2009;20:867–879. PMID: 19770637Article PubMed
7. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan Study GroupIrinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2000;343:905–914. PMID: 11006366Article PubMed
8. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355:1041–1047. PMID: 10744089Article PubMed
9. Kohne CH, Thuss-Patience P, Catane R, Klein H, Peretz T, Preusser P, et al. Final results of a phase II trial of CPT-11 in patients with advanced gastric cancer. Proc Am Soc Clin Oncol. 1999;18:Abstr 993
10. Bouché O, Raoul JL, Bonnetain F, Giovannini M, Etienne PL, Lledo G, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and eucovorin (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;22:4319–4328. PMID: 15514373Article PubMed
11. Yilmaz U, Oztop I, Alacacioglu A, Yaren A, Tarhan O, Somali I. Irinotecan combined with infusional 5-fluorouracil and high-dose leucovorin for the treatment of advanced gastric carcinoma as the first-line chemotherapy. Chemotherapy. 2006;52:264–270. PMID: 16873996Article PubMed
12. Rosati G, Cordio S, Caputo G, Condorelli S, Germano D, Mattina M, et al. Phase II trial of a biweekly regimen of fluorouracil and leucovorin plus irinotecan in patients with previously untreated advanced gastric cancer. J Chemother. 2007;19:570–576. PMID: 18073157Article PubMed
13. Park SH, Nam E, Park J, Cho EK, Shin DB, Lee JH, 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;19:729–733. PMID: 18083691Article PubMed
14. Seo MD, Lee KW, Lim JH, Yi HG, Kim DY, Oh DY, et al. Irinotecan combined with 5-fluorouracil and leucovorin as second-line chemotherapy for metastatic or relapsed gastric cancer. Jpn J Clin Oncol. 2008;38:589–595. PMID: 18772169Article PubMed
15. Assersohn L, Brown G, Cunningham D, Ward C, Oates J, Waters JS, et al. Phase II study of irinotecan and 5-fluorouracil/leucovorin in patients with primary refractory or relapsed advanced oesophageal and gastric carcinoma. Ann Oncol. 2004;15:64–69. PMID: 14679122Article PubMed
16. Lorizzo K, Fazio N, Radice D, Boselli S, Ariu L, Zampino MG, et al. Simplified FOLFIRI in pre-treated patients with metastatic gastric cancer. Cancer Chemother Pharmacol. 2009;64:301–306. PMID: 19034450Article PubMed
17. Kim SG, Oh SY, Kwon HC, Lee S, Kim JH, Kim SH, et al. A phase II study of irinotecan with bi-weekly, low-dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFIRI) as salvage therapy for patients with advanced or metastatic gastric cancer. Jpn J Clin Oncol. 2007;37:744–749. PMID: 17923456Article PubMed
18. Kim SH, Lee GW, Go SI, Cho SH, Kim HJ, Kim HG, et al. A phase II study of irinotecan, continuous 5-fluorouracil, and leucovorin (FOLFIRI) combination chemotherapy for patients with recurrent or metastatic gastric cancer previously treated with a fluoropyrimidine-based regimen. Am J Clin Oncol. 2010;33:572–576. PMID: 20042971Article PubMed
19. Liu JY, Qu K, Sferruzza AD, Bender RA. Distribution of the UGT1A1*28 polymorphism in Caucasian and Asian populations in the US: a genomic analysis of 138 healthy individuals. Anticancer Drugs. 2007;18:693–696. PMID: 17762398Article PubMed
20. Jäger E, Heike M, Bernhard H, Klein O, Bernhard G, Lautz D, et al. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. J Clin Oncol. 1996;14:2274–2279. PMID: 8708717Article PubMed
21. Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol. 2003;21:2059–2069. PMID: 12775730Article PubMed
22. de Gramont A, Vignoud J, Tournigand C, Louvet C, André T, Varette C, et al. Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer. 1997;33:214–219. PMID: 9135491Article PubMed
23. Mans DR, Grivicich I, Peters GJ, Schwartsmann G. Sequence-dependent growth inhibition and DNA damage formation by the irinotecan-5-fluorouracil combination in human colon carcinoma cell lines. Eur J Cancer. 1999;35:1851–1861. PMID: 10674003Article PubMed
24. Tournigand C, André T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229–237. PMID: 14657227Article PubMed
25. Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007;370:143–152. PMID: 17630037Article PubMed

Fig. 1

Time to progression (TTP) curve.

Fig. 2

Overall survival (OS) curve.

Table 1

Patient characteristics

Characteristics	No. of patients (%)
Gender
Male	22 (68.75)
Female	10 (31.25)
Median age (range, yr)	59 (33-72)
ECOG performance status
0	8 (25)
1	11 (34.4)
2	13 (40.6)
Extent of disease
Metastatic	27 (84.4)
Recurrent	3 (9.4)
Locally advanced	2 (6.2)
Operation
Curative	3 (9.4)
Palliative	2 (6.2)
Primary site
Unkown	1 (3.1)
Gastroesopheal junction	4 (12.5)
Body	27 (84.4)
Metastatic number
0	1 (3.1)
1	6 (18.8)
2	15 (46.9)
≥3	10 (31.2)
Metastatic lesion
Liver	6 (18.8)
Peritoneum	21 (65.6)
Bone	7 (21.9)
Measurable lesion
No measurable	10 (31.25)
Measurable	22 (68.75)
Differentiation
Well	0 (0)
Moderate	9 (28.1)
Poor	19 (59.4)
Unknown	4 (12.5)
Median complete blood count (range)
Hemoglobin (g/dL)	10.8 (7.5-14.2)
White blood cell (×10⁹/L)	5,450 (2,980-16,990)
Plate count (×10⁹/L)	197 (81-462)

ECOG, Eastern Clinical Oncology Group.

Table 2

Toxicity profiles of FOLFIRI (per patient)

	NCI-CTCAE grade (%)

	G1	G2	G3	G4	All
Non hematologic toxicities
Nausea	5 (15.6)	6 (18.8)	3 (9.4)	0	14 (43.8)
Vomiting	3 (9.4)	6 (18.8)	2 (6.2)	0	11 (34.4)
Diarrhea	1 (3.1)	1 (3.1)	0	0	2 (6.2)
Hepatoxicity	6 (18.8)	0	0	1 (3.1)	7 (21.9)
Hematologic toxicities
Neutropenia	5 (15.6)	7 (21.9)	0	7 (21.9)	19 (59.4)
Anemia	11 (34.4)	13 (40.6)	1 (3.1)	2 (6.2)	27 (84.4)
Thrombocytopenia	3 (9.4)	2 (6.2)	1 (3.1)	0	6 (18.8)
Febrile neutropenia	0	0	0	0	0

FOLFIRI, irinotecan, leucovorin and 5-fluorouracil; NCI-CTCAE ver. 3.0, National Cancer Institute-Common Toxicity Criteria for Adverse Events ver. 3.0.

Table 3

Efficacy of FOLFIRI

Response	No. of patients (%)	95% confidence interval
Complete response	0 (0)	-
Partial response	3 (9.4)	0-20.1
Stable disease	11 (34.4)	17.0-51.8
Progressive disease	10 (31.2)	14.3-48.2
Not assessable	8 (25)	-

FOLFIRI, irinotecan, leucovorin and 5-fluorouracil.

Table 4

Phase II studies on irinotecan, 5-FU, and LV combination chemotherapy for advanced gastric cancer

	Previous chemotherapy	No. of previous chemo-regimen	Regimen	RR (%)	SD (%)	TTP (mo)	OS (mo)
Lorizzo et al. [16]	Not restricted, fluoropyrimidine based, regimen (71.43%) included, no FOLFOX	1	I 180 mg/m² D1 LV 200 mg/m² bolus D1 5-FU 400 mg/m² bolus, 2,400 mg/m² over 46 hr	21	21	4	5
Assersohn et al. [15]	Not restricted, fluoropyrimidine based, regimen (97.4%) included, no FOLFOX	1	I 180 mg/m² D1 LV 125 mg/m² bolus D1 5-FU 400 mg/m² bolus, 1,200 mg/m² over 48 hr	29	34	3.7	6.4
Seo et al. [14]	Not restricted,
Seo et al. [14]	fluoropyrimidine based, regimen (75%) included, modified FOLFOX (29%) included	1	I 180 mg/m² D1 LV 200 mg/m² bolus D1, 2 5-FU 400 mg/m² bolus, 600 mg/m² over 22 hr D1, 2	18	29	3.2	9.1
Kim et al. [18]	Fluoropyrimidine based regimen	≥1	I 150 mg/m² D1 LV 20 mg/m² bolus D1, 2 5-FU 3,000 mg/m² over 48 hr	18.2	18.2	2.3	5.1
Kim et al. [17]	Not restricted, modified FOLFOX (52.6%) included	≥1	I 150 mg/m² D1 LV 20 mg/m² bolus D1, 2 5-FU 400 mg/m² bolus, 600 mg/m² over 22 hr D1, 2	10	36.7	3.3	10.9
This study	Modified FOLFOX	1	I 150 mg/m² D1 LV 20 mg/m² bolus D1, 2 5-FU 400 mg/m² bolus, 600 mg/m² over 22 hr D1, 2	9.1	34.4	2	5.84

5-FU, 5-fluorouracil; LV, leucovorin; RR, response rate; SD, stable diseases; TTP, time to progression; OS, overall survival; I, irinotecan; D, day.

Figure & Data

REFERENCES

Citations

Citations to this article as recorded by

Current therapeutic options for gastric adenocarcinoma
C.R. Akshatha, Smitha Bhat, R. Sindhu, Dharini Shashank, Sarana Rose Sommano, Wanaporn Tapingkae, Ratchadawan Cheewangkoon, Shashanka K. Prasad
Saudi Journal of Biological Sciences.2021; 28(9): 5371. CrossRef
Prognostic Nomogram and Patterns of Use of FOLFIRI-Aflibercept in Advanced Colorectal Cancer: A Real-World Data Analysis
Ana Fernández Montes, Carlos López López, Guillem Argilés Martínez, David Páez López, Ana María López Muñoz, Beatriz García Paredes, David Gutiérrez Abad, Carmen Castañón López, Paula Jiménez Fonseca, Javier Gallego Plazas, María Carmen López Doldán, Eva
The Oncologist.2019; 24(8): e687. CrossRef
Thymineless Death by the Fluoropyrimidine Polymer F10 Involves Replication Fork Collapse and Is Enhanced by Chk1 Inhibition
Chinnadurai Mani, Sachin Pai, Cinta Maria Papke, Komaraiah Palle, William H. Gmeiner
Neoplasia.2018; 20(12): 1236. CrossRef
Effect of FOLFOX4 combined with Brucea javanica emulsion on VEGF in patients with gastric cancer
Zheng Chen, Zhenyu Zhou, Zhigang Hu, Qiaodong Xu, Jie Wang
Oncology Letters.2017;[Epub] CrossRef
Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: a randomized, placebo-controlled phase II AIO trial with serum biomarker program
Markus Moehler, Irina Gepfner-Tuma, Annett Maderer, Peter C. Thuss-Patience, Joern Ruessel, Susanna Hegewisch-Becker, Hansjochen Wilke, Salah-Eddin Al-Batran, Mohammad-Reza Rafiyan, Florian Weißinger, Hans-Joachim Schmoll, Frank Kullmann, Ludwig Fischer v
BMC Cancer.2016;[Epub] CrossRef
5-Fluorouracil derivatives: a patent review (2012 – 2014)
Esmeralda Carrillo, Saúl Abenhamar Navarro, Alberto Ramírez, María Ángel García, Carmen Griñán-Lisón, Macarena Perán, Juan Antonio Marchal
Expert Opinion on Therapeutic Patents.2015; 25(10): 1131. CrossRef
Efficacy and Safety of FOLFIRI as Second-line Chemotherapy in Advanced Gastric Cancer
Sung Chul Park, Hoon Jai Chun
The Korean Journal of Gastroenterology.2015; 66(1): 1. CrossRef
Efficacy and Safety of FOLFIRI after Failure of FOLFOX-4 in Advanced Gastric Cancer
Hye Jung Kwon, Moo In Park, Seun Ja Park, Won Moon, Sung Eun Kim, Hae Won Lee, Youn Jung Choi, Jae Hyun Kim
The Korean Journal of Gastroenterology.2015; 66(1): 10. CrossRef
FOLFIRI as Second-line Chemotherapy after Failure of FOLFOX4 in Advanced Colorectal Cancer: A Korean Single-center Experience
Jae Hyun Kim, Seun Ja Park, Moo In Park, Won Moon, Sung Eun Kim, Ki Hwan Ku, Sung Eun Song, Je Hun Kim
The Korean Journal of Gastroenterology.2014; 63(1): 18. CrossRef
5-Fluorouracil derivatives: a patent review
Pablo Álvarez, Juan Antonio Marchal, Houria Boulaiz, Esmeralda Carrillo, Celia Vélez, Fernando Rodríguez-Serrano, Consolación Melguizo, Jose Prados, Roberto Madeddu, Antonia Aranega
Expert Opinion on Therapeutic Patents.2012; 22(2): 107. CrossRef
Outcomes of Third-Line Docetaxel-Based Chemotherapy in Advanced Gastric Cancer Who Failed Previous Oxaliplatin-Based and Irinotecan-Based Chemotherapies
Min Jeong Lee, In Gyu Hwang, Joung-Soon Jang, Jin Hwa Choi, Byeong-Bae Park, Myung Hee Chang, Seung Tae Kim, Se Hoon Park, Myoung Hee Kang, Jung Hun Kang
Cancer Research and Treatment.2012; 44(4): 235. CrossRef
Irinotecan, leucovorin and 5-fluorouracil (modified FOLFIRI) as salvage chemotherapy for frail or elderly patients with advanced gastric cancer
JUNG HAN KIM, HYEONG SU KIM, A RUM HAN, IN HO MOH, DOO CHEOL CHUNG, DAE RO CHOI, HYUN JOO JANG, JIN BAE KIM, DAE HYUN YANG, SOON IL LEE, DAE YOUNG ZANG
Oncology Letters.2012; 4(4): 751. CrossRef

PubReader
ePub Link

Cite

CITE: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

Modified FOLFIRI as Second-Line Chemotherapy after Failure of Modified FOLFOX-4 in Advanced Gastric Cancer

Cancer Res Treat. 2011;43(3):148-153. Published online September 30, 2011

DOI: https://doi.org/10.4143/crt.2011.43.3.148

XML Download

Abstract
Introduction
Materials and Methods
Results
Discussion
Conclusion
NOTES
REFERENCES

Modified FOLFIRI as Second-Line Chemotherapy after Failure of Modified FOLFOX-4 in Advanced Gastric Cancer

Fig. 1 Time to progression (TTP) curve.

Fig. 2 Overall survival (OS) curve.

Fig. 1

Fig. 2

Modified FOLFIRI as Second-Line Chemotherapy after Failure of Modified FOLFOX-4 in Advanced Gastric Cancer

Characteristics	No. of patients (%)
Gender
Male	22 (68.75)
Female	10 (31.25)
Median age (range, yr)	59 (33-72)
ECOG performance status
0	8 (25)
1	11 (34.4)
2	13 (40.6)
Extent of disease
Metastatic	27 (84.4)
Recurrent	3 (9.4)
Locally advanced	2 (6.2)
Operation
Curative	3 (9.4)
Palliative	2 (6.2)
Primary site
Unkown	1 (3.1)
Gastroesopheal junction	4 (12.5)
Body	27 (84.4)
Metastatic number
0	1 (3.1)
1	6 (18.8)
2	15 (46.9)
≥3	10 (31.2)
Metastatic lesion
Liver	6 (18.8)
Peritoneum	21 (65.6)
Bone	7 (21.9)
Measurable lesion
No measurable	10 (31.25)
Measurable	22 (68.75)
Differentiation
Well	0 (0)
Moderate	9 (28.1)
Poor	19 (59.4)
Unknown	4 (12.5)
Median complete blood count (range)
Hemoglobin (g/dL)	10.8 (7.5-14.2)
White blood cell (×10⁹/L)	5,450 (2,980-16,990)
Plate count (×10⁹/L)	197 (81-462)

	NCI-CTCAE grade (%)

	G1	G2	G3	G4	All
Non hematologic toxicities
Nausea	5 (15.6)	6 (18.8)	3 (9.4)	0	14 (43.8)
Vomiting	3 (9.4)	6 (18.8)	2 (6.2)	0	11 (34.4)
Diarrhea	1 (3.1)	1 (3.1)	0	0	2 (6.2)
Hepatoxicity	6 (18.8)	0	0	1 (3.1)	7 (21.9)
Hematologic toxicities
Neutropenia	5 (15.6)	7 (21.9)	0	7 (21.9)	19 (59.4)
Anemia	11 (34.4)	13 (40.6)	1 (3.1)	2 (6.2)	27 (84.4)
Thrombocytopenia	3 (9.4)	2 (6.2)	1 (3.1)	0	6 (18.8)
Febrile neutropenia	0	0	0	0	0

Response	No. of patients (%)	95% confidence interval
Complete response	0 (0)	-
Partial response	3 (9.4)	0-20.1
Stable disease	11 (34.4)	17.0-51.8
Progressive disease	10 (31.2)	14.3-48.2
Not assessable	8 (25)	-

	Previous chemotherapy	No. of previous chemo-regimen	Regimen	RR (%)	SD (%)	TTP (mo)	OS (mo)
Lorizzo et al. [16]	Not restricted, fluoropyrimidine based, regimen (71.43%) included, no FOLFOX	1	I 180 mg/m² D1 LV 200 mg/m² bolus D1 5-FU 400 mg/m² bolus, 2,400 mg/m² over 46 hr	21	21	4	5
Assersohn et al. [15]	Not restricted, fluoropyrimidine based, regimen (97.4%) included, no FOLFOX	1	I 180 mg/m² D1 LV 125 mg/m² bolus D1 5-FU 400 mg/m² bolus, 1,200 mg/m² over 48 hr	29	34	3.7	6.4
Seo et al. [14]	Not restricted,
Seo et al. [14]	fluoropyrimidine based, regimen (75%) included, modified FOLFOX (29%) included	1	I 180 mg/m² D1 LV 200 mg/m² bolus D1, 2 5-FU 400 mg/m² bolus, 600 mg/m² over 22 hr D1, 2	18	29	3.2	9.1
Kim et al. [18]	Fluoropyrimidine based regimen	≥1	I 150 mg/m² D1 LV 20 mg/m² bolus D1, 2 5-FU 3,000 mg/m² over 48 hr	18.2	18.2	2.3	5.1
Kim et al. [17]	Not restricted, modified FOLFOX (52.6%) included	≥1	I 150 mg/m² D1 LV 20 mg/m² bolus D1, 2 5-FU 400 mg/m² bolus, 600 mg/m² over 22 hr D1, 2	10	36.7	3.3	10.9
This study	Modified FOLFOX	1	I 150 mg/m² D1 LV 20 mg/m² bolus D1, 2 5-FU 400 mg/m² bolus, 600 mg/m² over 22 hr D1, 2	9.1	34.4	2	5.84

Table 1 Patient characteristics

ECOG, Eastern Clinical Oncology Group.

Table 2 Toxicity profiles of FOLFIRI (per patient)

FOLFIRI, irinotecan, leucovorin and 5-fluorouracil; NCI-CTCAE ver. 3.0, National Cancer Institute-Common Toxicity Criteria for Adverse Events ver. 3.0.

Table 3 Efficacy of FOLFIRI

FOLFIRI, irinotecan, leucovorin and 5-fluorouracil.

Table 4 Phase II studies on irinotecan, 5-FU, and LV combination chemotherapy for advanced gastric cancer

5-FU, 5-fluorouracil; LV, leucovorin; RR, response rate; SD, stable diseases; TTP, time to progression; OS, overall survival; I, irinotecan; D, day.