Abstract
Background: Metastatic pancreatic carcinoma is an incurable disease and gemcitabine remains the standard of care in first-line chemotherapy. Recently, fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) demonstrated their superiority in first-line therapy. The objective of this study was to determine the efficacy of FOLFIRINOX in either first- and second-line treatment and to compare its efficacy in regard to the location of the primary tumor. Patients and Methods: We performed a retrospective analysis of clinical factors associated with patients' survival using a cohort of 42 patients treated by FOLFIRINOX in either first- or second-line (2006-2011) and a control cohort of 42 patients matched on sex and age without FOLFIRINOX treatment was obtained from a previous period of time (2001-2005). Results: The median follow-up was 10 months. The median overall survival was 10 months for the whole cohort and 10 and 12 months for patients treated at first- and second-line, respectively (p<0.05). In this cohort using a multivariate model, among classical prognosis factors, only primary location in the head was associated with poor outcome. The median overall survival was 8 months for patients with primary location in the head and 14 months for patients with primary location in the corpse or tail (p=0.02). In the gemcitabine cohort, the median follow-up was 8 months. Using a multivariate model, only performance status was associated with outcome. The median overall survival was 9 versus 6.5 months for patients with tumor, of the head versus tail or corpse tumor respectively (p<0.05). Conclusion: This retrospective study suggests the same efficacy of FOLFIRINOX used either in first- or second- line therapy for pancreatic cancer. Importantly, FOLFIRINOX compared favorably to gemcitabine only for patients with tumor of the corpse or tail. Further prospective trials are warranted to evaluate the efficacy of FOLFIRINOX in patients with tumor of the head of the pancreas.
Pancreatic cancer is the fourth leading cause of cancer death in the Western world (1). Its prognosis is poor with a 5-year survival rate of less than 5% (1, 2). The nucleoside analogue gemcitabine is established as standard first-line chemotherapy for metastatic pancreatic adenocarcinoma (MPA) (3-5). This standard of treatment results from a randomized trial which showed significant improvement in the median overall survival (OS), as compared to fluorouracil administered as an intravenous bolus (5.6 vs. 4.4 months, p=0.002) and a clinical benefit as well (24 vs. 4.8%, p=0.0022). All subsequent clinical trials that tested gemcitabine in combination with other cytotoxic agents or target therapies failed to demonstrate any improvement in overall survival (6, 7).
Recently a multicenter phase III study showed that the three-drug regimen FOLFIRINOX (irinotecan, oxaliplatin and leucovorin (LV)-modulated fluorouracil), used as first-line therapy demonstrated superiority compared to gemcitabine. FOLFIRINOX was superior in disease control (70.2 vs. 50.9%; p=0.0003). The median TTP was 6.4 vs. 3.4 months (hazard ratio (HR)=0.47 confidence interval (CI) (0.37-0.59); p<0.0001). The median OS was 11.1 vs. 6.8 months (HR=0.57 (0.45-0.73); p<0.0001). However, the FOLFIRINOX regimen was more toxic than gemcitabine (8). FOLFIRINOX could be proposed as a first option for patients with good performance status. As always, we need to ask whether the participants enrolled in this trial are representative of the average patient with pancreatic cancer. The majority of individuals who participated in this study had non-pancreatic head tumors. This distribution of pancreatic tumor location is the opposite of what one might typically expect to see in clinical practice and in other clinical trials there was a 3:1 ratio of pancreatic cancers located in the head vs. the body or tail (9).
A significant percentage of patients with MPA (about 60%) progressing after gemcitabine-based chemotherapy are still in relatively good clinical condition and may require a second and even a third line of therapy (10). To date, no standard therapy has been approved for use after failure of gemcitabine. To our knowledge, the only available trial is a randomized phase III study comparing oxaliplatin/FU/folinic acid (OFF) with FU/folinic acid, which was presented at the 2008 ASCO Meeting (11). OFF was associated with a significantly longer median TTP (13 vs. 9 weeks, p=0.012) and a median OS (26 vs. 13 weeks, p=0.014).
In the current study we investigated whether FOLFIRINOX differently impacts on the survival of patients treated in first- or second-line and whether the location of the tumor influences the survival.
Patients and Methods
Patient selection. FOLFIRINOX usage started in 2006 at the Center Georges Francois Leclerc. We retrospectively analyzed medical records of all patients with MPA treated with FOLFIRINOX as first-or second-line therapy between January 2006 and November 2011. We compared this group to an age- and sex-matched cohort of the same number of patients treated for MPA with gemcitabine as first-line therapy without FOLFIRINOX usage. This cohort was collected from patients treated at our center between January 2001 and December 2005. Eligible patients were required to have histologically-proven pancreatic adenocarcinoma, at least one metastatic site, at least one measurable lesion and to be older than 18 years.
Study design. The study objectives were to assess and compare the efficacy of FOLFIRINOX used either in first- or second-line therapy and to compare the efficacy of FOLFIRINOX in patients with primary tumor located in the head vs. the tail and body of the pancreas. For the second point, we compared results in patients that underwent FOLFIRINOX treatment to historical patients' data that did not. In this study, we focused on the only objective criterion, overall survival from the beginning of treatment for metastatic disease. Toxic effects were graded using the National Cancer Institute Common Toxicity Criteria (version 3.0).
Chemotherapy. FOLFIRINOX consisted of oxaliplatin at 85 mg/m2 diluted in 5% glucose administered as a 2-h intravenous infusion followed by irinotecan at 180 mg/m2 administered as a 90-min infusion in 500 ml of 5% dextrose or normal saline, 1 h after the end of oxaliplatin infusion. The simplified LV/FU regimen was administered after the irinotecan infusion as follows: LV at 400 mg/m2 over 2 h followed by FU at 400 mg/m2 as a bolus and then FU at 2,400 mg/m2 as a 46-h continuous infusion. Prophylactic treatment of cholinergic syndrome with atropine (0.25 mg s.c.) was given at all subsequent cycles. Corticoids and setrons were administered before chemotherapy to prevent nausea and vomiting. Treatment cycles were repeated every two weeks until tumor progression or toxicity occurred. Patients were assessed for toxicity before each cycle. Chemotherapy was delayed until recovery if the neutrophil count was below 1×109/l or platelets were below 100×109/l, and dose adjustments were made according to nadir values and time of recovery to grade 1. Dose reductions were also made in cases of grade 3-4 diarrhea.
Statistical analyses. OS was measured from the first day of treatment for the metastatic disease to the date of death or last follow-up. Follow-up was calculated using the reverse Kaplan-Meier method. OS probabilities were estimated using the Kaplan-Meier method and were compared by the log-rank test. The hazard ratios (HR), with 95% confidence interval (CI), were calculated using the univariate Cox proportional hazards regression modeling. All variables with a univariate Cox p-value ≤0.20 were eligible for multivariate analyses.
Results
Patients' characteristics. We retrospectively analyzed the medical records of patients with either synchronous or metachronous MPA receiving FOLFIRINOX as first- or second-line therapy. We identified 42 patients and compared these patients with a sex- and age-matched cohort of 42 patients treated with gemcitabine before FOLFIRINOX usage. The baseline characteristics of the 42 patients from the FOLFIRINOX and gemcitabine cohorts are listed in Table I. The median age was 68 years (range: 43-83 years) in both cohorts. Ten and seven patients had metachronous metastases and were previously treated by complete resection of the pancreatic cancer by cephalic duodenopancreatic surgery followed by adjuvant chemotherapy with gemcitabine. The median CA19-9 was 400 and 600 U/ml for the gemcitabine and FOLFIRINOX cohort respectively. Only 10 and 12 patients had WHO performance status grade 2 in the gemcitabine and FOLFIRINOX cohort respectively. Eighteen patients had primary tumor located in the head and 9 had benefit from billiary prosthesis. In the FOLFIRINOX group, 23 patients were treated in first-line and 19 in second-line. Patients' characteristics did not significantly differ between the two cohorts (Table I).
Clinical outcome. The median follow-up at the time of analysis was 10 months (range=5-25 months) in the FOLFIRINOX cohort and 8 months in the gemcitabine cohort (range=3-25 months). The median OS was 10 months (95% CI=8-14 months) and 7 months (95% CI=6-10 months) in the FOLFIRINOX and gemcitabine cohorts, respectively (Figure 1). In the FOLFIRINOX cohort, univariate analysis demonstrated that among usual prognostic variables, only WHO performance status and primary tumor location were associated with outcome (Table II). Only tumor location remained significant in the multivariate model. Interestingly, patient survival was similar for patients treated in first- and second-line by FOLFIRINOX (9 vs. 12 months, p=0.2), while patients with primary tumor of the pancreatic head had a shorter survival compared to patients with tumor of the tail or body (8 vs. 14 months, p=0.02) (Figure 2). In the gemcitabine cohort, univariate analysis only detected WHO performance status as a prognostic factor (Table II). In this cohort, tumor location did not influence the prognosis (Figure 2).
Patients' characteristics (median age=68 years, range 43–83 years).
Safety. No toxic death was observed in either cohort. Not surprisingly toxicities were higher in the FOLFIRINOX cohort compared to the gemcitabine cohort. In the FOLFIRINOX group, the most common toxicity was hematological, with 57% grade 3-4 neutropenia and 14% febrile neutropenia. Grade 3 and 4 nausea and vomiting occurred in 24% of the patients, and grade 3-4 diarrhea occurred in 30% of the patients. Grade 3 neuropathy occurred in 25% of patients (Table III).
Discussion
Pancreatic carcinoma is a highly chemoresistant tumor with a very poor prognosis. In our study we found that FOLFIRINOX could be used both in first- and second-line therapy for metastatic pancreatic carcinoma with similar efficacy when examining the OS starting from the diagnosis of metastatic disease. Surprisingly, we also found that the FOLFIRINOX regimen seemed more efficient for patients with primary tumor of the pancreatic body or tail than for those with primary tumor of the pancreatic head. When we compared these results with a historical cohort treated without FOLFIRINOX, the primary tumor location did not influence survival. These data suggest that the benefit of FOLFIRINOX in OS is only present for patients with primary tumors of the tail and body.
In a previous series, the authors recorded an OS of 8.5 months (from the beginning of the treatment to death) in a series of 27 cases of metastatic pancreatic cancer (12). Although the global OS from diagnosis of metastatic disease to death was not reported. These results are suprising while both populations seem uncomparable. In particular we must mension the high rate of metachronous metastatic disease which may harbor better prognosis. In addition the proportion of primary tumor of the head versus tail and corpse was not represented. In our series the OS for patients treated by FOLFIRINOX in the second-line group from the beginning of FOLFIRINOX to death was 12 months. These results are in line with previous studies with focus on FOLFIRI3 regimen or FOLFOX-like regimen (13, 14).
Kaplan–Meier curves of overall survival (OS) in the FOFLIRINOX and gemcitabine cohort.
The first second-line study CONKO-003, compared infusional FU plus oxaliplatin (OFF regimen) regarding best supportive care and reported longer OS in the experimental group (median OS=26 vs. 13 weeks, p=0.014) (15). Gebbia et al. (16) reported the results of a retrospective survey on the efficacy and safety of the FOLFOX4 regimen as a second-line treatment of MPA in a series of 42 patients progressing after gemcitabine-based first-line therapy. In their series of unselected patients median OS was 6.7 months. Taieb et al. (14) conducted a randomized phase II study using the FOLFIRI3 regimen as second-line treatment in patients with gemcitabine-refractory pancreatic cancer. The FOLFIRI3 combination showed favorable efficacy and toxicity profiles in gemcitabine-pre-treated patients with MPA. The median OS was 12 months.
The second point in this study is the difference of survival between patients with primary tumor of the pancreatic head vs. tumor of the body and tail. Importantly, we observed an increase in survival with FOLFIRINOX usage only in patients with tumor of the tail and body. These results contrast with results from the PRODIGE 11 study (8). In the PRODIGE 11 study, FOLFIRINOX efficacy seems equivalent for both tumor types. The selection criteria of patients were rigorous and only patients with very good performance status and no patients with bilirubin elevation were included. These criteria may select a biased population which does not reflect all patients bearing MPA. In particular, only 38% of our patients had carcinoma of the pancreatic head, while we found them to be about 70% in previous trials. It might be suspected that in a less selected population, patients with tumor of the head may be at higher risk of side-effects upon FOLFIRINOX administration and may be undertreated.
Univariate and multivariate analysis for both cohorts.
Grade 3 or 4 toxicities experienced by patients
Kaplan–Meier curves of overall survival (OS) in the FOLFIRINOX cohort as a function of theray line (A) and as a function of the location of primary tumor (B). Kaplan-Meier curves of OS as a function of the location of primary tumor in the gemcitabine cohort (C).
The limitations of our study are its retrospective design and the heterogeneity of the populations in terms of patient treatments. However, both cohorts show comparable survival with those reported in previous studies.
In conclusion, this study underlines the possibility for the use of FOLFIRINOX either in first- or second-line for MPA with almost comparable efficacy. However, this study raises questions about the efficacy of FOLFIRINOX for patients with tumor of the head of pancreas. Additional trials are warranted in order to determine the efficacy of FOLFIRINOX in these patients.
Footnotes
-
Conflicts of Interest
Authors declare no financial disclosure or conflicts of interest.
- Received May 18, 2012.
- Revision received July 20, 2012.
- Accepted July 23, 2012.
- Copyright© 2012 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.