FOLFIRINOX for advanced pancreatic adenocarcinoma in Brazil: a single-institution experience

Keywords:

Pancreatic neoplasms/drug therapy - FOLFIRINOX - Cohort studies - Brazil

Descritores:

Neoplasias pancreáticas/tratamento farmacológico - FOLFIRINOX - Estudos de coortes - Brasil

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDA) is the fourth most lethal in cancer worldwide, with 41,780 deaths estimated for 2016 in the United States alone. The 5-year survival for this disease is around 8%. Metastatic disease, which accounts to more than half of patients with PDA, presents with even lower survival rates (2.6%).([1],[2]) In Brazil, 8,070 deaths for pancreatic cancer were registered in 2013.([3])

Relevant improvements were recently achieved in first-line treatment of metastatic pancreatic cancer patients with the publication of two phase III studies showing superiority of FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin),([4]) as well as the association of gemcitabine with nab-paclitaxel over gemcitabine alone, considered the standard of care up to that time.([5]) In PRODIGE 4/ACCORD 11 trial, FOLFIRINOX was shown to increase median overall survival, progression free survival and objective response rate over gemcitabine, at the expense of a worse toxicity profile. Notwithstanding the significant gains, only a minority of patients with advanced or metastatic PDA fulfills the restrictive criteria of ACCORD 11.([6]) The data from MPACT (gemcitabine plus nab-paclitaxel versus gemcitabine) is similar.([7])

During the past few years, many distinct centers have reported their experience with the use of FOLFIRINOX or modified FOLFIRINOX regimens in real-life experience for advanced PDA, with heterogeneous results regarding efficacy and toxicity.([8]-[19]) Indeed, a meta-analysis of 13 studies (11 of them retrospective studies and none of them conducted in developing countries) confirmed the survival improvement after FOLFIRINOX treatment when compared to gemcitabine in patients with locally advanced pancreatic cancer (LAPC). In this way, reports of FOLFIRINOX administration for advanced PDA in low to mid-income countries and South America are still lacking in the literature and may pose a relevant piece of evidences in everyday clinical decision-making.

Objectives: The aim of this study was to report outcomes of efficacy and safety in the setting of a Brazilian large cancer tertiary institution.

METHODS

Patients

Data from consecutive patients with histologically proven locally advanced or metastatic pancreatic ductal adenocarcinoma who have received FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², folinic acid 400 mg/m2, 5-fluorouracil as a bolus of 400 mg/m² and 2,400 mg/m2 infused in 46 hours - repeated each 2 weeks until maximum benefit, disease progression or unacceptable toxicity at physician’s discretion), as described([4]), as first, second or third-line treatment regimen were retrospectively assessed after a chart review using the local database of Instituto do Câncer do Estado de São Paulo, Brazil. Only patients who completed at least one full cycle of FOLFIRINOX were included. Histologies other than adenocarcinoma and presence of other active or previous primary neoplasia (except non-melanoma skin cancer) were exclusion criteria for this analysis. Approval by the local Research and Ethics Committee was obtained previously to gathering or analyzing any data (Protocol number: 210/14).

Assessment and outcomes

We assessed and recorded data on age, gender, date of relapse, use of adjuvant chemotherapy or radiotherapy, location of primary tumor, clinical and radiological staging according to the 7th AJCC, histological grade and differentiation, surgical procedures previously performed, presence of biliary derivations or stents, and Eastern Clinical Oncology Group performance status (ECOG-PS) at time of diagnosis. Data on outcomes after the FOLFIRINOX regimen was collected as well: date of progression or death, number of received cycles, reason of discontinuation, and best response after FOLFIRINOX as defined by RECIST 1.1.([20]) CT scans were analyzed by two independent radiologists. The primary endpoint was overall survival; secondary outcomes were safety and response rate after FOLFIRINOX treatment. Adverse events were graded by Common Toxicity Criteria Adverse Events (CTCAE v. 4.0).

Statistics

Patient characteristics and outcomes were reported with descriptive statistics. Overall survival (OS) was calculated as the date of first dose of FOLFIRINOX to the date of death or last follow-up. Kaplan-Meier estimates were calculated and plotted for OS. Log-rank test and Cox proportional hazard model were used when appropriate to compare time-to-event outcomes. P < 0.05 was considered to set statistical significance. All analyses were performed using IBM SPSS version 21.

RESULTS

Patient demographics

From November 2012 to January 2016, 61 consecutive patients with LAPC or metastatic PDA who received at least 1 cycle of FOLFIRINOX were identified. Database was closed in July 2016. Patient demographics and tumor characteristics are summarized in [table 1]. Median age at the beginning of cycle 1 was 61 years (range 37-74) and there was no predominance between the genders. Most patients presented with ECOG-PS 0 (31.1%) or 1 (57.4%). However, we found 9.8% and 1.6% with ECOG-PS 3 or 4, respectively. Many patients were submitted to surgical bypass (39.2%) or biliary stents (32.8%) previous to the treatment.

Table 1 Patients demographics and tumor characteristics

Characteristic	Result
Total	61
Age - median (range)	61 (37-74)
Sex
Male - n (%)	30 (49.2)
Female - n (%)	31 (50.8)
ECOG-PS- n (%)
0	19 (31.1)
1	35 (57.4)
2	6 (9.8)
3	1 (1.6)
Surgical bypass previous to treatment - n (%)	24 (39.2)
Biliary stent previous to treatment - n (%)	20 (32.8)
Status at diagnosis - n (%)
Localized	8 (13.1)
LAPC	24 (39.3)
Metastatic	29 (47.5)
Status at FOLFIRINOX start - n (%)
Metastatic	31 (50.8)
LAPC	30 (49.2)
Location of primary tumor - n (%)
Head	45 (73.8)
Body or tail	16 (26.2)
Tumor staging - n (%)
T1	2 (3.3)
T2	4 (6.6)
T3	10 (16.4)
T4	45 (73.8)
Tx	1 (1.6)
Node staging - n (%)
N0	36 (59)
N1	22 (36.1)
Nx	3 (4.9)
CA19.9 - median	1277

LAPC: locally advanced pancreatic cancer

At the time of analysis, thirty-two patients had metastatic disease and 31 had locally advanced unresectable disease. Metastatic sites were liver (25 pts - 40.9%), lung (6 pts - 9.8%), peritoneum (21 pts - 34.4%), brain (1 pt - 1.6%) and bones (3 pts - 4.9%). Three patients (4.9%) had histological diagnosis of mucinous adenocarcinoma of the pancreas. Approximately two-thirds (45 pts - 73.8%) of primary tumors were located in the head of pancreas. We found a predominance of T3 and T4 staging (16.4% and 73.8%, respectively). Two patients had T1 and 4 patients had T2 disease. N-positive disease was detected in 22 patients (36.1%). Seven patients (11.1%) had been previously submitted to upfront resection of primary tumor, 6 of them had R0 resections and 4 received adjuvant gemcitabine. No patient received radiotherapy in adjuvant or neoadjuvant setting. Fifty patients had CA19.9 expression (baseline median level = 1277 U/mL); CA 19.9 levels were missing in two patients.

Treatment with FOLFIRINOX

As depicted in [table 2], the majority of patients had received FOLFIRINOX as first-line treatment (54 pts - 88.5%). Six were treated in second-line (9.8%) and 1 in third-line (1.6%). Median number of completed cycles was 10 (range 1-32). Sixty-four percent (39 pts) received more than 6 cycles; and 13 patients (21.3%) received 1 to 3 cycles. Reasons for discontinuation were disease progression (34 pts - 55.7%), limiting toxicity (19 pts - 31.1%) and maximum benefit (8 pts - 13.1%). Second-line gemcitabine was administered in 23 patients (37.7% of full cohort, and 42.5% when considered only patients who received FOLFIRINOX as the first-line treatment).

Table 2 Characteristics related to FOLFIRINOX treatment

Characteristic	Result
Number of cycles - median (range)	10 (1-32)
Number of cycles - n (%)
>6 cycles	39 (64)
4-6 cycles	9 (14.7)
1-3 cycles	13 (21.3)
Line of treatment - n (%)
First	54 (88.5)
Second	6 (9.8)
Third	1 (1.6)
Reason for discontinuation - n (%)
Maximum benefit	8 (13.1)
Disease progression	34 (55.7)
Limiting toxicity	19 (31.1)
Dose reduction - n (%)
Reduction in the first cycle	18 (29.5)
Reduction in 1 or more drugs	50 (81.9)
Reduction in oxaliplatin	34 (55.7)
Omission of 5-FU bolus	38 (62.2)
Reduction in irinotecan	30 (49.1)
Reduction in infusional 5-FU	15 (24.5)
Hospitalization	19 (31.1)
Use of filgrastim	3 (4.9)
Second-line gemcitabine	23 (37.7)

Dose reductions, safety and toxicities

Dose-reductions were made in the first-cycle in 18 patients (29.5%). Reduction in 1 or more drugs considering all cycles occurred in 50 patients (81.9%). Omission of 5-FU bolus was the most common modification (38 pts - 62.2%), followed by reductions in oxaliplatin (34 pts - 55.7%), reductions in irinotecan (30 pts - 49.1%) and in infusional 5-FU (15 pts - 24.5%). Hospitalization during treatment with FOLFIRINOX occurred 23 times in 19 patients (31.1%; 0.03 hospitalizations/cycle) ([Table 2]). When considering only patients with ECOG 0 or 1, hospitalizations occurred 20 times in 17 patients (31.4%; 0.03 hospitalizations/ cycle). When considering the group of patients that started FOLFIRINOX with up-front dose reductions, 26.6% interrupted chemotherapy due to limiting toxicities, against 28.2% in the group that started with full-dose regimen.

Grade ≥ 3 side effects were reported in 37 patients (60.6%) at any time of treatment ([Table 3]). Most common grade ≥ 3 side-effects were: hematological (22 pts - 36%), neuropathy (12 pts - 19.6%) diarrhea (9 pts - 14.7%), fatigue (5 pts - 8.2%) and nausea/vomiting (4 pts - 6.5%). Neutropenia grade ≥ 3 occurred in 15 patients (24.6%), and febrile neutropenia in 2 patients (3.2%). Only three patients received filgrastim as preventive measure to neutropenia after FOLFIRINOX. Potential treatment-related deaths were reported in 3 cases (two due to severe colitis and one due to febrile neutropenia).

Table 3 Patients presenting grade ≥ 3 FOLFIRINOX-related toxicities

Toxicity	Result n (%)
Grade ≥ 3 toxicity	37 (60.6)
Hematological	22 (36)
Neutropenia	15 (24.6)
Febrile neutropenia	2 (3.2)
Diarrhea	9 (14.7)
Neuropathy	12 (19.6)
Fatigue	5 (8.2)
Acute myocardial infarction	1 (1.6)
Nausea/vomiting	4(6.5)
Potential treatment-related deaths	3 (4.9)

Clinical outcomes

Median OS was 16.26 months (95% CI: 14.58-17.94). In patients with metastatic disease and LAPC, median OS was 13.60 months (95% CI: 8.02-19.17) and 18.70 months (95% CI: 15.25-22.14), respectively. These differences were statistically significant (log-rank test; P = 0.041; HR = 0.556 - 95% CI = 0.31-0.98). Partial responses were found in 24 patients (39.3%) and stable disease in 20 patients (32.8%). No complete responses were detected. One patient with LAPC was submitted to R0 tumor resection after a partial response to 6 cycles of FOLFIRINOX ([Table 4]).

Table 4 Clinical outcomes after FOLFIRINOX treatment

	Full cohort	Metastatic disease N = 31	LAPC N = 30
OS - median (95% CI)	16.2 (14.5-17.9)	13.60 (8.0-19.1)	18.7 (15.2-22.1)
Response (%)
PR	24 (39.3)	10 (32.2)	13 (43.3)
CR	0	0	0
SD	20 (32.8)	7 (22.5)	12 (38.7)

CA19.9

Fifty patients had elevated CA19.9, and median level was 1277 U/mL; CA 19.9 levels were missing in two patients. Twenty-seven patients had >50% decreases in CA 19.9 levels after FOLFIRINOX treatment and there was a trend to increased OS (HR=0.77; 95% CI = 0.40-1.45) in this group (median OS: 19.10 months) when compared with the group who had less than 50% decrease or increase in CA19.9 (median OS: 16.26 months).

DISCUSSION

The present study retrospectively reviewed patients with LAPC or metastatic PDA treated with FOLFIRINOX at Instituto do Câncer do Estado de São Paulo, a large public Cancer Center in Brazil. Median OS was 16.26 months (13.6 months in metastatic and 18.7 in LAPC disease). As detailed in [table 5], our results are consistent with others, acknowledging all caveats surrounding cross-studies comparisons. The median OS in the pioneer PRODIGE study was 11.1 months in the FOLFIRINOX group. The fact that PRODIGE included only patients with metastatic PDA may be among the factors that would explain our study with slightly higher median OS detected.([4])

Table 5 Real-world experiences with FOLFIRINOX regimen for advanced pancreatic cancer

Study	Year	N	OS (median in months)	Response rate (%)	Serious AEs[ * ] (%)
Mota et al.	2017	61	Full cohort: 16.26; Metastatic:13.6; LAPC: 18.70	Full cohort: 39.3; Metastatic: 32.2; LAPC: 43.3	60.6
Rombouts et al.(26)	2016	50	Metastatic: 9.0; LAPC: 14.80	Full cohort: 25; Metastatic: 32; LAPC: 12	52
Chllamma et al. ([10])	2016	102	Metastatic: 12.9; LAPC: 23	13	N/R (43.1% of grade3/4 hematological AEs)
Ghorani et al. Δ([13])	2015	18	8.9	46.7	N/R
Zahir et al.([14])	2015	101	10.5	N/R	N/R
Takeda et al. #([12])	2015	10	N/R	10	N/R
					N/R
Moorcraft et al.([15])	2014	49	12.9	41	(29% of grade 3/4 neutropenia)
Kraemer et al.([16])	2014	16	8.45	50	N/R
Hohla et al.([17])	2014	49	13	55.1	N/R
Amireault et al.([9])	2014	46	12.6	N/R	N/R (3 treatment-related deaths)
Mahseth et al. †([18])	2013	60	16.4	30	40
Gunturu et al.([11])	2013	35	not reached	48	2.9
Peddi et al.([8])	2012	61	13.5	25	N/R (19.7% of hematological AEs)

^* G3, G4 or G5 AEs; # Only Japanese patients; used a modified (m)FOLFIRINOX scheme as follows: oxaliplatin at 85 mg/m2, leucovorin at 200 mg/m2 and irinotecan at 150 mg/m2, followed by continuous infusion of 5-FU over 46 hours at 2,400mg/m2; N/R means not reported; @ This study did not report the rate of all G3 and 4 AEs, however the reported rate of G3 and 4 hematologic AEs was 43.1 %; Δ used a modified (m)FOLFIRINOX scheme as follows: oxaliplatin at 85 mg/m2, leucovorin at 400 mg/m2 and irinotecan at 135 mg/m2, followed by continuous infusion of 5-FU over 46 hours at 2,400mg/m2, with routine filgrastim; † used a mFOLFIRINOX regimen: oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2 and 5-FU 2400 mg/m2 over 46 hours with routine pegfilgrastim at D+3

Despite baseline CA19.9 and a decrease in CA19.9 levels having been shown to correlate with response after FOLFIRINOX treatment,([10],[17],[21]) we only detected a non-significant trend in increased OS after a 50% decrease in CA19.9 levels, perhaps due to the small sample size.

Significant differences in outcomes between patients with LAPC and metastatic disease (median OS: 13.6 vs 18.7 months; HR = 0.55; p = 0.041) were detected in our cohort. Accordingly, a Canadian retrospective study (median OS: 14 months in metastatic disease and 18.4 months in LAPC)([22]) and the Royal Marsdem experience showed similar results (median OS: 10.4 months in metastatic disease and 18.4 months in LAPC).([15]) These similarities in outcomes between our study and others are of particular relevance, specially considering ours was conducted in an emerging country. On the other side, a Pakistani study assessed patients with metastatic PDA who have received FOLFIRINOX and found a median OS of 10.5 months and median PFS of 7.3 months.([23])

The majority of patients received FOLFIRINOX as firstline treatment; but almost 10% received FOLFIRINOX as second-line treatment. In this cohort, dose reductions were common and occurred in 29.5% in the first cycle and in 81.9% considering all cycles. Small single-center experiences detected similar outcomes and acceptable toxicities after removing the 5-FU bolus ([18]) or reducing irinotecan dose to 135 mg/m2([13]) in the original FOLFIRINOX scheme. A phase 2 study evaluated a modified FOLFIRINOX regimen (25% reduction in 5-FU bolus and irinotecan) and showed similar survival outcomes with reduced adverse events comparing to the historical controls.([24]) In the present study, hospitalization during treatment with FOLFIRINOX occurred in 31.1% of patients; the main cause was sepsis/infection, and this is in consonance with other reports.([8]-[10]) No catheter complications were detected.

Serious adverse events (grade ≥ 3) occurred in 60.4% of patients and led to limiting toxicity as the reason for discontinuing FOLFIRINOX in 31.1% of analyzed patients. Major toxicities were neutropenia, diarrhea, neuropathy and fatigue. Importantly, we detected 3 potential treatment-related deaths. The rate of grade 3 or more adverse events was apparently higher than other previous reports.([10],[13]) For example, in the Royal Marsdem cohort, limiting toxicity was considered a reason for discontinuation in only 4%.([15]) Filgrastim was administered in only 4.9% of patients. This is a provocative finding, if we consider that our cohort had 24.6% grade 3 or 4 neutropenia and only 2 patients with febrile neutropenia. In the PRODIGE study, which led the approval of FOLFIRINOX for advanced PDA, 42.5% of patients received filgrastim and febrile neutropenia occurred in 5.4% of them.([4]) Furthermore, a small retrospective study showed the incidence of G3/4 neutropenia as 33% of patients receiving FOLFIRINOX and prophylactic G-CSF.([25]) The increased flexibility to dose reduce or interrupt chemotherapy in the real-world scenario may have contributed to these potential differences.

Our study has several limitations. First, the retrospective assessment may produce biases, such as patient selection and inaccuracies in data collections. Because there were no standardized methods for dose reductions and FOLFIRINOX interruption, these were made at physician’s discretion.

CONCLUSIONS

In summary, the present retrospective study provided relevant insights into the safety and clinical outcomes of FOLFIRINOX treated in an emerging country in South America. Considering the limitations of a retrospective analysis, this study supports the efficacy of FOLFIRINOX without routine filgrastim against advanced PDA in good-performance status patients, despite high rates of hospitalization, dose reductions and toxicities. These findings may increase the notion that FOLFIRINOX should be offered to fit patients in centers where emergency care is promptly available.

Author’s Contributions

Conception and design: José Mauricio Mota, Andre Henares Campos Silva, Andre Silva Franco, Aley Talans , Felipe Ribeiro-Ferreira, Tiago Biachi de Castria, Jorge Sabbaga, Paulo M Hoff

Acquisition of data: José Mauricio Mota, Andre Henares Campos Silva, Andre Silva Franco, Aley Talans , Felipe Ribeiro-Ferreira, Tiago Biachi de Castria,

Analysis and interpretation of data: José Mauricio Mota, Andre Henares Campos Silva, Andre Silva Franco, Aley Talans , Felipe Ribeiro-Ferreira, Tiago Biachi de Castria, Jorge Sabbaga, Paulo M Hoff

Writing, review, and/or revision of the manuscript: José Mauricio Mota, Andre Henares Campos Silva, Andre Silva Franco, Aley Talans , Felipe Ribeiro-Ferreira, Tiago Biachi de Castria, Jorge Sabbaga, Paulo M Hoff

Study supervision: Jorge Sabbaga, Paulo M Hoff

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