Clinical Trials Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Dec 15, 2018; 10(12): 505-515
Published online Dec 15, 2018. doi: 10.4251/wjgo.v10.i12.505
Multicenter phase II trial of modified FOLFIRINOX in gemcitabine-refractory pancreatic cancer
Moon Jae Chung, Huapyong Kang, Ho Gak Kim, Jong Jin Hyun, Jun Kyu Lee, Kwang Hyuck Lee, Myung Hwan Noh, Dae Hwan Kang, Sang Hyub Lee, Seungmin Bang, Pancreatobiliary Cancer Study Group of Korean Society of Gastrointestinal Cancer
Moon Jae Chung, Huapyong Kang, Seungmin Bang, Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea
Ho Gak Kim, Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu 42471, South Korea
Jong Jin Hyun, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan 15355, South Korea
Jun Kyu Lee, Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang 10326, South Korea
Kwang Hyuck Lee, Division of Gastroenterology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
Myung Hwan Noh, Department of Internal Medicine, Dong-A University College of Medicine, Busan 49201, South Korea
Dae Hwan Kang, Department of Internal Medicine, Medical Research Institute, Pusan National University School of Medicine and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, South Korea
Sang Hyub Lee, Departments of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, South Korea
ORCID number: Moon Jae Chung (0000-0002-5920-8549); Huapyong Kang (0000-0003-1790-0809); Ho Gak Kim (0000-0003-3365-1662); Jong Jin Hyun (0000-0002-5632-7091); Jun Kyu Lee (0000-0002-2694-3598); Kwang Hyuck Lee (0000-0002-2898-6233); Myung Hwan Noh (0000-0003-3460-2264); Dae Hwan Kang (0000-0002-7539-0723); Sang Hyub Lee (0000-0003-2174-9726); Seungmin Bang (0000-0001-5209-8351).
Author contributions: Chung MJ, Lee SH and Bang S led the study design; the study was managed by Lee SH and Bang S; Kang H and Chung MJ performed the data analysis; Chung MJ, Kang H, Kim HG, Hyun JJ, Lee JK, Lee KH, Noh MH, Kang DH, Lee SH and Bang S interpreted the data; Chung MJ, Kang H and Bang S wrote the manuscript; all versions of the manuscript were reviewed by Chung MJ, Kang H, Kim HG, Hyun JJ, Lee JK, Lee KH, Noh MH, Kang DH and Lee SH; all authors approved the final manuscript; Chung MJ and Kang H contributed equally to this work as primary authors; Lee SH and Bang S contributed equally to this work as corresponding authors.
Institutional review board statement: This study was approved by the Institutional Review Board of all participating institutions and carried out in accordance with the Declaration of Helsinki.
Clinical trial registration statement: This trial is registered with ClinicalTrials.gov, number NCT02440958.
Informed consent statement: Written, informed consent was obtained from each participant after potential treatment complications had been fully explained.
Conflict-of-interest statement: All authors declare no conflicts-of-interest related to this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author to: Seungmin Bang, MD, PhD, Professor, Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea. bang7028@yuhs.ac
Telephone: +82-2-22281932 Fax: +82-2-3936884
Received: September 19, 2018
Peer-review started: September 19, 2018
First decision: October 15, 2018
Revised: October 24, 2018
Accepted: November 25, 2018
Article in press: November 26, 2018
Published online: December 15, 2018

Abstract
AIM

To evaluate the efficacy and safety of modified FOLFIRINOX as a second-line treatment for gemcitabine (GEM)-refractory unresectable pancreatic cancer (PC).

METHODS

This study was a prospective, multicenter, one-arm, open-label, phase II trial. Patients with unresectable PC, who showed disease progression during GEM-based chemotherapy were enrolled. All patients were administered FOLFIRINOX with reduced irinotecan and oxaliplatin (RIO; irinotecan 120 mg/m2 and oxaliplatin 60 mg/m2), which was set according to the phase I study of FOLFIRINOX. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse events were evaluated. Additionally, changes in quality of life (QoL) were assessed using a questionnaire on QoL.

RESULTS

Between August 2015 and May 2016, a total of 48 patients were enrolled. The median follow-up time was 259 d with a median of 8.5 cycles. The ORR and DCR were 18.8% and 62.5%, respectively, including one patient who showed complete remission. The median PFS was 5.8 mo [95% confidence interval (CI): 3.7-7.9] and median OS was 9.0 mo (95%CI: 6.4-11.6). Neutropenia (64.6%) was the most common grade 3-4 adverse event, followed by febrile neutropenia (16.7%). Although 14.6% of patients experienced grade 3 fatigue, most non-hematologic AEs were under grade 2. In the QoL analysis, the global health status score before treatment was not different from the score at the last visit after treatment (45.43 ± 22.88 vs 48.66 ± 24.14, P = 0.548).

CONCLUSION

FOLFIRINOX with RIO showed acceptable toxicity and promising efficacy for GEM-refractory unresectable PC. However, this treatment requires careful observation of treatment-related hematologic toxicities.

Key Words: Pancreatic cancer, FOLFIRINOX, Clinical Trial, Phase II, Chemotherapy, Gemcitabine refractory

Core tip: For gemcitabine (GEM)-refractory unresectable pancreatic cancer (PC), there are limited options of second-line chemotherapy regimen. To find new treatment option for GEM-refractory unresectable PC, we conducted a multicenter phase II trial, which evaluated the efficacy and safety of uniquely modified FOLFIRINOX with reduced irinotecan and oxaliplatin. In our results, FOLFIRINOX with reduced irinotecan and oxaliplatin showed acceptable toxicity and promising efficacy. With careful observation of treatment-related hematologic toxicities, this chemotherapy regimen is a promising option for patients with GEM-refractory PC after first-line treatment failure.



INTRODUCTION

Pancreatic cancer (PC) is among the major causes of cancer-related deaths in the United States[1]. In South Korea, PC is the eighth highest-diagnosed cancer and the fifth most common cause of cancer-related death[2]. Metastatic pancreatic cancer (MPC) accounts for 60% of all cases; the median survival of patients with MPC is 3-6 mo. Systemic chemotherapy is pivotal for treating such patients; however, effective regimens remain limited. Recently, two first-line combination regimens-FOLFIRINOX [a combination of oxaliplatin, folinic acid (FA), irinotecan, and 5-fluorouracil (5-FU)] and nanoparticle albumin-bound (nab) paclitaxel in combination with GEM-prolonged survival compared to gemcitabine (GEM) monotherapy and became standard treatments[3,4]. However, the median progression-free survival (PFS) of these new treatment regimens was only 6.4 and 5.5 mo, respectively.

Proper second-line treatment can improve survival of patients with locally advanced pancreatic cancer (LAPC) or MPC who fail first-line treatment. Although some previous phase III trials showed survival improvement with their study regimens, the standard treatment remains unclear[5-7].

Patients who received first-line FOLFIRINOX or nab-paclitaxel plus GEM may benefit from a novel second-line treatment, although toxicity should also be considered. FOLFIRINOX, a standard first-line treatment, has been proposed as a second-line treatment for patients with good performance status who failed GEM-based chemotherapy. However, as the condition of many patients deteriorates after first-line chemotherapy, second-line therapy requires administration at attenuated doses and/or schedules, even in patients who maintain a preserved comorbidity profile.

Standard FOLFIRINOX has limited broad use as a second-line therapy because of toxicity; it includes irinotecan (180 mg/m2), oxaliplatin (85 mg/m2), 5-FU (400 mg/m2 administered as a bolus followed by 2400 mg/m2 administered as a 46-h continuous infusion), and leucovorin (400 mg/m2) every 2 wk[3]. Several FOLFIRINOX trials have investigated reducing dosages while maintaining efficacy[8-10]. However, studies focused on the efficacy and safety of a modified dose of FOLFIRINOX for patients with GEM-refractory PC are still rare. Therefore, we conducted a prospective, multicenter, one-arm, open-label, phase II trial using a modified FOLFIRINOX with reduced oxaliplatin and irinotecan (RIO) to minimize adverse events (AEs). Our aim was to evaluate the efficacy and safety of FOLFIRINOX with (RIO) in patients with unresectable PC who had earlier been treated with a GEM-based regimen until disease progression.

MATERIALS AND METHODS
Study population

This study was a prospective, multicenter, one-arm, open-label, phase II trial and conducted in eight Korean university hospitals. The inclusion criteria for this study were patients between 19 and 75 years old; Eastern Cooperative Oncology Group performance status ≤ 2; cytologically or histologically proven unresectable pancreatic adenocarcinoma that progressed after first-line GEM-based chemotherapy; adequate bone marrow function (white blood cell count ≥ 3500/μL, absolute neutrophil count ≥ 1500/μL, and platelet count ≥ 100000/μL); adequate hepatic function (total bilirubin ≤ 1.5 × the upper limit of the normal range [ULN], serum aspartate and alanine transaminase ≤ 3 × ULN, and alkaline phosphatases ≤ 3 × ULN or ≤ 5 × ULN in case of liver metastasis); adequate renal function (serum creatinine ≤ 1.5 mg/dL); and adequate cardiopulmonary function. Patients were excluded if they had a concurrent malignancy other than PC; a serious, uncontrollable medical condition; or a psychiatric disorder. The study was performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki. Written, informed consent was obtained from each participant after potential treatment complications had been fully explained. The institutional review boards at all participating institutions approved this study. This trial is registered with ClinicalTrials.gov, number NCT02440958.

Study endpoints

The primary endpoints were objective response rate [ORR; complete remission (CR) + partial response (PR)] and disease control rate (DCR; CR + PR + stable disease (SD)). The secondary endpoints were PFS, overall survival (OS), changes in quality of life (QoL), and safety. OS was calculated from the date of enrollment until death from any cause. In the absence of an event, data were censored on the last day of survival confirmation. PFS was calculated from the initiation of treatment until either imaging-confirmed disease progression or death from any cause; in their absence, data for such patients were censored on the day of their last imaging procedure.

Determination of study drug dose

In the phase I study of FOLFIRINOX, febrile neutropenia, prolonged (≥ 7 d) severe neutropenia, and severe non-hematologic AEs were not reported at a dose level of 120 mg/m2 irinotecan and 60 mg/m2 oxaliplatin[11]. Based on these data, we set the study drug regimen – FOLFIRINOX with RIO – to 120 mg/m2 irinotecan (66.6% of standard dose) and 60 mg/m2 oxaliplatin (70.5% of standard dose) with standard dose of bolus and infusional 5-FU.

Treatment protocol and dose adjustments

Oxaliplatin was first administered as a 2-h intravenous infusion (IVF); 1 h later, irinotecan was administered as a 90-min IVF. Leucovorin (400 mg/m²) was administered as a 90-min IVF immediately after oxaliplatin and irinotecan. The 5-FU dose was a 400 mg/m2 bolus followed by 2400 mg/m2 administered over 46 h of IVF. Each cycle of FOLFIRINOX with RIO was administered every 2 wk and repeated until either evidence of progressive disease (PD), significant clinical deterioration, or withdrawal of patient consent. All patients routinely received palonosetron 30 min before the initiation of chemotherapy as a prophylactic anti-emetic agent. Atropine was administered to patients with irinotecan-caused cholinergic reactions. High-dose loperamide was administered for delayed diarrhea, followed by prophylactic oral fluoroquinolones if diarrhea continued for over 48 h. Granulocyte colony-stimulating factor (G-CSF) was administered for severe neutropenia. AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03) before each cycle. In the event of predefined hematologic or non-hematologic AEs, protocol-specified treatment modifications or delays were performed to minimize additional treatment-related AEs.

For each patient, the study lasted up to 15 cycles with drugs donated by the pharmaceutical manufacturers; patients who completed these cycles without PD were admitted to a post-study phase and continued chemotherapy according to the study protocol at their own expense. Treatment was discontinued if PD or intolerable toxicity was observed, if the patient withdrew from the study, or at the physician’s discretion.

Data assessment

Pre-treatment evaluations included taking a complete medical history, physical examination, and laboratory tests. Evaluations were performed within 2 wk before, and every 2 wk during treatment. Tumor responses were assessed according to the Response Evaluation Criteria in Solid Tumors (version 1.1) based on high-resolution computed tomography scans every 8 wk. QoL was assessed every 8 wk using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)[12] and its supplement for patients with pancreatic cancer (QLQ-PAN26)[13]. Additionally, changes in body weight and pain scale were checked every 2 wk. The Korean version of the questionnaire, officially translated and distributed by EORTC, was used. All patients filled-out and submitted the questionnaire by themselves on the day of visit. QoL changes between baseline and the last visit were analyzed, considering that the participation period varied among patients. Scores of all QoL scales range from 0 to 100; a higher score indicates a better functional status or a worse symptom.

Statistical analysis

When this clinical trial was being designed, the previously reported ORR of second-line chemotherapy for unresectable PC with GEM failure ranged from 0% to 11.4%[5,14-17]. With this background, this trial was performed according to a Simon optimal two-stage design (P0 = 0.100, P1 = 0.250, alpha = 0.050, and beta = 0.200; P0 and P1 are the response proportions of a poor and good drug, respectively)[18,19]. In the first stage, accepting a type I error of 10% and a power of 80%, 46 patients were planned for enrollment. If three or fewer of the 22 enrolled patients demonstrated an objective response, we would terminate the experiment at that stage based on the regimen’s low efficacy. Otherwise, the regimen would be recommended for further testing and accrual would continue to 46 patients (assuming a 15% dropout rate).

All patients who received the study regimen at least once were included in the intention-to-treat (ITT) and toxicity analysis populations. All efficacy assessments were based on the ITT analyses. PFS and OS were estimated using Kaplan-Meier methods with 95% confidence interval (CIs). When comparing data (QoL questionnaire, weight, and pain scale) between baseline and last visit, the paired t-test was used for normally distributed data while the Wilcoxon signed rank test was used for non-normally distributed data. All statistical analyses were performed using IBM SPSS (version 23.0, IBM Corp., Armonk, NY, United States). A P-value < 0.05 was considered statistically significant.

RESULTS
Baseline characteristics of patients

Between August 2015 and May 2016, 48 patients were enrolled. The median age at the time of enrollment was 63.5 years [interquartile range (IQR), 57.5–69.0 years]. All patients had cytologically or histologically confirmed adenocarcinoma according to the inclusion criteria. Also, all patients had LAPC or MPC including 38 patients (79.2%) with accompanying distant metastasis (Table 1). Close to 80% of the patients received GEM plus erlotinib as their first-line GEM-based treatment. Because GEM plus nab-paclitaxel became available in January 2016 in Korea, only one patient was administered this regimen prior to the study.

Table 1 Baseline characteristics.
Characteristics of the patientsn = 48Percent
Age (yr)median (IQR)63.5 (57.5-69.0)
40-4948.3
50-591020.8
60-692552.1
70-79918.8
SexMale2347.9
Female2552.1
ECOG-PS02245.8
12450
224.2
Duration since diagnosis (mo)median (IQR)7.0 (3.0-12.0)
Location of pancreatic cancerHead1837.5
Body and tail1735.4
Recurrence after resection1327.1
Number of metastatic site01020.8
11837.5
21429.2
≥ 3612.5
Metastatic sites (> 5%)Liver2858.3
Peritoneum1633.3
Distant lymph node816.7
Lung612.5
Level of CA 19-9Normal1020.8
> ULN3879.2
Prior GEM CTxGEM monotherapy612.5
GEM + Erlotinib3879.2
GEM + Capecitabine24.2
GEM + Cisplatin12.1
GEM + Nab-paclitaxel12.1
Period of prior CTx (mo)median (IQR)4.1 (1.9-7.8)
Prior treatment other than CTxOperation1327.1
CCRT612.5
Treatment exposure

A flowchart of the 48 patients’ treatments is shown in Supplementary Figure 1; at the time of analysis, 38 of these patients had died while two patients remained on FOLFIRINOX with RIO. Treatment was discontinued prior to completing 15 cycles in 33 patients, including 14 who showed PD, 10 who had treatment delays for unresolved infections (n = 2) or grade 3/4 toxicities (n = 8), five who declined further treatment, two who died after treatment (one of septic shock and the other of unknown reasons at another location), one who had acute cerebral infarction, and one who showed radiologic CR. All patients combined received a total of 493 cycles of chemotherapy. The median follow-up time was 259 d (IQR, 103.3–427.8 d), and the median number of chemotherapy cycles per patient was 8.5 (IQR, 3.0–16.5), with a median treatment duration of 145 d (IQR, 30.5–286.3 d). The relative dose intensity (proportion of the administered accumulated dose relative to the planned accumulated dose) of bolus 5-FU, infusional 5-FU, combined bolus plus infusional 5-FU, irinotecan, and oxaliplatin was 93.60% ± 15.86%, 93.60% ± 15.86%, 93.60% ± 15.86%, 95.65% ± 8.16%, and 95.65% ± 8.16%, respectively.

Figure 1
Figure 1 Kaplan-Meier analysis of survival data. A: The estimated median progression-free survival was 5.8 mo (95%CI: 3.7-7.9); B: The estimated median overall survival was 9.0 mo (95%CI: 6.4-11.6).
Tumor responses and survival

Tumor responses and survival analysis are shown in Table 2. The ORR and DCR of all patients were 18.8% and 62.5%, respectively. The DCR was 80% in ten LAPC patients, but no CR or PR was reported. Among 38 MPC patients (79.2% of all patients), the ORR and DCR were 23.7% and 57.9%, respectively. A sixty-year-old female patient, who progressed to multiple liver metastasis after GEM monotherapy, achieved radiologic CR after 12 cycle of FOLFIRINOX with RIO. After twelfth cycle, the patient had not experienced disease recurrence on serial radiologic studies without chemotherapy for a year, until peritoneal seeding and liver metastasis were confirmed.

Table 2 Tumor responses and survivals (intention-to-treat population).
All (n = 48)LAPC (n = 10)MPC (n = 38)
Response, n (%)
CR1 (2.1)0 (0.0)1 (2.6)
PR8 (16.7)0 (0.0)8 (21.1)
SD21 (43.8)8 (80.0)13 (34.2)
PD7 (14.6)1 (10.0)6 (15.8)
Could not be evaluated11 (22.9)1 (10.0)10 (26.3)
ORR9 (18.8)0 (0.0)9 (23.7)
DCR30 (62.5)8 (80.0)22 (57.9)
Survival, mo (95%CI)
Median PFS5.8 (3.7-7.9)8.8 (6.0-11.6)5.4 (2.9-7.9)
Median OS (from 2nd-line CTx)9.0 (6.4-11.6)12.5 (4.9-20.1)8.4 (5.4-11.4)
Median OS (from 1st-line CTx)17.1 (10.6-23.6)19.1 (13.8-24.4)16.8 (8.8-24.8)

The median PFS was 5.8 mo (95%CI: 3.7–7.9 mo) and the median OS was 9.0 mo (95%CI: 6.4–11.6 mo) for all patients (Figure 1). The PFS rates at 6, 12, and 18 mo were 47.9%, 27.1%, and 6.3%, respectively, while the OS rates at 6, 12, and 18 mo were 60.4%, 37.5% and 10.4%, respectively. Eighteen patients (37.5%) survived more than 1 year. The estimated OS from the beginning of first-line treatment was 17.1 mo (95%CI: 10.6–23.6 mo). The median PFS and OS were respectively 5.4 and 8.4 mo for MPC patients, and 8.8 and 12.5 mo for LAPC patients. Analysis of changes in laboratory tests between before and after therapy showed that the median CA19-9 significantly decreased from 366.3 (1–16351) to 311.7 (2–16287) U/mL (P = 0.041).

Safety analysis

AEs that occurred in more than 5% of the 48 patients are listed in Table 3. Common AEs observed in more than 20% of patients were neutropenia (68.8%), fatigue (22.9%), nausea and vomiting (66.7%), diarrhea (35.4%), oral mucositis (31.3%), anorexia (20.8%), and fever (20.8%). Of a total of 511 AEs, 358 (70.1%) were considered related to therapy, and 163 (31.9%) were severe AEs (grade 3 or 4). The most common severe AE was neutropenia (64.6%), followed by febrile neutropenia and fatigue (16.7% for both). None of the patients experienced severe nausea/vomiting or constipation. One patient died of septic shock related to grade 4 neutropenia after treatment.

Table 3 Adverse events (≥ 5%).
N = 48n (%)Intensity according to the NCI-CTCAE v4.03
Grade 1Grade 2Grade 3Grade 4
Non-hematologic
Fatigue11 (22.9)3 (6.3)08 (16.7)-
Nausea and vomiting32 (66.7)17 (35.4)15 (31.3)00
Diarrhea17 (35.4)7 (14.6)9 (18.8)1 (2.1)0
Constipation8 (16.7)4 (8.3)4 (8.3)00
Oral mucositis15 (31.3)4 (8.3)10 (20.8)1 (2.1)0
Anorexia10 (20.8)9 (18.8)01 (2.1)0
Peripheral neuropathy7 (14.6)6 (12.5)01 (2.1)0
Biliary tract infection3 (6.3)003 (6.1)0
Fever10 (20.8)1 (2.1)9 (18.8)00
Hematologic
Neutropenia33 (68.8)02 (4.2)11 (22.9)20 (41.7)
Thrombocytopenia6 (12.5)01 (2.1)1 (2.1)4 (8.3)
Febrile neutropenia8 (16.7)--5 (10.4)3 (6.3)
Changes in QoL

The average body weight was 58.9 ± 9.81 kg at baseline and 59.0 ± 9.83 kg at the last visit. The average pain scale (Visual Analogue Scale) at baseline and the last visit were 2.12 ± 2.31 and 1.90 ± 2.15, respectively. There were no significant changes in body weight and pain scale (P = 0.93 and P = 0.71, respectively). QoL questionnaires were available for 31 patients. The global health status scores of the EORTC QLQ-C30 did not worsen after treatment (P = 0.548). In general, most functional scores were not significantly decreased except role and cognitive functioning (P = 0.044 and P = 0.015, respectively) (Supplementary Table 1). Among symptom scores, fatigue and dyspnea were significantly worse than those in the pre-treatment period (P = 0.021 and P = 0.038, respectively). Among separate QLQ-PAN26 questions, worsening of dry mouth was observed (P = 0.011). In patients who achieved disease control (n = 29), the global health status score did not worsen after treatment, but some individual items including cognitive function, fatigue, digestive symptoms, and dry mouth were significantly worsened. Only one item (future worries) was significantly improved (Supplementary Table 2). In patients who completed 15 cycles, constipation and pancreatic pain were significantly improved by the end of treatment; only digestive symptoms were aggravated (Supplementary Table 3).

DISCUSSION

FOLFIRINOX with RIO showed an acceptable toxicity profile and promising efficacy as a second-line treatment for GEM-refractory unresectable PC. Although severe neutropenia occurred in almost 65% of participants, other severe AEs, particularly non-hematologic AEs, were infrequently reported. Moreover, the global health status scores of the EORTC QLQ-C30 were not changed significantly after treatment.

Second-line chemotherapy may be considered for many patients[20]. At present, there is no recognized standard for patients with unresectable PC who experience PD after first-line chemotherapy, and PFS is consistently < 4 mo in patients receiving second-line chemotherapy. A meta-analysis showed that median OS was 6.0 mo with chemotherapy versus 2.8 mo with best supportive care[21]. Patients whose cancers progress after first-line therapy have difficulty undergoing second-line chemotherapy since they are often older, unwell, and at risk of rapid deterioration[22].

Only a few prospective trials have shown encouraging results with oxaliplatin plus 5-FU using various doses and schedules[5,6,14,17,23]. Two phase III trials produced conflicting results. The CONKO-003 trial comparing 5-FU plus FA (FF) and oxaliplatin plus FF (OFF) showed survival benefits of second-line OFF in patients with unresectable GEM-refractory PC[6]. In contrast, the PANCREOX trial evaluating the modified FOLFOX6 (mFOLFOX6) found no difference in PFS, while the OS of mFOLFOX6 was inferior to that of FF[24].

Research on irinotecan plus 5-FU as second-line chemotherapy for PC was also performed[15,25]. The NAPOLI-1 phase III trial comparing nanoliposomal irinotecan (nal-IRI) alone or combined with FF showed that the combination of nal-IRI and FF was more effective than FF alone, but caused more frequent severe AEs[7].

A recent comparative systematic review of four randomized trials evaluating oxaliplatin- or irinotecan-containing regimens as post-GEM therapies for patients with unresectable PC showed significant dissimilarity between them; therefore, it is unclear which regimen is best-suited for patients with unresectable PC previously treated with GEM[26]. Table 4 summarizes clinical trials of second-line treatment for GEM-pre-treated unresectable PC. Our results using second-line FOLFIRINOX with RIO showed results that were superior to those in most previous trials.

Table 4 Clinical trials of second-line treatment for gemcitabine pre-treated unresectable pancreatic cancer.
Author (yr)Type of studyRegimenPatients, nKPS ≥ 90 or ECOG ≤ 1, %MPC, %ORR, %DCR, %PFS/TTP, moOS, mo
Yoo et al[15] 2009IIModified FOLFOX30971007176.0 wk14.9 wk
Modified FOLFIRI.3311001000238.3 wk16.6 wk
Novarino et al[14] 2009IIOxaliplatin/5-FU/LV2373.969.6023.511.6 wk117.1 wk
Pelzer et al[5] 2011IIIBSC2352.269.60NANA2.3
Oxaliplatin/5-FU/LV (OFF)2347.873.90NANA4.8 (P = 0.008)
Chung et al[23] 2013IIFOLFOX444NA10011.440.99.9 wk131.1 wk
Oettle et al[6] 2014III5-FU/LV (FF)8447.688.1NANA23.3
Oxaliplatin/5-FU/LV (OFF)8453.988.2NANA2.9 (P = 0.019)5.9 (P = 0.01)
Zaanan et al[17] 2014Prospective cohortFOLFOX22744.4100036.41.74.3
Wang-Gillam et al[7] 2016III5-FU/LV119481001NA1.54.2
Nal-IRI/5-FU/LV1175910016NA3.1 (P < 0.001)6.1 (P = 0.01)
Nal-IRI151571006NA2.7 (P = 0.1)4.9 (P = 0.94)
Gill et al[24] 2016IIIModified FOLFOX65488.992.613.244.73.16.1
Infusional 5FU/LV5494.394.48.5 (P = 0.36)55.32.9 (P = 0.99)9.9 (P = 0.02)
Present studyIIFOLFIRINOX with RIO48 (MPC: 38)95.879.218.8 (MPC: 23.7)62.5 (MPC: 57.9)5.8 (MPC: 5.4)9 (MPC: 8.4)

Toxicities associated with standard FOLFIRINOX have prompted trials evaluating modifications of FOLFIRINOX[8-10]. These previous studies of FOLFIRINOX modifications suggested that upfront dose attenuations of standard FOLFIRINOX can improve tolerability without reducing efficacy. A recent phase II trial showed that the efficacy of first-line FOLFIRINOX with reduced doses of the 5-FU bolus and irinotecan was comparable to that of the standard regimen; furthermore, neutropenia, vomiting, and fatigue were significantly reduced[10]. However, only a few studies have evaluated FOLFIRINOX for patients with unresectable PC after failure of GEM-based chemotherapy; patients’ performance statuses are likely to deteriorate after first-line treatment; necessitating second-line dose reductions as in our study. A Japanese phase II trial used modified FOLFIRINOX reducing only irinotecan for 18 MPC patients[27]. Findings of that trial were consistent with our results except the PFS, which was longer in the present study (2.8 mo vs 5.8 mo).

FOLFIRINOX and nab-paclitaxel plus GEM are two of the most effective first-line treatments for MPC, but the appropriate sequence of administration is unclear. A previous study in France concluded that nab-paclitaxel plus GEM appears to be effective, with a manageable toxicity profile, after FOLFIRINOX failure in patients with MPC[28]. However, studies evaluating the reverse sequence of administration have not been performed to date. Only three studies have been performed evaluating second-line FOLFIRINOX following first-line GEM-based treatment (Table 5)[27,29,30]. To our knowledge, this study is the first prospective multicenter phase II trial, which evaluated the efficacy and safety of FOLFIRINOX in GEM-refractory PC using unique dose modification called “FOLFIRINOX with RIO”.

Table 5 Comparison with previous studies focused on FOLFIRINOX as a second-line therapy.
Study characteristicsPatients characteristicsTreatment outcomesGrade ≥ 3 AE (%)
Author (yr)TypeDose modificationPatients, nAge, median (range)ECOGCancer status (%)ORR, %DCR, %PFS, moOS, moNPFebrile NPFatigueNauseaDiarrhoea
Assaf et al[29] 2011RetroStandard2763 (45-83)1-3MPC (100)18.562.938.5563.7NA1111
Lee et al[30] 2013RetroStandard1857 (44-68)0-1MPC (88.9)27.855.62.88.438.911.1NA38.90
LAPC (11.1)
Kobayashi et al[27] 2017IIIrinotecan 56% or 67%1863 (46-68)0-1MPC (100)22.261.12.89.866.75.6NA00
Present studyIIIrinotecan 67%4864 (40-79)0-2MPC (79.2)All: 18.8All: 62.5All: 5.8All: 9.064.616.716.702.1
Oxaliplatin 71%LAPC (20.8)MPC: 23.7MPC: 57.9MPC: 5.4MPC: 8.4
LAPC: 0.0LAPC: 80.0LAPC: 8.8LAPC: 12.5

In our study, the relatively higher incidences of severe neutropenia may be related to the patients’ deteriorated physical status after first-line chemotherapy and the lack of prophylactic G-CSF support. For non-hematologic AEs, no grade 3 or 4 vomiting was observed, unlike in the PRODIGE 4/ACCORD 11 trial[3]. This improved non-hematologic tolerability may be related to the routine administration of prophylactic palonosetron during every cycle of treatment. Peripheral neuropathy was also significantly reduced compared with the previous study, likely because of oxaliplatin dose reduction. In comparison with nal-IRI plus 5-FU regimen of the NAPOLI-1 trial, the preferred second-line therapy for MPC in current guidelines[31,32], most severe non-hematologic AEs of the present study occurred at lower rates (diarrhea, 13% vs 2.1%; vomiting, 11% vs 0%; anorexia, 4% vs 2.1%)[7]. However, the rate of severe neutropenia was much higher in the present study (27% vs 64.6%).

Considering QoL, some functional scales such as role and cognitive functioning were significantly reduced in our patients, and some symptom scales such as fatigue and dyspnea were significantly worsened. However, these changes were predictable given our patients’ ages and performance statuses. Global QoL indicators did not significantly deteriorate; moreover, the “physical functioning” QoL score (regarded as one of the strongest prognostic values[33]) did not significantly worsen throughout treatment.

This study had several limitations. First, it was a non-randomized, single arm trial with a relatively small sample size. A prospective randomized trial including sufficient patients is warranted to provide the clinical recommendation about the treatment sequence for MPC. Second, we included patients with LAPC and MPC who were treated with various prior GEM-based regimens. This heterogeneity in patient population and first-line chemotherapy regimens needs to be improved in future research.

In conclusion, FOLFIRINOX with RIO showed encouraging results in terms of efficacy, with an acceptable safety profile. In addition to nal-IRI plus 5-FU regimen, FOLFIRINOX with RIO may be considered as a treatment option in patients with GEM-refractory unresectable PC. Because the condition of such patients can quickly deteriorate owing to rapid disease progression and treatment toxicity, this regimen may provide acceptable tolerability for patients in terms of patient QoL. However, the presence of hematologic toxicities should be carefully observed, nevertheless, and the routine use of G-CSF should be considered to minimize the risk of hematologic toxicities.

ARTICLE HIGHLIGHTS
Research background

Proper second-line treatment can improve survival of patients with unresectable pancreatic cancer (PC) who fail first-line treatment with gemcitabine (GEM)-based regimen. Although some previous phase III trials showed survival improvement with their study regimens, the standard second-line treatment remains unclear.

Research motivation

FOLFIRINOX, a standard first-line treatment for PC, has been proposed as a second-line treatment regimen; however, concerns about relatively high toxicity limited broad use of FOLFIRINOX as a second-line therapy.

Research objectives

We evaluated the efficacy and safety of modified dose of FOLFIRINOX as a second-line treatment for GEM-refractory unresectable PC.

Research methods

In this prospective, multicenter, one-arm, open-label, phase II trial, unresectable PC patients, who showed disease progression during GEM-based therapy were enrolled. All patients were administered FOLFIRINOX with reduced irinotecan and oxaliplatin (RIO; irinotecan 120 mg/m2 and oxaliplatin 60 mg/m2), which was set according to the previous phase I study of FOLFIRINOX, with the standard dose of 5-fluorouracil (5-FU). The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse events, and changes in quality of life (QoL) were evaluated.

Research results

A total of 48 patients were enrolled in eight Korean centers. The ORR and DCR were 18.8% and 62.5%, respectively, including one patient who showed complete remission. The median PFS was 5.8 mo [95% confidence interval (CI): 3.7-7.9] and median OS was 9.0 mo (95%CI: 6.4-11.6). Neutropenia (64.6%) was the most common grade 3-4 adverse event. Although 14.6% of patients experienced grade 3 fatigue, most non-hematologic AEs were under grade 2. In the QoL analysis, the global health status score before treatment was not different from the score at the last visit after treatment (45.43 ± 22.88 vs 48.66 ± 24.14, P = 0.548).

Research conclusions

FOLFIRINOX with RIO showed acceptable tolerability for patients in terms of patient QoL and may be considered as a treatment option in patients with GEM-refractory unresectable PC. However, the presence of hematologic toxicities should be carefully observed and the routine use of granulocyte colony-stimulating factor should be considered to minimize the risk of hematologic toxicities.

Research perspectives

Prospective study with larger population comparing the efficacy and safety between FOLFIRINOX with RIO and 5-FU plus leucovorin needs to be conducted.

Footnotes

CONSORT 2010 statement: The guidelines of the CONSORT 2010 Statement have been adopted in this article.

Manuscript source: Unsolicited manuscript

Specialty type: Oncology

Country of origin: South Korea

Peer-review report classification

Grade A (Excellent): 0

Grade B (Very good): B, B

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): 0

P- Reviewer: Chandrasinghe PC, Kuo SH, Yang F S- Editor: Ji FF L- Editor: A E- Editor: Song H

References
1.  Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67:7-30.  [PubMed]  [DOI]
2.  National Cancer Information Center (Republic of Korea). Cancer Statistics in Korea. Ministry of Health and Welfare, Korea Central Cancer Registry, National Cancer Center. 2017; Available from: https://ncc.re.kr/main.ncc?uri=english/sub04_Statistics.  [PubMed]  [DOI]
3.  Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-1825.  [PubMed]  [DOI]
4.  Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-1703.  [PubMed]  [DOI]
5.  Pelzer U, Schwaner I, Stieler J, Adler M, Seraphin J, Dörken B, Riess H, Oettle H. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer. 2011;47:1676-1681.  [PubMed]  [DOI]
6.  Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014;32:2423-2429.  [PubMed]  [DOI]
7.  Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387:545-557.  [PubMed]  [DOI]
8.  Mahaseth H, Brutcher E, Kauh J, Hawk N, Kim S, Chen Z, Kooby DA, Maithel SK, Landry J, El-Rayes BF. Modified FOLFIRINOX regimen with improved safety and maintained efficacy in pancreatic adenocarcinoma. Pancreas. 2013;42:1311-1315.  [PubMed]  [DOI]
9.  Ghorani E, Wong HH, Hewitt C, Calder J, Corrie P, Basu B. Safety and Efficacy of Modified FOLFIRINOX for Advanced Pancreatic Adenocarcinoma: A UK Single-Centre Experience. Oncology. 2015;89:281-287.  [PubMed]  [DOI]
10.  Stein SM, James ES, Deng Y, Cong X, Kortmansky JS, Li J, Staugaard C, Indukala D, Boustani AM, Patel V. Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer. Br J Cancer. 2016;114:737-743.  [PubMed]  [DOI]
11.  Ychou M, Conroy T, Seitz JF, Gourgou S, Hua A, Mery Mignard D, Kramar A. An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/5-fluorouracil every 2 weeks in patients with advanced solid tumors. Ann Oncol. 2003;14:481-489.  [PubMed]  [DOI]
12.  Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC. 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.  [PubMed]  [DOI]
13.  Fitzsimmons D, Johnson CD, George S, Payne S, Sandberg AA, Bassi C, Beger HG, Birk D, Büchler MW, Dervenis C. Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study Group on Quality of Life. Eur J Cancer. 1999;35:939-941.  [PubMed]  [DOI]
14.  Novarino A, Satolli MA, Chiappino I, Giacobino A, Bellone G, Rahimi F, Milanesi E, Bertetto O, Ciuffreda L. Oxaliplatin, 5-fluorouracil, and leucovorin as second-line treatment for advanced pancreatic cancer. Am J Clin Oncol. 2009;32:44-48.  [PubMed]  [DOI]
15.  Yoo C, Hwang JY, Kim JE, Kim TW, Lee JS, Park DH, Lee SS, Seo DW, Lee SK, Kim MH. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer. 2009;101:1658-1663.  [PubMed]  [DOI]
16.  Chung MJ, Park JY, Bang S, Park SW, Song SY. Phase II clinical trial of ex vivo-expanded cytokine-induced killer cells therapy in advanced pancreatic cancer. Cancer Immunol Immunother. 2014;63:939-946.  [PubMed]  [DOI]
17.  Zaanan A, Trouilloud I, Markoutsaki T, Gauthier M, Dupont-Gossart AC, Lecomte T, Aparicio T, Artru P, Thirot-Bidault A, Joubert F. FOLFOX as second-line chemotherapy in patients with pretreated metastatic pancreatic cancer from the FIRGEM study. BMC Cancer. 2014;14:441.  [PubMed]  [DOI]
18.  Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1-10.  [PubMed]  [DOI]
19.  Conroy T, Paillot B, François E, Bugat R, Jacob JH, Stein U, Nasca S, Metges JP, Rixe O, Michel P. Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer--a Groupe Tumeurs Digestives of the Federation Nationale des Centres de Lutte Contre le Cancer study. J Clin Oncol. 2005;23:1228-1236.  [PubMed]  [DOI]
20.  Nagrial AM, Chin VT, Sjoquist KM, Pajic M, Horvath LG, Biankin AV, Yip D. Second-line treatment in inoperable pancreatic adenocarcinoma: A systematic review and synthesis of all clinical trials. Crit Rev Oncol Hematol. 2015;96:483-497.  [PubMed]  [DOI]
21.  Rahma OE, Duffy A, Liewehr DJ, Steinberg SM, Greten TF. Second-line treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials. Ann Oncol. 2013;24:1972-1979.  [PubMed]  [DOI]
22.  Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605-1617.  [PubMed]  [DOI]
23.  Chung JW, Jang HW, Chung MJ, Park JY, Park SW, Chung JB, Song SY, Bang S. Folfox4 as a rescue chemotherapy for gemcitabine-refractory pancreatic cancer. Hepatogastroenterology. 2013;60:363-367.  [PubMed]  [DOI]
24.  Gill S, Ko YJ, Cripps C, Beaudoin A, Dhesy-Thind S, Zulfiqar M, Zalewski P, Do T, Cano P, Lam WYH. PANCREOX: A Randomized Phase III Study of Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy. J Clin Oncol. 2016;34:3914-3920.  [PubMed]  [DOI]
25.  Gebbia V, Maiello E, Giuliani F, Borsellino N, Arcara C, Colucci G. Irinotecan plus bolus/infusional 5-Fluorouracil and leucovorin in patients with pretreated advanced pancreatic carcinoma: a multicenter experience of the Gruppo Oncologico Italia Meridionale. Am J Clin Oncol. 2010;33:461-464.  [PubMed]  [DOI]
26.  Vogel A, Ciardiello F, Hubner RA, Blanc JF, Carrato A, Yang Y, Patel DA, Ektare V, de Jong FA, Gill S. Post-gemcitabine therapy for patients with advanced pancreatic cancer - A comparative review of randomized trials evaluating oxaliplatin- and/or irinotecan-containing regimens. Cancer Treat Rev. 2016;50:142-147.  [PubMed]  [DOI]
27.  Kobayashi N, Shimamura T, Tokuhisa M, Goto A, Endo I, Ichikawa Y. Effect of FOLFIRINOX as second-line chemotherapy for metastatic pancreatic cancer after gemcitabine-based chemotherapy failure. Medicine (Baltimore). 2017;96:e6769.  [PubMed]  [DOI]
28.  Portal A, Pernot S, Tougeron D, Arbaud C, Bidault AT, de la Fouchardière C, Hammel P, Lecomte T, Dréanic J, Coriat R. Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort. Br J Cancer. 2015;113:989-995.  [PubMed]  [DOI]
29.  Assaf E, Verlinde-Carvalho M, Delbaldo C, Grenier J, Sellam Z, Pouessel D, Bouaita L, Baumgaertner I, Sobhani I, Tayar C. 5-fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma. Oncology. 2011;80:301-306.  [PubMed]  [DOI]
30.  Lee MG, Lee SH, Lee SJ, Lee YS, Hwang JH, Ryu JK, Kim YT, Kim DU, Woo SM. 5-Fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) as second-line chemotherapy in patients with advanced pancreatic cancer who have progressed on gemcitabine-based therapy. Chemotherapy. 2013;59:273-279.  [PubMed]  [DOI]
31.  Sohal DP, Mangu PB, Khorana AA, Shah MA, Philip PA, O’Reilly EM, Uronis HE, Ramanathan RK, Crane CH, Engebretson A. Metastatic Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34:2784-2796.  [PubMed]  [DOI]
32.  Ducreux M, Cuhna AS, Caramella C, Hollebecque A, Burtin P, Goéré D, Seufferlein T, Haustermans K, Van Laethem JL, Conroy T. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v56-v68.  [PubMed]  [DOI]
33.  Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Boige V. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013;31:23-29.  [PubMed]  [DOI]