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Annals of Oncology Advance Access originally published online on December 8, 2006
Annals of Oncology 2007 18(3):498-503; doi:10.1093/annonc/mdl427
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© 2006 European Society for Medical Oncology

gastrointestinal tumors

FOLFIRI.3, a new regimen combining 5-fluorouracil, folinic acid and irinotecan, for advanced pancreatic cancer: results of an Association des Gastro-Entérologues Oncologues (Gastroenterologist Oncologist Association) multicenter phase II study

J Taïeb1,*, T Lecomte2, T Aparicio3, A Asnacios1, T Mansourbakht1, P Artru4, D Fallik5, JP Spano6, B Landi2, G Lledo4 and J Desrame7

1 Service d'Hépato-gastro-entérologie, Groupe Hospitalier Pitié Salpétrière, Paris cedex 13
2 Service d'Hépato-gastro-entérologie, Hôpital Européen Georges Pompidou, Paris cedex 15
3 Service d'Hépato-gastro-entérologie, Hôpital Bichat, Paris cedex 18
4 Clinique Saint Jean, Lyon
5 Clinique Jeanne D'Arc, Gien
6 Service d'oncologie médicale, Groupe Hospitalier Pitié Salpétrière, Paris cedex 13
7 Service d'Hépato-gastro-entérologie, Hôpital du Val de Grâce, Paris cedex 5, France

* Correspondence to: Dr J. Taïeb, Service d'Hépatogastro-entérologie, Groupe Hospitalier Pitié Salpêtrière, 47-89, Bd de l'Hôpital, 75013 Paris, France. Tel: +33-1-421-61041; Fax: +33-1-421-61425; E-mail: jtaieb{at}club-internet.fr


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 References
 
Background: The purpose of the study was to prospectively evaluate the efficacy and tolerability of the FOLFIRI.3 regimen in patients with unresectable pancreatic adenocarcinoma.

Patients and methods: Chemotherapy-naive patients with histologically proven advanced pancreatic adenocarcinoma were treated with the FOLFIRI.3 regimen, consisting of irinotecan 90 mg/m2 as a 60-min infusion on day 1, leucovorin 400 mg/m2 as a 2-h infusion on day 1, followed by 5-fluorouracil (5-FU) 2000 mg/m2 as a 46-h infusion and irinotecan 90 mg/m2, repeated on day 3, at the end of the 5-FU infusion, every 2 weeks.

Results: Forty patients were enrolled, of whom 29 (73%) had metastatic disease. A total of 441 cycles were delivered (1–53). Grade 3–4 neutropenia occurred in 35% of the patients, accompanied by fever in two cases. Other relevant grade 3–4 toxic effects were nausea-vomiting (27%) and diarrhea (25%). Grade 2 alopecia occurred in 48% of the patients. There were no treatment-related deaths. The confirmed response rate was 37.5%. Stable disease was observed in 27.5% of the patients. The median progression-free and overall survivals were 5.6 months and 12.1 months, respectively. The 1-year survival rate was 51%.

Conclusion: The FOLFIRI.3 regimen seems to be active on advanced pancreatic cancer and to have a manageable toxicity profile. The lack of cross-resistance between FOLFIRI.3 and gemcitabine-based regimens allows efficient second-line therapies.

Key words: irinotecan, pancreatic cancer, systemic chemotherapy


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 References
 
Pancreatic cancer causes about 50 000 deaths annually in Europe and is the fourth leading cause of death by cancer in the Western countries; the mortality and incidence rates are similar [1–3]. The overall 6-month and 1-year survival rates among patients with advanced disease are, respectively, 35% and <10% in most studies [1–3]. About 80% of patients have unresectable or metastatic forms at diagnosis [4]. Systemic chemotherapy protocols for unresectable pancreatic cancer have given disappointing results during the last 20 years. Several drugs, given alone or in combination, have been tested in phase II and III trials, with objective response rates ranging from 0% to 20% and median survival times not exceeding 6 months [5]. One randomized trial showed the superiority of single-agent gemcitabine over single-agent 5-fluorouracil (5-FU) therapy and established gemcitabine as the reference for advanced pancreatic cancer [6]. The objective response rates, however, in large randomized trials of gemcitabine ranged from 4% to 16%, and the median survival time was only 4.6–6 months [7–10].

Irinotecan (Aventis, France), a camptothecin analogue, has a stronger growth-inhibiting effect than cisplatin, mitomycin C and fluorouracil on cultured pancreatic adenocarcinoma cells [11]. Irinotecan is also highly active on pancreatic tumor cells in culture and in xenograft models. [12, 13] Irinotecan monotherapy has been tested in patients with previously untreated pancreatic cancer, yielding response rates of 9%–27% [14, 15]. Second-line irinotecan monotherapy has also shown a degree of activity [16, 17]. In most trials, however, the response rates were low (<10%) and survival was poor.

In vitro studies indicate that synergism between irinotecan and 5-FU is sequence dependent, cytotoxicity being stronger when irinotecan is administered before 5-FU [18–20]. In vivo, however, a phase II randomized study of colorectal cancer patients indicated that cytotoxicity was stronger when irinotecan was administered after 5-FU [21]. These studies gave rise to the FOLFIRI.2 regimen, consisting of a simplified LV5FU2 administration, followed by irinotecan 180 mg/m2 at the end of 5-FU infusion [22]. The latter phase II study, involving heavily pretreated colorectal cancer patients, showed encouraging efficacy but major toxicity. The same team subsequently designed a regimen (FOLFIRI.3) in which the irinotecan dose is administered in two halves, one before 5-FU and the other at the end of the 5-FU infusion. This regimen was then tested in a multicenter phase II study involving patients with metastatic colorectal cancer who had previously received FOLFOX. The response rate was 26% and the median progression-free and overall survival times were 5.1 and 10 months, respectively [23].

Here, in a multicenter phase II study, we evaluated the FOLFIRI.3 regimen in previously untreated patients with advanced pancreatic cancer.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 References
 
patients
The following criteria were used for patient selection: histologically or cytologically proven pancreatic ductal adenocarcinoma; unresectable locally advanced or metastatic disease; at least one measurable lesion (response evaluation in solid tumors (RECIST) criteria); no previous chemotherapy or radiotherapy; age between 18 and 75 years; World Health Organization (WHO) performance status (PS) of less than three; initial morphologic assessment at least 3 weeks before treatment; adequate bone marrow status (polymorphonuclear neutrophils >1.5 g/l, platelets >100 g/l and hemoglobin >10 g/dl), renal function (serum creatinine level <125 µmol/l) and liver function [serum bilirubin level <1.5 x the upper limit of normal (ULN), alkaline phosphatase (ALP) and transaminase levels <3 x ULN] and estimated life expectancy >2 months. Surgical unresectablility was observed during laparotomy or decided by a multidisciplinary staff meeting in each participating center. The study was approved by the Pitié Salpêtrière Hospital ethics committee, and written informed consent was obtained from each patient. Patients were fully informed of the type and modalities of the treatment, as well as possible adverse effects and expected benefits. The pretherapeutic work-up included a complete physical examination, WHO PS, body weight, symptoms, abdominal computed tomography (CT) scan, CA 19-9 assay, standard chest X-ray examination and, if required, thoracic CT scan.

the FOLFIRI.3 regimen
FOLFIRI.3 consists of irinotecan 90 mg/m2 administered as a 60-min infusion on day 1, together with leucovorin 400 mg/m2 over 2 h, 5-FU 2000 mg/m2 administered as a 46-h infusion and irinotecan 90 mg/m2 repeated on day 3, at the end of the 5-FU infusion (Figure 1). The chemotherapy cycles were repeated every 2 weeks if the polymorphonuclear neutrophil count was >1500/mm3, the platelet count >100 000/mm3 and the serum bilirubin level <1.5 x ULN.


Figure 1
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  		Figure 1. The FOLFIRI.3 regimen.

 
The use of antiemetic prophylaxis was decided locally. Patients who developed a severe cholinergic syndrome received preventive treatment with atropine (0.25 mg subcutaneously) during all subsequent cycles. Patients who developed late-onset diarrhea received high-dose loperamide following specific guidelines. If severe neutropenia occurred and/or if neutropenia did not recover to grade 1 or 0 on day 14, a granulocyte colony-stimulating factor (G-CSF) could be used during subsequent cycles.

The irinotecan dosage was reduced to 80 mg/m2 and the 5-FU dosage was reduced by 20% if grade 3–4 toxicity occurred; other dose adjustments were decided on an individual basis. Dose reescalation was not permitted.

Treatment was interrupted if the tumor progressed or severe toxicity occurred, and at the patient's request. Second-line chemotherapy with gemcitabine, oxaliplatin, 5-FU and cisplatin was offered if the chemotherapist considered it appropriate.

assessment of therapeutic efficacy and symptom relief
The primary end point for efficacy was the tumor response rate, defined as the sum of complete and partial responses based on the RECIST criteria [24]. Tumor responses were assessed by means of helicoidal CT every 2 months (four cycles) or earlier in patients with suspected progression. Complete responses were defined as complete disappearance of all assessable disease. Partial responses were defined as a decrease of >30% in the sum of the largest diameters of target lesions. Stable disease was defined as a decrease of <30% or an increase of <20% in measurable lesions. Progressive disease was defined as an increase of at least 20% in measurable lesions or the appearance of new malignant lesions.

A second CT scan was carried out 4 and 8 weeks after the first scan to confirm complete and partial responses. All CT scans for responder patients were reviewed by an external response review committee (ERRC), composed of two independent radiologists who were not otherwise involved in the study. Secondary end points for efficacy included the time to progression and the progression-free and overall survival times. Body weight, WHO PS and symptoms were recorded at the beginning of each chemotherapy session.

toxicity
Toxicity was assessed with the National Cancer Institute Common Toxicity Criteria (version 3.0). A full blood count was carried out each week to assess hematological toxicity, and the patients had a complete physical examination and serum bilirubin, transaminase, ALP and creatinine assays before each treatment cycle. The patients were interviewed before each session, focusing on pain, nausea, vomiting, mucositis, diarrhea, asthenia, weight loss and neurological disorders. All patients who received at least one treatment session were considered assessable for toxicity.

statistical analysis
The main purpose of this study being to assess the response rate to the FOLFIRI.3 regimen, Simon's two-stage method was used for statistical analysis [25]. The population size was calculated to demonstrate treatment efficacy for an objective response rate ≥30% and treatment inefficacy for an objective response rate ≤10%, with a 5% alpha risk and 90% power. At the end of the first phase (18 patients included), the trial was to be stopped for treatment inefficacy if the number of objective responses was zero or one. If more than one objective response was observed, the trial was to be continued until a total of 35 patients had been enrolled. Assuming that 15% of the patients would be inassessable, 40 patients needed to be enrolled. All analyses have been carried out on intention-to-treat. The results are expressed as means ± standard deviation or as ranges, as appropriate. Follow-up started at the outset of treatment. The censoring event for responses was the start of disease progression. The censoring event for survival was the date of death. Overall and progression-free survivals were determined using the Kaplan–Meier method.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 References
 
From June 2003 to June 2005, 40 patients with advanced pancreatic adenocarcinoma were enrolled by seven French centers participating in this prospective study. The patients' clinical features and laboratory findings are shown in Table 1. Median age was 58 years (range 42–74) and the male–female sex ratio was 1.67 (25 men and 15 women). Twenty-nine patients (73%) had metastatic disease. Twenty patients had undergone surgery before inclusion, seven for curative treatment and 13 for palliative treatment or exploration. Concerning the seven patients who underwent a previous curative surgery, they all relapsed within 3–12 months after surgery and five of them had more than one metastatic site at relapse. One patient with metastatic relapse had received external irradiation (45 Gy) >6 months before the study treatment was initiated. Thirty-nine patients were assessable for toxicity and 34 for the tumor response.


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  		Table 1. Characteristics of the patients before treatment

 
tumor responses and survival
Six objective responses were observed in the first 18 assessable patients, authorizing further recruitment. The overall results are shown in Table 2. Objective tumor responses were observed in 37.5% of the 40 patients [95% confidence interval (CI) 24% to 53%]. There was one complete response and 14 partial responses. Eleven patients (27.5%) had stable disease. Tumor progression occurred in eight patients (20%) and six patients (15%) were not assessable, mainly because death occurred before the first planned evaluation. Three patients were classified as responders by the investigators but not by the ERRC, who considered that the sum of the largest diameters of the target lesions had fallen by <30% (24%–28%). Finally, the overall response rate was 41% (95% CI 25% to 59%) in metastatic patients and 36% (95% CI 15% to 65%) in patients with locally advanced disease.


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  		Table 2. Efficacy results (n = 40)

 
With a median follow-up of 21.5 months, the mean progression-free and overall survival times were 5.6 and 12.1 months, respectively. The 1-year survival rate was 51% (Figure 2). As usually observed in this setting, median overall survivals were 12.1 (95% CI 5–12.1), 15.6 (95% CI 8–17.9) and 5.8 months (95% CI 4–10.3) in patients with WHO PS of zero, one and two, respectively.


Figure 2
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  		Figure 2. Overall survival (OS) and progression-free survival (PFS).

 
Two patients underwent surgical resection of their tumor remnants. The first patient was treated for metachronous liver metastases (n = 5) and had a durable (2 year) major response (>90%) to the FOLFIRI.3 regimen. He underwent right hepatectomy followed by a further 6 months of FOLFIRI.3 and is still alive with no detectable disease 8 months after surgery. The second patient was treated for a single pathologically proven metachronous lung metastasis. She had a partial response lasting for 6 months, then underwent lobectomy of the right lung and received a further 3 months of adjuvant FOLFIRI.3. A metastasis appeared in the left lung 6 months later and the pulmonary resection was again carried out. She refused adjuvant chemotherapy, and is alive and free of detectable disease 6 months after the last surgical procedure.

PS improved in 16 (51%, 95% CI 35–68) of the 31 patients whose initial WHO PS was more than zero. Weight gain was observed in 50% of the patients with initial weight loss and initial signs such as pain, asthenia or anorexia declined in 14 (52%) of the 27 initially symptomatic patients. Median delay to symptom relief was 4 weeks.

Six patients were still being treated with the FOLFIRI.3 regimen at the time of the final analysis. Three patients with locally advanced disease were given concomitant radiochemotherapy after 8, 11 and 12 FOLFIRI.3 cycles. Another 22 patients were given second-line chemotherapy consisting of gemcitabine + oxaliplatin (n = 13), gemcitabine alone (n = 6) or 5-FU + cisplatin C (n = 3). Six patients received a third line of chemotherapy with 5-FU or gemcitabine.

toxicity
Thirty-nine patients were included in the toxicity assessment (Table 3). A total of 441 chemotherapy sessions were administered, with a median of eight per patient (range 1–53). There were no treatment-related deaths. Fourteen patients (35%) developed grade 3–4 neutropenia. Grade 4 febrile neutropenia occurred in two patients who were not receiving growth factors. Five patients received G-CSF, for a total of 13 cycles. No new grade 3–4 toxic events were observed after cytotoxic dose reduction and/or G-CSF initiation.


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  		Table 3. Toxicity

 
Nonhematologic grade 3–4 toxic effects mainly consisted of gastrointestinal (GI) disorders. Despite routine prophylaxis with corticosteroids and setrons, grade 3 nausea-vomiting (considered to be one event) was the most frequent adverse effect, being observed in 11 patients (27%). Nausea-vomiting generally began 3 h after starting the infusion and lasted 1–3 days. Ten patients (25%) experienced grade 3 diarrhea, leading to hospitalization in two cases. All but one of the patients were able to continue treatment after a cytotoxic dose reduction and/or symptomatic treatment intensification. Aprepitant was necessary to control nausea and vomiting in three patients.


   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
References
 
Until recently, pancreatic cancer was considered to be chemoresistant. This apparent chemoresistance was partly attributed to overexpression of the multidrug resistance and glutathione S-transferase genes in the normal and tumor-bearing pancreas [26, 27]. Despite disappointing results overall, chemotherapy has, over the last 10 years, improved the survival and quality of life of some patients with advanced pancreatic cancer [28]. 5-FU was widely used before 1997 to treat locally advanced and metastatic cancer of the pancreas [29]. In 1997, gemcitabine, which is easy to administer and well tolerated, was shown to be superior to 5-FU and became the new reference standard for this disease, although combinations based on platinum analogues and 5-FU are still widely used in France. Randomized trials of gemcitabine in combination with a second cytotoxic agent have failed to demonstrate any superiority over gemcitabine monotherapy, except for the gemcitabine plus capecitabine combination, but the final results of the two promising phase III studies are still awaited [7, 8, 10, 30–35]. Recently, the addition of anti-EGFR (epidermal growth factor) and anti-vascular endothelial growth factor to gemcitabine therapy was reported to yield response rates of 12%–21% and overall survival times of 7.1–8.8 months [36, 37]. Therefore, better systemic treatments using more efficient therapeutic regimens are still needed to treat advanced pancreatic cancer patients.

Irinotecan-based chemotherapies have previously been used for palliative treatment of pancreatic cancer [17, 31, 38–40]. The gemcitabine–irinotecan combination (IRINOGEM) gave promising results in phase II trials [40, 41], with objective response rates of 20%–25% and survival times of 5.7–7 months, but a subsequent phase III trial versus gemcitabine monotherapy gave negative results, with a response rate of only 16% and a median overall survival time of 6 months [31]. More recently, Conroy et al. [38] reported the results of a multicenter phase II trial testing 5-FU, oxaliplatin and CPT-11 combination therapy (FOLFIRINOX) in patients with locally advanced and metastatic pancreatic cancer. The objective response rate was 26%, as confirmed by an ERRC. The overall survival time was 10.2 months, the time to progression was 8.2 months and the median progression-free survival time is not given in the final publication.

We observed a 37.5% objective response rate in our trial. Furthermore, two of our patients with metachronous metastatic relapses were able to undergo secondary surgical R0 resection after long-lasting objective responses to the FOLFIRI.3 regimen. The tumor response is often difficult to assess in patients with locally advanced disease because of a frequent desmoplastic reaction around the organ. Major differences between the assessments of the investigators and the ERRC were observed in this subgroup, with three patients out of 11 classified as responders by the investigators and as stable by the ERRC. Moreover, the overall response rate was a little bit better in metastatic patients (41%) than in patients with locally advanced disease (36%). Concerning survival, it is noteworthy that the progression-free survival time was about half the overall survival time. Although second-line chemotherapy is classically considered ineffective on advanced pancreatic cancer, more than two-thirds of our patients received gemcitabine- or platinum-based second-line chemotherapy, and 45% of them had an objective response or disease stabilization. Thus, second-line chemotherapy with drugs showing no cross-resistance with the FOLFIRI.3 regimen might have improved the overall survival rate in this study. These results are in keeping with the trend in routine practice to offer further chemotherapy to patients with unresectable pancreatic cancer whose tumor progresses after first-line chemotherapy, as reported in other phase II and phase III trials [17, 39, 42–44]. Finally, although quality of life was not specifically assessed in this trial, about 50% of the patients gained weight, experienced symptom relief and had an improvement in their PS. These good results are not due to a patient selection bias, as about one-third of our patients had PS of two (WHO), one-quarter had more than two metastatic sites and five patients died before the first assessment of treatment efficacy. Thus, the objective response rate (37.5%, as confirmed by an ERRC) and the median overall survival time (12.1 months) observed in this study compare very favorably with the results of the latter two trials [31, 38] of irinotecan-based chemotherapies in pancreatic cancer.

The FOLFIRI.3 regimen has acceptable tolerability despite hematological and GI toxicity. These toxic effects were manageable in all the patients, and only 12.5% of patients had to stop the treatment because of severe adverse effects. No toxic deaths occurred. In future, however, patients with poor PS and other factors of poor prognosis such as a low albumin level, loss of appetite and high ALP or lactate dehydrogenase levels [7, 32, 45] may not be eligible for this regimen. Indeed, 50% of our patients with an initial PS of two experienced grade 3–4 neutropenia, 30% died before the first efficacy assessment and no tumor responses were observed in this subgroup of patients (only three had stable disease). Overall, 35% of the patients had grade 3 nausea-vomiting (taken as one event) and/or diarrhea. Only four of these patients had to be hospitalized for a few days and only one had to stop treatment of a GI adverse event. Concerning hematotoxicity, with grade 3–4 neutropenia in 35% of patients and only one case of grade 3 thrombocytopenia, the FOLFIRI.3 regimen seems to be more toxic than gemcitabine monotherapy but to be better tolerated than the FOLFIRINOX [38] and IRINOGEM regimens [31]. These results may be further improved by more frequent use of G-CSF prophylaxis.

In conclusion, with an objective response rate of 37.5%, a median overall survival time of 12 months and acceptable tolerability, the FOLFIRI.3 regimen seems to be active in patients with previously untreated advanced pancreatic cancer. The lack of cross-resistance between FOLFIRI.3 and gemcitabine-based regimens allowed efficient second-line therapy at treatment failure in this work. The FOLFIRI.3 regimen should now be tested in a randomized phase III trial versus gemcitabine.

Received for publication September 21, 2006. Revision received October 17, 2006. Accepted for publication October 17, 2006.


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 results
 discussion
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