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Annals of Oncology Advance Access originally published online on December 13, 2007
Annals of Oncology 2008 19(4):729-733; doi:10.1093/annonc/mdm502
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© The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

gastrointestinal tumors

Randomized phase II study of irinotecan, leucovorin and 5-fluorouracil (ILF) versus cisplatin plus ILF (PILF) combination chemotherapy for advanced gastric cancer

S. H. Park1, E. Nam1, J. Park1, E. K. Cho1, D. B. Shin1,*, J. H. Lee1, W. K. Lee2, M. Chung2 and S. I. Lee3

1 Division of Hematology and Oncology, Department of Internal Medicine
2 Department of General Surgery, Gachon University Gil Medical Center, Incheon
3 Department of Internal Medicine, Dankook University Hospital, Cheonan, Korea

* Correspondence to: Dr D. B. Shin, Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 405-760, Korea. Tel: +82-32-460-3817; Fax: +82-32-460-3233; E-mail: dbs{at}gilhospital.com


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
Background: Irinotecan, in combination with 5-fluorouracil (5-FU) or cisplatin, has demonstrated efficacy against advanced gastric cancer (AGC).

Patients and methods: Chemotherapy-naive AGC patients were randomly assigned to receive irinotecan 150 mg/m2 on day 1, leucovorin 20 mg/m2 and a 22-h infusion of 5-FU 1000 mg/m2 on days 1 and 2 (ILF) or ILF plus cisplatin 30 mg/m2 on day 2 (PILF). Treatment was repeated every 2 weeks.

Results: Of 91 registered patients, 45 patients were treated with ILF and 45 with PILF. For both arms, 687 chemotherapy cycles were delivered (median = 7 for ILF and 8 for PILF). Both ILF and PILF were generally well tolerated and there was no relevant difference in the occurrence of overall grade 3/4 toxic effects between the two arms. Four patients died during treatment: one in the ILF and three in the PILF arm. The objective response rate was 42% for both arms. There was no significant difference in therapeutic efficacy between ILF and PILF with respect to progression-free survival (4.8 versus 6.2 months; P = 0.523) and overall survival (10.7 versus 10.5 months; P = 0.850).

Conclusion: Both ILF and PILF are active as first-line chemotherapy for AGC. The addition of cisplatin, however, has no clear advantage over ILF.

Key words: chemotherapy, cisplatin, 5-fluorouracil, irinotecan, stomach cancer


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 Acknowledgements
 References
 
The benefit of systemic chemotherapy for advanced gastric cancer (AGC) in the palliative setting has long been known. Several randomized trials have demonstrated that 5-fluorouracil (5-FU)-based chemotherapy is superior to best supportive care in terms of survival and preservation of quality of life (QoL) [1, 2]. To date, only two triplet combinations, namely, ECF (epirubicin, cisplatin and 5-FU) and DCF (docetaxel, cisplatin and 5-FU), have demonstrated survival benefit for patients with AGC [3, 4]. The obtained median survival times, however, were limited to within 10 months.

Irinotecan is a water-soluble camptothecin derivative and has been shown to exhibit antitumor activity against gastric cancer both as a single agent [5] and in combination with leucovorin/5-FU (ILF) [6] or cisplatin (IP) [7]. A previous randomized study of ILF regimen versus IP showed that ILF produced an overall response rate of 42% and a median survival of 10.7 months [8], which were significantly better than the results with IP regimen. However, since cisplatin is still considered to be one of the key drugs for the treatment of gastric cancer, a combination of these three active drugs (cisplatin, irinotecan and leucovorin/5-FU [PILF]) seemed to be a promising strategy to treat AGC. This three-drug combination has been reported to have promising therapeutic efficacy of 74%–85% objective response rates [9, 10], but at the cost of considerable toxicity (i.e. severe neutropenia in 90% of patients).

We previously conducted a pilot feasibility study on 17 chemotherapy-naive patients with AGC, and they were administered cisplatin 30 mg/m2 combined with ILF regimen [11]. There was good adherence to treatment and the combination was found to be potentially active for AGC. On the basis of these observations, we adapted a modified regimen of biweekly administered PILF. This randomized phase II study was conducted in patients with AGC to evaluate the safety profile and antitumor activity of ILF and PILF chemotherapy regimens given as first-line therapy.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 Acknowledgements
 References
 
Patients aged ≤75 years with histologically confirmed, measurable AGC were enrolled for this single-center randomized phase II study. Other inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of two or less, a life expectancy of at least 3 months and adequate major organ functions. No prior chemotherapy or only adjuvant chemotherapy that had been completed >6 months before registration and no radiotherapy within 4 weeks before study registration were allowed. This study protocol was reviewed and approved by the Gil Medical Center (Incheon, Korea) institutional review board. To obtain informed consent, the nature of the study was fully discussed with the patients before the initiation of treatment, including an explanation of the risk and possible discomfort, as well as the potential benefits.

Patients were randomly assigned to receive ILF or PILF (Figure 1). ILF consisted of irinotecan 150 mg/m2 on day 1 and leucovorin 20 mg/m2 plus a 22-h infusion of 5-FU 1000 mg/m2 on days 1 and 2. In the PILF arm, cisplatin 30 mg/m2 was administered on day 2, along with appropriate i.v. hydration before and again after cisplatin infusion. Each cycle of chemotherapy was given every 2 weeks if the patient's blood count had returned to normal and non-hematologic toxic effects had resolved. Treatment was repeated until disease progression and/or unacceptable toxicity was detected. Dosage of the subsequent cycles was adjusted according to the toxic effects that developed during the preceding cycle. The use of hematopoietic growth factors was not allowed during treatment, except for patients with febrile neutropenia or grade 4 myelosuppression. No primary prophylaxis with atropine was given unless a patient experienced grade ≥2 diarrhea. Throughout the study, the dose of leucovorin was unchanged.


Figure 1
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  		Figure 1. Flow diagram of all registered patients.

 
Follow-up history, physical examinations and toxicity assessment were carried out before each 2-week cycle of treatment. Toxicity grading was based on the National Cancer Institute criteria (National Cancer Institute—Common Terminology Criteria for Adverse Events version 3). The first evaluation with imaging was done after the completion of four cycles of chemotherapy. Response was evaluated according to the World Health Organization criteria. We also assessed QoL using the validated Korean version of the European Organization for Research and Treatment of Cancer questionnaire (EORTC QLQ-C30), which contains 30 questions addressing various aspects of QoL [12, 13]. This self-administered questionnaire was completed by patients at baseline, at every four cycles and at the end of treatment.

The primary end point was the overall response rate. This randomized phase II trial was statistically treated as two simultaneous phase II studies and the single-stage design was applied separately for each treatment arm. The sample size estimation was on the basis of the assumption that the response rate would be ≥30% in each group of the treated population. Thirty-five patients per group were required with a significance level set at 0.05. All analyses were carried out on the intent-to-treat population, defined as all registered patients who signed an informed consent.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 Acknowledgements
 References
 
From October 2004 to November 2006, a total of 91 patients with AGC (46 patients in the ILF arm and 45 in the PILF arm) were registered. One patient assigned to the ILF arm did not receive protocol therapy because of the rapid deterioration of general condition. The clinical characteristics were available for all patients and are listed in Table 1.


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  		Table 1. Patient characteristics

 
treatment delivery
A total of 335 ILF (median = 7; range = 1–16) and 352 PILF (median = 8; range = 1–16) cycles were delivered. Of the 90 patients who started treatment, the main reasons for discontinuing treatment in the ILF and PILF arms were progressive disease (71% versus 47%), toxicity (9% versus 29%) and the patient's refusal (20% versus 24%). For the patients treated with ILF, the median dose intensity of irinotecan 68 mg/m2/week corresponded to 91% of the scheduled dose, and the median duration of therapy was 4.3 months [95% confidence interval (CI) = 3.4–5.2 months). In the PILF arm, the median dose intensity of irinotecan was 67 mg/m2/week (89% of the scheduled dose), and the median treatment duration was 5.6 months (95% CI = 4.2–7.0 months). The relative dose intensities of 5-FU were 90% for both arms. In the PILF arm, the median administered dose intensity for cisplatin was 14 mg/m2/week, which corresponded to 92% of the planned dose. One ILF patient was felt to have resectable primary lesion after 16th cycle and discontinued chemotherapy for resection with a curative intent.

safety outcomes
There was no relevant difference in the occurrence of overall grade 3 or 4 toxic effects between the two arms (37% versus 46%, respectively; P = 0.431). The toxicity profiles are presented in Table 2. One PILF patient developed oliguric renal failure that required a period of dialysis. There are four deaths during the treatment period. In the ILF arm, one patient died of massive upper gastrointestinal bleeding shortly after receiving the third cycle of chemotherapy. Three patients in the PILF arm died of causes possibly related to treatment: one with neutropenic sepsis complicating by diarrhea, one with pulmonary embolism and one with intracranial bleeding.


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  		Table 2. Maximum grade toxic effects per patient

 
efficacy outcomes
There were 1 complete and 18 partial responses in each of the arms (response rate = 42%; 95% CI = 28% to 57%). Ten (22%) ILF and 17 (38%) PILF patients, respectively, had stable disease.

The median follow-up duration for all patients was 17.1 months. Both arms showed similar progression-free survival (PFS) (Figure 2; 4.8 months for the ILF arm versus 6.2 months for the PILF arm; P = 0.523) and overall survival (OS) (Figure 3; 10.7 months for the ILF arm versus 10.5 months for the PILF arm; P = 0.850). Although not specified in the protocol, we offered second-line chemotherapy to 44 patients (48%) after failure.


Figure 2
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  		Figure 2. Kaplan–Meier estimates for progression-free survival by the treatment arm.

 

Figure 3
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  		Figure 3. Kaplan–Meier estimates for overall survival by the treatment arm.

 
Baseline QoL questionnaires were completed by 56 (62%) patients: 27 in the ILF arm and 29 in the PILF arm. The scores for the baseline QoL were similar in both arms. For both arms, the compliance of subsequent QoL questionnaires decreased to 37% after fourth cycle of chemotherapy. Over the whole treatment period, no relevant difference between arms was detected in the proportion of patients reporting QoL changes from baseline to post-treatment.


   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
Acknowledgements
 References
 
The present randomized phase II study was initiated because there is no current reference chemotherapy regimen for AGC and there is an urgent need for such therapy; further, the recent data indicated the efficacy and tolerability of irinotecan-based regimen [8]. To define an appropriate combination regimen for further improvement, we selected irinotecan, leucovorin/5-FU and cisplatin on the basis of their proven clinical activity against gastric cancer and their apparent synergistic activity and because they are not cross-resistant. The results confirmed that antitumor activity and tolerability were achieved with irinotecan-based chemotherapy for AGC. However, when compared with ILF, the addition of cisplatin did not improve efficacy. The compliance of patients in the QoL analysis was generally poor for both arms (37% at the end of fourth cycle). The low compliance rate makes interpretation of the results difficult and raises the risk of bias owing to ill patients being unable to complete QoL questionnaires or staff being unwilling to approach them.

The best choice of chemotherapy regimen for patients with AGC is still a matter of controversy and requires further investigation [14]. The overall response rate of 42% and the median OS of 10.7 months obtained with ILF arm are consistent with those reported in the previous studies that applied the same regimen [6, 8]. A randomized phase III study carried out on chemotherapy-naive patients with AGC showed that ILF had better safety profiles and a trend towards superior time to progression than 5-FU plus cisplatin [15]. The rationale for designing this study to compare ILF with PILF was on the basis of the potential for improved antitumor activity [11]. This study was designed as it was anticipated that a further incremental improvement in the response rate might be achieved with the addition of cisplatin. An identical dose regimen of irinotecan and leucovorin/5-FU was used for both treatment arms. Thus, the administration of cisplatin 30 mg/m2 was the only different variable between the two treatment arms.

It is presently unclear whether the addition of platinum is superior to ILF for AGC patients. Unlike colorectal cancer, for which cisplatin has no proven efficacy, cisplatin has shown activity against gastric cancer. Although cisplatin is often used in combination with other agents, it is well known that cisplatin is associated with significant toxicity and usually requires a high level of clinical monitoring and supportive care. Oxaliplatin-based regimens have been actively investigated to improve the efficacy and tolerability of combination chemotherapy for AGC. Oxaliplatin has significant activity against some cisplatin-resistant tumors and a favorable safety profile over cisplatin [16]. Oxaliplatin plus ILF (FOLFOXIRI) for AGC was studied in a phase II study [17]. The authors reported that FOLFOXIRI has antitumor activity, with a response rate of 67% and a median survival of 14.8 months, as well as good tolerability. FOLFOXIRI was compared with FOLFIRI (irinotecan 165 mg/m2 on day 1, leucovorin 200 mg/m2 on day 1 and a 48-h continuous infusion 5-FU 3200 mg/m2 starting on day 1, every 2 weeks) in a recently published phase III study [18]. FOLFOXIRI improved response rate, PFS and OS with an increased toxicity in patients with metastatic colorectal cancer. In contrast, FOLFOXIRI and FOLFIRI showed similar efficacy in another phase III study [19]. This discrepancy is mainly attributable to patient selection. The REAL-2 study by Cunningham et al. [20] indicated that for the first-line chemotherapy of AGC, oxaliplatin could replace cisplatin. The results of the REAL-2 study showed that there were no significant differences in response rates comparing ECF with EOF (epirubicin, oxaliplatin and 5-FU), ECX (epirubicin, cisplatin and capecitabine) and EOX (epirubicin, oxaliplatin and capecitabine) (41%, 42%, 46% and 48%, respectively). Moreover, a phase III study that compared leucovorin/5-FU and cisplatin with leucovorin/5-FU and oxaliplatin in AGC patients demonstrated that superior efficacy and safety were achieved with oxaliplatin-based chemotherapy [21].

In conclusion, the combination chemotherapy of PILF (the addition of cisplatin to ILF) was feasible and effective as the first-line treatment for AGC, but it did not prove to be superior to ILF in terms of response rate or survival. Given the comparable efficacy results, ILF could be a reasonable standard chemotherapy for untreated AGC patients. The survival results, however, reported here are by no means the best yet observed with other combination regimens for patients with AGC [3, 4]. Other active and tolerable agents are now available and it is conceivable that addition of oxaliplatin or molecularly targeted agents to ILF could improve the efficacy for treating AGC patients without compromising tolerability.


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
References
 
This study was presented in part at the 31st European Society for Medical Oncology Congress, Istanbul, Turkey, 29 September to 3 October, 2006, and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, 1 to 5 June, 2007. This study was registered in advance to ClinicalTrials.gov (no. NCT00320294 [ClinicalTrials.gov] ). We indicated no potential conflicts of interest.

Received for publication July 16, 2007. Revision received September 27, 2007. Accepted for publication September 28, 2007.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
1. Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M. 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 (1995) 71:587–591.[Web of Science][Medline]

2. Glimelius B, Ekstrom K, Hoffman K, et al. Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol (1997) 8:163–168.[Abstract/Free Full Text]

3. 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 (1997) 15:261–267.[Abstract/Free Full Text]

4. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol (2006) 24:4991–4997.[Abstract/Free Full Text]

5. Kohne CH, Catane R, Klein B, et al. Irinotecan is active in chemonaive patients with metastatic gastric cancer: a phase II multicentric trial. Br J Cancer (2003) 89:997–1001.[CrossRef][Web of Science][Medline]

6. Bouche O, Raoul JL, Bonnetain F, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study–FFCD 9803. J Clin Oncol (2004) 22:4319–4328.[Abstract/Free Full Text]

7. 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 (2002) 94:641–646.[CrossRef][Web of Science][Medline]

8. 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 (2004) 15:1773–1781.[Abstract/Free Full Text]

9. Schleucher N, Tewes M, Wilke HJ, et al. Phase I/II study with weekly infusional high-dose 5-fluorouracil/leucovorin/irinotecan in combination with biweekly cisplatin as first-line chemotherapy for metastatic gastric carcinoma. Proc Am Soc Clin Oncol (2003) 22:343. (Abstr 1378).

10. Niederman TM, Stone E. Fluorouracil, leucovorin, irinotecan, and cisplatin (FLIP) in chemotherapy naïve metastatic gastric carcinoma: final results of a pilot phase II trial. Proc Gastrointest Cancer Symp (2006) (Abstr 79).

11. Park SH, Jeon SY, Ko KI, et al. A pilot study of cisplatin, irinotecan, leucovorin and 5-fluorouracil (PILF) combination chemotherapy for advanced gastric cancer. Cancer Res Treat (2006) 38:121–125.

12. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst (1993) 85:365–376.[Abstract/Free Full Text]

13. Yun YH, Park YS, Lee ES, et al. Validation of the Korean version of the EORTC QLQ-C30. Qual Life Res (2004) 13:863–868.[CrossRef][Web of Science][Medline]

14. Ohtsu A, Yoshida S, Saijo N. Disparities in gastric cancer chemotherapy between the East and West. J Clin Oncol (2006) 24:2188–2196.[Abstract/Free Full Text]

15. Dank M, Zaluski J, Barone C, et al. Randomized phase 3 trial of irinotecan (CPT-11) + 5FU/folinic acid (FA) vs CDDP + 5FU in 1st-line advanced gastric cancer patients. Proc Am Soc Clin Oncol (2005) 23. (Abstr 4003).

16. Cvitkovic E. Ongoing and unsaid on oxaliplatin: the hope. Br J Cancer (1998) 77(Suppl 4):8–11.[Medline]

17. Lee J, Kang WK, Kwon JM, et al. Phase II trial of irinotecan plus oxaliplatin and 5-fluorouracil/leucovorin in patients with untreated metastatic gastric adenocarcinoma. Ann Oncol (2007) 18:88–92.[Abstract/Free Full Text]

18. Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol (2007) 25:1670–1676.[Abstract/Free Full Text]

19. Souglakos J, Androulakis N, Syrigos K, et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer (2006) 94:798–805.[CrossRef][Web of Science][Medline]

20. Cunningham D, Rao S, Starling N, et al. Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer: the REAL 2 trial. Proc Am Soc Clin Oncol (2006) 24. (Abstr LBA4017).

21. Al-Batran S, Hartmann J, Probst S, et al. A randomized phase III trial in patients with advanced adenocarcinoma of the stomach receiving first-line chemotherapy with fluorouracil, leucovorin and oxaliplatin (FLO) versus fluorouracil, leucovorin and cisplatin (FLP). Proc Am Soc Clin Oncol (2006) 24. (Abstr LBA4016).


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