Next Article in Journal
Medullary Thyroid Carcinoma Mutational Spectrum Update and Signaling-Type Inference by Transcriptional Profiles: Literature Meta-Analysis and Study of Tumor Samples
Next Article in Special Issue
Comparison of the New Neo-Glasgow Prognostic Score Based on the Albumin-Bilirubin Grade with Currently Used Nutritional Indices for Prognostic Prediction following Surgical Resection of Hepatocellular Carcinoma: A Multicenter Retrospective Study in Japan
Previous Article in Journal
Analysis of Molecular Biomarkers in Resected Early-Stage Non-Small Cells Lung Cancer: A Narrative Review
Previous Article in Special Issue
Targeted Therapies for Perihilar Cholangiocarcinoma
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 14
Issue 8
10.3390/cancers14081950
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Modified FOLFIRINOX as a Second-Line Treatment for Patients with Gemcitabine-Failed Advanced Biliary Tract Cancer: A Prospective Multicenter Phase II Study

by
Yong-Pyo Lee
1,†,
Sung Yong Oh
2,†,
Kwang Min Kim
3,
Se-Il Go
4,
Jung Hoon Kim
5,
Seok Jae Huh
6,
Jung Hun Kang
7,* and
Jun Ho Ji
1,*
1
Division of Hematology-Oncology, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Korea
2
Division of Hematology and Oncology, Department of Internal Medicine, Dong-A University Hospital, Dong-A University College of Medicine, Busan 49201, Korea
3
Division of Gastroenterology, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 51353, Korea
4
Division of Hematology/Oncology, Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon 51472, Korea
5
Division of Hematology/Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Jinju 52727, Korea
6
Department of Internal Medicine, Dong-A University College of Medicine, Busan 49201, Korea
7
Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine Gyeongsang National University, Jinju 52727, Korea
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2022, 14(8), 1950; https://doi.org/10.3390/cancers14081950
Submission received: 2 March 2022 / Revised: 4 April 2022 / Accepted: 10 April 2022 / Published: 13 April 2022
(This article belongs to the Collection Treatment of Hepatocellular Carcinoma and Cholangiocarcinoma)
Browse Figures
Review Reports Versions Notes

Abstract

:

Simple Summary

Biliary tract cancer is a malignant tumor of the biliary tract and gallbladder. Most patients are diagnosed at an advanced stage, and the basis of treatment is combination chemotherapy. However, the survival outcomes for biliary tract cancer, especially for patients who have failed frontline treatment, are poor. Accordingly, there have been various studies on effective subsequent treatments, and this study is one of those efforts. Through this study, we attempted to demonstrate the efficacy of enhanced chemotherapy in relapsed or refractory biliary tract cancer.

Abstract

Background: After the publication of the ABC-02 trial, gemcitabine and cisplatin combination therapy (GP) became the standard first-line treatment for advanced biliary tract cancer (BTC). Despite GP therapy, most patients suffer from disease progression. The ABC-06 trial recommended FOLFOX as a second-line treatment, but its efficacy was modest. In this phase II study, we looked at the efficacy and safety of a second-line modified dose of FOLFIRINOX (mFOLFIRINOX) for patients who had failed first-line gemcitabine-based treatment. Methods: From January 2020 to January 2021, 34 patients with advanced BTC who failed first-line gemcitabine-based chemotherapy were enrolled. We evaluated the clinical efficacy and safety outcomes of mFOLFIRINOX. Results: With a median follow-up duration of 13.4 months, the median progression-free survival and overall survival was 2.8 months (95% confidence interval (CI): 1.6–4.0 months) and 6.2 months (95% CI: 5.0–7.4 months), respectively. The objective response rate was 14.7% with no complete response. The disease control rate was 61.7%, with a disease control duration of 4.2 months. Due to the rapid progression of the disease, approximately half of all patients received less than three cycles of treatment. The most common type of adverse event (AEs) was hematopoietic AEs. The incidence of non-hematopoietic AEs was relatively low. Conclusions: The efficacy of mFOLFIRINOX as a second-line treatment in advanced BTC patients after the failure of gemcitabine-based first-line treatment was replicated, albeit with slightly shorter survival results compared to previous studies. Long-term administration of mFOLFIRINOX with toxicity management might offer a survival benefit.

1. Introduction

Biliary tract cancers (BTCs) are heterogeneous malignancies, including intrahepatic cholangiocarcinoma (IHCCC), extrahepatic cholangiocarcinoma (EHCCC), and gallbladder (GB) cancer. Because BTC is frequently asymptomatic in the early stages, is difficult to access for biopsy, and the diagnostic imaging criteria are unclear, most patients are diagnosed at an advanced stage [1]. The role of systemic chemotherapy has been actively studied in advanced BTC because the effect of local treatments is meager [2,3,4]. After the publication of the ABC-02 trial [5], the combination of gemcitabine and cisplatin (GP) became the most widely used first-line treatment for advanced BTC. Despite GP therapy, however, most patients’ disease progression continues, while some patients maintain their general health and can tolerate subsequent treatments [6,7]. As a result, there is a need for salvage treatments for these patients. Second-line chemotherapy for BTC has mainly been performed with drugs such as 5-fluorouracil (5-FU) or gemcitabine, but their efficacy was based on retrospective studies with small sample sizes, and even these results were not satisfactory [8,9]. According to the findings of the ABC-06 trial, FOLFOX therapy, which consists of 5-FU, leucovorin, and oxaliplatin, is now considered a standard second-line treatment for relapsed BTC [10]. However, as the survival benefit of FOLFOX is relatively modest, effective treatment options are still needed. Recently, many studies for immunotherapy and molecular targeted therapy have been introduced. Nonetheless, the role of immunotherapy in BTC is limited only to some patients with mismatch repair and microsatellite instability [11,12,13,14], and the prevalence of novel molecular targets, such as isocitrate dehydrogenase 1 (IDH1), fibroblast growth factor receptor 2 (FGFR2), human epidermal growth factor receptor 2 (HER2), and v-Raf murine sarcoma viral oncogene homolog B (BRAF), is approximately less than 20%, and heterogeneous by type of BTC [15,16,17,18,19]. As a result, many studies on the role of cytotoxic chemotherapy in BTC salvage treatment are still ongoing. FOLFIRINOX is an intensified cytotoxic chemotherapy used to treat pancreatic cancer that is adjacent to the biliary tract and has histological and molecular characteristics similar to BTC [20]. Accordingly, clinical studies using FOLFIRINOX as a first-line or salvage-line treatment were conducted in BTC [21,22,23,24,25]. In this study, we conducted a phase II study to assess the efficacy and safety of a modified dose of FOLFIRINOX therapy (mFOLFIRINOX) as a second-line treatment for Korean patients with BTC who had failed gemcitabine-based therapy.

2. Methods

2.1. Study Design and Treatment

This was a single-arm, multicenter, open-label prospective phase II study. Patients were treated with mFOLFIRINOX (oxaliplatin 65 mg/m2, irinotecan 135 mg/m2, and leucovorin 400 mg/m2, followed by continuous infusion of 1000 mg/m2/day of 5-FU for two consecutive days) every two weeks. The study treatment was intended to be administered for a minimum of three cycles and a maximum of twelve cycles, but it could be extended at the discretion of the investigator. In the case of disease progression, the occurrence of unacceptable toxicities, or withdrawal of consent, the study treatment was discontinued. In the case of grade 3/4 toxicities, treatment was postponed until the toxicities improved to grade 2 or lower, and when treatment was resumed, a 25% dose reduction was performed. Additional dose reduction was permitted if grade 3/4 toxicity persisted after the first dose adjustment. The study was terminated in patients who had delayed treatment for more than three weeks or who were considered to be unsuitable for further treatment. The granulocyte colony-stimulating factor (G-CSF) could be used in patients with febrile neutropenia or severe infection, but its prophylactic use was not permitted. Every three cycles of treatment, a response evaluation using computed tomography or magnetic resonance imaging was carried out following the Response Evaluation Criteria in Solid Tumors (RECIST) [26]. Toxicities were assessed at each treatment cycle according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 [27].

2.2. Eligibility

The main eligibility criteria were histologically confirmed adenocarcinoma of the biliary tract, which relapsed after the failure of gemcitabine-based chemotherapy. Other eligibility criteria were the following: between the ages of 19 and 75 years, Eastern Cooperative Oncology Group (ECOG) performance status 2 or lower, at least one measurable lesion based on RECIST criteria, and adequate organ function (absolute neutrophil count ≥1.5 × 109/L, platelets ≥100 × 109/L, bilirubin ≤1.5 × upper limit of normal (ULN), aspartate transaminase and/or alanine transaminase ≤3 × ULN, creatinine ≤1.5 mg/dL or creatinine clearance ≥50 mL/min, and ejection fraction ≥50% measured by echocardiography). The following were key exclusion criteria: BTC eligible for curative surgical treatment or radiation therapy, receiving chemotherapy or radiation therapy within two weeks or three weeks of registration, uncontrolled lesions in the central nervous system, severe cardiopulmonary comorbidity and/or active infection, pregnant or lactating women, and hypersensitivity reaction to the drugs. This study was approved by the institutional review board of each institution, and the study was registered with the Clinical Research Information Service of Korea (CRIS, KCT0004433). All patients signed written informed consent.

2.3. Quality of Life Measurement

The quality of life (QOL) was assessed with the use of a cancer-specific, 30-item score questionnaire, QLQ-C30-Version 3.0 [28], and a 21-item questionnaire, QLQ-BIL21 [29], which was developed by the European Organisation for Research and Treatment of Cancer (EORTC). The EORTC QOL group procedures were used to transform and analyze the questionnaire items and scales. As a baseline, patients completed the questionnaire one week before receiving their first dose of treatment, and then one week before beginning subsequent treatment every three cycles.

2.4. Statistical Analysis

The primary objective of this study was to evaluate the median progression-free survival (PFS) of mFOLFIRINOX. Secondary goals included estimating the median overall survival (OS) and assessing the objective response rate (ORR), disease control rate (DCR), and treatment safety profiles. PFS time was estimated as the time from enrollment in the study to the date of disease progression or death related to any cause. The OS time was calculated as the time from study enrollment to the date of death or the last follow-up date. ORR was defined as the proportion of patients who achieved a complete response (CR) or partial response (PR) as their best response to treatment, and DCR was defined as the proportion of patients with CR, PR, and stable disease. According to Simon, the study sample size was determined as a phase II [30], optimal two-stage study with PFS at six months as the primary endpoint. Published historical outcomes of PFS at 6 months for second-line treatment of BTC ranged from 17% to 40% [16,31,32]. Thus, this phase II study was designed to detect an increase in 6 months PFS from 10% to 30%. The alpha error was set to 0.05 and the power was set to 0.8. Then, we calculated the number of needed subjects under a hypothesis of interest in which mFOLFIRINOX PFS at six months was >30% (H1 = 30%) and a null hypothesis in which it reached a PFS at six months <10% (H0 = 10%). At least one responder among the first ten subjects was needed, and at the second stage, a responder was needed for 29 subjects. We decided to include at least 33 patients to account for nonassessable subjects. Proportions were determined using standard descriptive statistics, and medians for categorical variables were assessed using the Mann–Whitney U test, paired t-test, or Fisher’s exact test. The Kaplan–Meier method was used to evaluate PFS and OS. All data were analyzed using the Statistical Package for Social Sciences software, version 24.0 (IBM Corp., Armonk, NY, USA).

3. Results

3.1. Patient Characteristics

Between January 2020 and January 2021, we enrolled a total of 34 patients with BTC who failed gemcitabine-based first-line chemotherapy. Baseline characteristics at the time of registration are shown in Table 1. The median age across all patients was 65 years (range, 40–78). There were 13 patients with IHCCC, 13 with EHCCC, and 8 with GB cancers among the 34 patients. All patients received GP therapy as first-line chemotherapy. The median number of GP cycles was five (range, 1–33) and the median PFS was 4.3 months. In each group, seven patients received GP therapy for more than six months or less than three months, while half of the patients received GP therapy for more than three months but less than six months.

3.2. Clinical Outcomes of mFOLFIRINOX

With a median follow-up duration of 13.4 months, the median PFS and OS were 2.8 months (95% confidence interval (CI): 1.6–4.0 months) and 6.2 months (95% CI: 5.0–7.4 months), respectively (Figure 1A,B). The median number of treatment cycles was four (range, 1–22). The response to treatment was assessed in all 34 patients, including three who died before the first response evaluation (two patients died of infection, and one withdrew from the study due to hypersensitivity to oxaliplatin). Five patients achieved PR and sixteen patients obtained SD, while thirteen patients did not respond to treatment. The ORR and DCR were 14.7% and 61.7%, respectively. The median duration of disease control was 4.2 months. The largest changes in tumor volume from baseline are shown in Figure 2. Better clinical outcomes were observed in patients who achieved objective responses or at least obtained disease control (Figure S1A–D). Additionally, when patients were divided into three groups according to the number of mFOLFIRINOX administrations (that is, 3 or less, 3 to 12 or less, and more than 12), the patients who received a higher number of treatments had better survival outcomes (Figure S2A,B). There was no statistically significant difference in survival according to the type of BTC or the duration of first-line GP therapy (Figure S3A–D).

3.3. Safety Outcomes

The most common type of toxicity was hematopoietic adverse events (AEs). In particular, approximately one-third of patients experienced grade 3/4 neutropenia, of which more than 50% of patients had dose reduction in treatment (Table 2). In our study, 44% (n = 15) of patients received dose reductions, of which 40% (n = 6) experienced two dose reductions (50% reduction in total dose). The incidence of grade 3/4 non-hematopoietic AEs was low in comparison, resulting in an approximately 17% dose reduction in total patients. At the end of the follow-up, all patients had discontinued the study treatment, and most of the cases of mFOLFIRINOX discontinuation were due to disease progression (n = 25, 80.6%). During the study period, three deaths were reported, but all were caused by infections, and no deaths were caused by treatment.

3.4. Quality of Life

After measuring the baseline QOL before initiation of study treatment, the QOL scores at the time of maximal disease control were obtained from the patients who achieved disease control. Following that, QOL data were collected at the end of treatment to compare the changes in QOL scores over time. A total of 21 patients (61.7%) were included in the QOL analysis, with data collected at three time points (baseline, at the time of maximal disease control, and at the end of treatment) for 16 patients, excluding five patients who were unable to answer the questions due to the study’s unavoidable discontinuation. The number of patients who completed QOL measurements continued to decrease as the study progressed; however, subjective QOL improved with disease control in most patients (Table 3). Unfortunately, with disease progression, overall deterioration in QOL of the patients was observed.

4. Discussion

This is a prospective phase II study that evaluated the efficacy and safety of mFOLFIRINOX as a second-line treatment in Korean advanced BTC patients who failed gemcitabine-based treatment. The dose of mFOLFIRINOX used in our study was lower than that of the previous studies, and even that dose reduction occurred in 40% of total patients, but the ORR and DCR were not significantly different from previous studies (Table S1) [23,24]. Although survival outcomes were somewhat disappointing, it should be noted that half of the patients received less than three cycles of study treatment because disease progression was so rapid, which resulted in shorter PFS and OS. Survival analysis according to the number of mFOLFIRINOX administrations showed that patients who received more cycles of treatment had longer PFS and OS (Figure S2A). The incidence of dose reduction also increased with the increase in the number of treatments (p-value < 0.001), but it did not affect the survival outcomes in patients who received more than three cycles of treatment.
In our study, the most common type of AEs were hematopoietic toxicities, including neutropenia and anemia (Table 2). Grade 3/4 hematopoietic toxicities were frequently detected in the absence of a bolus dosage of 5-FU that was followed by myelosuppression. Hematopoietic toxicities resulted in dose reduction in the treatment in 20% of all patients, and also prolongation of treatment intervals. As a result, this needs to be controlled to some extent through adjuvant treatments, such as G-CSF or erythropoietin [33]. In a study on the effect of prophylactic pegylated G-CSF in front-line FOLFIRINOX for metastatic pancreatic cancer, researchers found that using pegylated G-CSF increased the cumulative relative dose intensity (cRDI), reduced neutropenia, and even improved survival rates [34]. Furthermore, considering the results of a study in which cRDI of FOLFIRINOX was one of the independent prognostic factors for survival [35], the prophylactic use of G-CSF was expected to contribute to stable administration of FOLFIRINOX.
Recently, with advances in the understanding of the molecular landscape of BTC, various studies have been conducted on precisional approaches, using targeted agents and immune checkpoint inhibitors. In particular, FGFR inhibitor [17] and IDH1 inhibitor [16] are in the spotlight, and a slew of clinical trials using a variety of actionable target molecules are currently underway. Despite the development of various novel agents for BTC, realistic problems such as a somewhat unsatisfying expression rate of molecular targets and cost burdens for novel agents are difficult obstacles. As a result, further research into the intensification of cytotoxic chemotherapy is required. FOLFIRINOX is a widely studied chemotherapy regimen for BTC, which stems from its usefulness in the treatment of pancreatic cancer [36,37,38]. Unlike pancreatic cancer, however, FOLFIRINOX had little efficacy in BTC, which was in line with a recently published phase II study comparing the efficacy of GP and mFOLFIRINOX [25]. Similarly, in this study, intensified chemotherapy elicited some tumor responses, but not survival benefits. Nevertheless, the results of the NIFTY trial [39] demonstrated that the combination of oxaliplatin and irinotecan with 5-FU still may be an attractive option as a salvage therapy for BTC. Thus, in order for FOLFIRINOX to be one of the most appealing options for advanced BTC treatment, an adequate therapeutic dose must be established, and patients who are predicted to benefit from treatment must be identified. Compared to the previous original regimen of FOLFIRINOX, the survival outcomes and response rate of mFOLFIRINOX were comparable and presented fewer AEs in pancreatic cancer treatment, leading to the use of a dose-attenuated FOLFIRINOX regimen in practice as well as clinical studies [40]. However, because FOLFIRINOX dosage modification is not standardized, several variants of the dose-adjusted treatment are used. As this is also the case with BTC, finding the optimal dose of FOLFIRINOX in BTC treatment should be studied in the future. Furthermore, the identification of prognostic and predictive factors aimed at administering FOLFIRINOX to appropriate patients is required. Several studies have revealed that levels of carbohydrate antigen 19-9 or the maximal standardized uptake value of 18F-fluorodeoxyglucose positron emission tomography are predictive variables for FOLFIRINOX therapy in pancreatic cancer treatment [41,42]. As a result, future studies on prognostic and predictive factors for FOLFIRINOX therapy in BTC are needed, and more attention is needed in selecting patients who will receive the maximum benefit from treatment.
There are several limitations in our study: (1) the sample size was not large enough to draw some exceptional conclusions, (2) we could not specify the characteristics of patients who experienced rapid disease progression, and (3) in the absence of molecular study, we were unable to identify predictive markers for a good response to mFOLFIRINOX therapy.

5. Conclusions

The efficacy of mFOLFIRINOX in advanced BTC as a second-line treatment after the failure of gemcitabine-based treatment was reproduced. In future research, it will be necessary to improve cRDI with effective drug delivery in addition to managing and preventing AEs following mFOLFIRINOX. Moreover, to select optimal patients for mFOLFIRINOX, it is important to find biological markers that can predict treatment responses.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers14081950/s1, Figure S1: Kaplan–Meier curves of progression-free survival (A) and overall survival (B) for achieving objective responses. Kaplan–Meier curves of progression-free survival (C) and overall survival (D) for obtaining disease control; Figure S2: Kaplan–Meier curves of progression-free survival (A) and overall survival (B) according to the number of mFOLFIRINOX administration; Figure S3: Kaplan–Meier curves of progression-free survival (A) and overall survival (B) according to the type of biliary tract cancer. Kaplan–Meier curves of progression-free survival (C) and overall survival (D) according to the duration of first-line gemcitabine/cisplatin; Table S1: Comparison of dose, response rate, and survival results according to studies.

Author Contributions

Conceptualization, J.H.K. (Jung Hun Kang) and J.H.J.; methodology, J.H.K. (Jung Hun Kang) and J.H.J.; software, Y.-P.L. and S.Y.O.; validation, J.H.K. (Jung Hun Kang) and J.H.J.; formal analysis, Y.-P.L., S.Y.O., K.M.K., S.-I.G., J.H.K. (Jung Hoon Kim), S.J.H., J.H.K. (Jung Hun Kang) and J.H.J.; investigation, Y.-P.L., S.Y.O., K.M.K., S.-I.G., J.H.K. (Jung Hoon Kim), S.J.H., J.H.K. (Jung Hun Kang) and J.H.J.; resources, Y.-P.L., S.Y.O., K.M.K., S.-I.G., J.H.K. (Jung Hoon Kim), S.J.H., J.H.K. (Jung Hun Kang) and J.H.J.; data curation, Y.-P.L., S.Y.O., K.M.K., S.-I.G., J.H.K. (Jung Hoon Kim), S.J.H., J.H.K. (Jung Hun Kang) and J.H.J.; writing—original draft preparation, Y.-P.L. and S.Y.O.; writing—review and editing, Y.-P.L. and S.Y.O.; visualization, Y.-P.L. and S.Y.O.; supervision, J.H.K. (Jung Hun Kang) and J.H.J.; project administration, J.H.J.; funding acquisition, S.Y.O. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by Dong-A University Research fund 2022.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Samsung Changwon Hospital (Protocol version 1.1 approved on 19 December 2019/Protocol version 2.0 approved on 14 April 2020/Protocol version 3.0 approved on 30 November 2021).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author.

Acknowledgments

Oxaliplatin was supported by Samyang Biopharmaceutical Co., Ltd. Irinotecan and Ondant (ondansetron) were supplied by Hanmi Pharmarceutical Co., Ltd.

Conflicts of Interest

The authors have declared no conflict of interest.

References

  1. Banales, J.M.; Marin, J.J.G.; Lamarca, A.; Rodrigues, P.M.; Khan, S.A.; Roberts, L.R.; Cardinale, V.; Carpino, G.; Andersen, J.B.; Braconi, C.; et al. Cholangiocarcinoma 2020: The next horizon in mechanisms and management. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 557–588. [Google Scholar] [CrossRef] [PubMed]
  2. Glimelius, B.; Hoffman, K.; Sjödén, P.O.; Jacobsson, G.; Sellström, H.; Enander, L.K.; Linné, T.; Svensson, C. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann. Oncol. 1996, 7, 593–600. [Google Scholar] [CrossRef] [PubMed]
  3. Gebbia, V.; Giuliani, F.; Maiello, E.; Colucci, G.; Verderame, F.; Borsellino, N.; Mauceri, G.; Caruso, M.; Tirrito, M.L.; Valdesi, M. Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: Results of a multicenter phase II study. J. Clin. Oncol. 2001, 19, 4089–4091. [Google Scholar] [CrossRef] [PubMed]
  4. Rao, S.; Cunningham, D.; Hawkins, R.E.; Hill, M.E.; Smith, D.; Daniel, F.; Ross, P.J.; Oates, J.; Norman, A.R. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br. J. Cancer 2005, 92, 1650–1654. [Google Scholar] [CrossRef] [Green Version]
  5. Valle, J.; Wasan, H.; Palmer, D.H.; Cunningham, D.; Anthoney, A.; Maraveyas, A.; Madhusudan, S.; Iveson, T.; Hughes, S.; Pereira, S.P.; et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 2010, 362, 1273–1281. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Walter, T.; Horgan, A.M.; McNamara, M.; McKeever, L.; Min, T.; Hedley, D.; Serra, S.; Krzyzanowska, M.K.; Chen, E.; Mackay, H.; et al. Feasibility and benefits of second-line chemotherapy in advanced biliary tract cancer: A large retrospective study. Eur. J. Cancer 2013, 49, 329–335. [Google Scholar] [CrossRef]
  7. Bridgewater, J.; Palmer, D.; Cunningham, D.; Iveson, T.; Gillmore, R.; Waters, J.; Harrison, M.; Wasan, H.; Corrie, P.; Valle, J. Outcome of second-line chemotherapy for biliary tract cancer. Eur. J. Cancer 2013, 49, 1511. [Google Scholar] [CrossRef]
  8. Lamarca, A.; Hubner, R.A.; David Ryder, W.; Valle, J.W. Second-line chemotherapy in advanced biliary cancer: A systematic review. Ann. Oncol. 2014, 25, 2328–2338. [Google Scholar] [CrossRef]
  9. Ying, J.; Chen, J. Combination versus mono-therapy as salvage treatment for advanced biliary tract cancer: A comprehensive meta-analysis of published data. Crit. Rev. Oncol. Hematol. 2019, 139, 134–142. [Google Scholar] [CrossRef]
  10. Lamarca, A.; Palmer, D.H.; Wasan, H.S.; Ross, P.J.; Ma, Y.T.; Arora, A.; Falk, S.; Gillmore, R.; Wadsley, J.; Patel, K.; et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): A phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021, 22, 690–701. [Google Scholar] [CrossRef]
  11. Frenel, J.S.; Le Tourneau, C.; O’Neil, B.; Ott, P.A.; Piha-Paul, S.A.; Gomez-Roca, C.; van Brummelen, E.M.J.; Rugo, H.S.; Thomas, S.; Saraf, S.; et al. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: Results from the phase Ib KEYNOTE-028 trial. J. Clin. Oncol. 2017, 35, 4035–4041. [Google Scholar] [CrossRef] [PubMed]
  12. Marabelle, A.; Le, D.T.; Ascierto, P.A.; Di Giacomo, A.M.; De Jesus-Acosta, A.; Delord, J.P.; Geva, R.; Gottfried, M.; Penel, N.; Hansen, A.R.; et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Results from the phase II KEYNOTE-158 study. J. Clin. Oncol. 2020, 38, 1–10. [Google Scholar] [CrossRef] [PubMed]
  13. Kim, R.D.; Chung, V.; Alese, O.B.; El-Rayes, B.F.; Li, D.; Al-Toubah, T.E.; Schell, M.J.; Zhou, J.M.; Mahipal, A.; Kim, B.H.; et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol. 2020, 6, 888–894. [Google Scholar] [CrossRef] [PubMed]
  14. Lamarca, A.; Barriuso, J.; McNamara, M.G.; Valle, J.W. Molecular targeted therapies: Ready for “prime time” in biliary tract cancer. J. Hepatol. 2020, 73, 170–185. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Yoo, C.; Shin, S.H.; Park, J.O.; Kim, K.P.; Jeong, J.H.; Ryoo, B.Y.; Lee, W.; Song, K.B.; Hwang, D.W.; Park, J.H.; et al. Current status and future perspectives of perioperative therapy for resectable biliary tract cancer: A multidisciplinary review. Cancers 2021, 13, 1647. [Google Scholar] [CrossRef]
  16. Abou-Alfa, G.K.; Macarulla, T.; Javle, M.M.; Kelley, R.K.; Lubner, S.J.; Adeva, J.; Cleary, J.M.; Catenacci, D.V.; Borad, M.J.; Bridgewater, J.; et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): A multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020, 21, 796–807. [Google Scholar] [CrossRef]
  17. Abou-Alfa, G.K.; Sahai, V.; Hollebecque, A.; Vaccaro, G.; Melisi, D.; Al-Rajabi, R.; Paulson, A.S.; Borad, M.J.; Gallinson, D.; Murphy, A.G.; et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: A multicentre, open-label, phase 2 study. Lancet Oncol. 2020, 21, 671–684. [Google Scholar] [CrossRef]
  18. Jeong, H.; Jeong, J.H.; Kim, K.P.; Lee, S.S.; Oh, D.W.; Park, D.H.; Song, T.J.; Park, Y.; Hong, S.M.; Ryoo, B.Y.; et al. Feasibility of HER2-targeted therapy in advanced biliary tract cancer: A prospective pilot study of trastuzumab biosimilar in combination with gemcitabine plus cisplatin. Cancers 2021, 13, 161. [Google Scholar] [CrossRef]
  19. Valle, J.W.; Lamarca, A.; Goyal, L.; Barriuso, J.; Zhu, A.X. New horizons for precision medicine in biliary tract cancers. Cancer Discov. 2017, 7, 943–962. [Google Scholar] [CrossRef] [Green Version]
  20. Schmuck, R.B.; de Carvalho-Fischer, C.V.; Neumann, C.; Pratschke, J.; Bahra, M. Distal bile duct carcinomas and pancreatic ductal adenocarcinomas: Postulating a common tumor entity. Cancer Med. 2016, 5, 88–99. [Google Scholar] [CrossRef]
  21. Rauthan, A.; Patil, P. Modified FOLFIRINOX regimen in advanced biliary tract adenocarcinoma. J. Clin. Oncol. 2017, 35, 484. [Google Scholar] [CrossRef]
  22. Ulusakarya, A.; Karaboué, A.; Ciacio, O.; Pittau, G.; Haydar, M.; Biondani, P.; Gumus, Y.; Chebib, A.; Almohamad, W.; Innominato, P.F. A retrospective study of patient-tailored FOLFIRINOX as a first-line chemotherapy for patients with advanced biliary tract cancer. BMC Cancer 2020, 20, 515. [Google Scholar] [CrossRef] [PubMed]
  23. Belkouz, A.; de Vos-Geelen, J.; Mathôt, R.A.A.; Eskens, F.A.L.M.; van Gulik, T.M.; van Oijen, M.G.H.; Punt, C.J.A.; Wilmink, J.W.; Klümpen, H.-J. Efficacy and safety of FOLFIRINOX as salvage treatment in advanced biliary tract cancer: An open-label, single arm, phase 2 trial. Br. J. Cancer 2020, 122, 634–639. [Google Scholar] [CrossRef] [PubMed]
  24. Ye, L.-F.; Ren, C.; Bai, L.; Liang, J.-Y.; Hu, M.-T.; Yang, H.; Wang, Z.-Q.; Wang, F.-H.; Xu, R.-H.; Li, Y.-H.; et al. Efficacy and safety of modified FOLFIRINOX as salvage therapy for patients with refractory advanced biliary tract cancer: A retrospective study. Investig. New Drugs 2021, 39, 836–845. [Google Scholar] [CrossRef]
  25. Phelip, J.m.; Desrame, J.; Edeline, J.; Barbier, E.; Terrebonne, E.; Michel, P.; Perrier, H.; Dahan, L.; Bourgeois, V.; Akouz, F.K.; et al. Modified FOLFIRINOX versus CISGEM chemotherapy for patients with advanced biliary tract cancer (PRODIGE 38 AMEBICA): A randomized phase II study. J. Clin. Oncol. 2022, 40, 262–271. [Google Scholar] [CrossRef] [PubMed]
  26. Schwartz, L.H.; Litière, S.; de Vries, E.; Ford, R.; Gwyther, S.; Mandrekar, S.; Shankar, L.; Bogaerts, J.; Chen, A.; Dancey, J.; et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur. J. Cancer 2016, 62, 132–137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. Washington, DC, USA. Available online: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf (accessed on 26 February 2019).
  28. Aaronson, N.K.; Ahmedzai, S.; Bergman, B.; Bullinger, M.; Cull, A.; Duez, N.J.; Filiberti, A.; Flechtner, H.; Fleishman, S.B.; de Haes, J.C.; et al. The European Organization for research and treatment of cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J. Natl. Cancer Instig. 1993, 85, 365–376. [Google Scholar] [CrossRef] [PubMed]
  29. Kaupp-Roberts, S.D.; Yadegarfar, G.; Friend, E.; O’Donnell, C.M.; Valle, J.W.; Byrne, C.; Bahar, I.; Finch-Jones, M.; Gillmore, R.; Johnson, C.D.; et al. Validation of the EORTC QLQ-BIL21 questionnaire for measuring quality of life in patients with cholangiocarcinoma and cancer of the gallbladder. Br. J. Cancer 2016, 115, 1032–1038. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Simon, R. Optimal two-stage designs for phase II clinical trials. Control. Clin. Trials 1989, 10, 1–10. [Google Scholar] [CrossRef] [Green Version]
  31. Philip, P.A.; Mahoney, M.R.; Allmer, C.; Thomas, J.; Pitot, H.C.; Kim, G.; Donehower, R.C.; Fitch, T.; Picus, J.; Erlichman, C. Phase II study of erlotinib in patients with advanced biliary cancer. J. Clin. Oncol. 2006, 24, 3069–3074. [Google Scholar] [CrossRef]
  32. Demols, A.; Borbath, I.; Van den Eynde, M.; Houbiers, G.; Peeters, M.; Marechal, R.; Delaunoit, T.; Goemine, J.C.; Laurent, S.; Holbrechts, S.; et al. Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial. Ann. Oncol. 2020, 31, 1169–1177. [Google Scholar] [CrossRef] [PubMed]
  33. Del Mastro, L.; Venturini, M.; Lionetto, R.; Garrone, O.; Melioli, G.; Pasquetti, W.; Sertoli, M.R.; Bertelli, G.; Canavese, G.; Costantini, M.; et al. Randomized phase III trial evaluating the role of erythropoietin in the prevention of chemotherapy-induced anemia. J. Clin. Oncol. 1997, 15, 2715–2721. [Google Scholar] [CrossRef] [PubMed]
  34. Jung, J.H.; Shin, D.W.; Kim, J.; Lee, J.C.; Hwang, J.H. Primary granulocyte colony-stimulating factor prophylaxis in metastatic pancreatic cancer patients treated with FOLFIRINOX as the first-line treatment. Cancers 2020, 12, 3137. [Google Scholar] [CrossRef] [PubMed]
  35. Lee, J.-C.; Kim, J.W.; Ahn, S.; Kim, H.W.; Lee, J.; Kim, Y.H.; Paik, K.-H.; Kim, J.; Hwang, J.-H. Optimal dose reduction of FOLFIRINOX for preserving tumour response in advanced pancreatic cancer: Using cumulative relative dose intensity. Eur. J. Cancer 2017, 76, 125–133. [Google Scholar] [CrossRef]
  36. Conroy, T.; Desseigne, F.; Ychou, M.; Bouché, O.; Guimbaud, R.; Bécouarn, Y.; Adenis, A.; Raoul, J.-L.; Gourgou-Bourgade, S.; de la Fouchardière, C.; et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 2011, 364, 1817–1825. [Google Scholar] [CrossRef] [Green Version]
  37. Conroy, T.; Hammel, P.; Hebbar, M.; Ben Abdelghani, M.; Wei, A.C.; Raoul, J.-L.; Choné, L.; Francois, E.; Artru, P.; Biagi, J.J.; et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N. Engl. J. Med. 2018, 379, 2395–2406. [Google Scholar] [CrossRef]
  38. Go, S.-I.; Lee, S.-C.; Bae, W.K.; Zang, D.Y.; Lee, H.W.; Jang, J.S.; Ji, J.H.; Kim, J.H.; Park, S.; Sym, S.J.; et al. Modified FOLFIRINOX versus S-1 as second-line chemotherapy in patients with gemcitabine-failed metastatic pancreatic cancer: A randomized phase III trial (MPACA-3). J. Clin. Oncol. 2021, 39, 4119. [Google Scholar] [CrossRef]
  39. Yoo, C.; Kim, K.-P.; Kim, I.; Kang, M.J.; Cheon, J.; Kang, B.W.; Ryu, H.; Jeong, J.H.; Lee, J.S.; Kim, K.W.; et al. Liposomal irinotecan (nal-IRI) in combination with fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic biliary tract cancer (BTC) after progression on gemcitabine plus cisplatin (GemCis): Multicenter comparative randomized phase 2b study (NIFTY). J. Clin. Oncol. 2021, 39, 4006. [Google Scholar] [CrossRef]
  40. Tong, H.; Fan, Z.; Liu, B.; Lu, T. The benefits of modified FOLFIRINOX for advanced pancreatic cancer and its induced adverse events: A systematic review and meta-analysis. Sci. Rep. 2018, 8, 8666. [Google Scholar] [CrossRef] [Green Version]
  41. Lambert, A.; Jarlier, M.; Gourgou Bourgade, S.; Conroy, T. Response to FOLFIRINOX by gender in patients with metastatic pancreatic cancer: Results from the PRODIGE 4/ ACCORD 11 randomized trial. PLoS ONE 2017, 12, e0183288. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Choi, Y.H.; Lee, S.H.; You, M.S.; Shin, B.S.; Paik, W.H.; Ryu, J.K.; Kim, Y.T.; Kwon, W.; Jang, J.Y.; Kim, S.W. Prognostic factors for patients with borderline resectable or locally advanced pancreatic cancer receiving neoadjuvant FOLFIRINOX. Gut Liver 2021, 15, 315–323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Cancers 14 01950 g001 550
Figure 1. Kaplan–Meier curves for progression-free survival (A) and overall survival (B).
Figure 1. Kaplan–Meier curves for progression-free survival (A) and overall survival (B).
Cancers 14 01950 g001
Cancers 14 01950 g002 550
Figure 2. Waterfall plot of modified FOLFIRINOX according to the best response.
Figure 2. Waterfall plot of modified FOLFIRINOX according to the best response.
Cancers 14 01950 g002
Table
Table 1. Baseline demographics and disease characteristics at the time of enrollment (n = 34).
Table 1. Baseline demographics and disease characteristics at the time of enrollment (n = 34).
Characteristicsn (%)
Age, year
Median, range65 (40–78)
Sex
Male28 (82.3%)
Female6 (17.6%)
ECOG performance status
08 (23.5%)
126 (76.4%)
20 (0.0%)
Primary tumor site
Intrahepatic bile duct13 (38.2%)
Extrahepatic bile duct13 (38.2%)
Gallbladder8 (23.5%)
Differentiation
Well-differentiated6 (17.6%)
Moderate-differentiated11 (32.3%)
Poorly differentiated6 (17.6%)
Unknown11 (32.3%)
Baseline tumor markers according to the primary site
Intrahepatic bile duct CEA (ng/mL), mean ± SD83.2 ± 254.0
CA 19-9 (U/mL), mean ± SD2041.0 ± 3541.8
Extrahepatic bile ductCEA (ng/mL), mean ± SD92.1 ± 270.1
CA 19-9 (U/mL), mean ± SD2183.7 ± 3713.9
GallbladderCEA (ng/mL), mean ± SD50.8 ± 151.5
CA 19-9 (U/mL), mean ± SD1686.0 ± 3269.8
Type of first-line chemotherapy
Gemcitabine plus Cisplatin34 (100.0%)
Median number of first-line chemotherapy, range5 (1–33)
Duration of first-line chemotherapy
<3 months7 (20.5%)
3 months ≤ 6 months18 (52.9%)
6 months ≤7 (20.5%)
Unknown2 (5.8%)
ECOG, Eastern Cooperative Oncology Group; CEA, Carcino Embryonic Antigen; CA 19-9, Carbohydrate antigen 19-9.
Table
Table 2. Adverse events of mFLOFIRINOX treatment.
Table 2. Adverse events of mFLOFIRINOX treatment.
Number of Patients (%)
Hematopoietic Adverse EventsAll gradesGrade 1Grade 2Grade 3–4
Neutropenia23 (67.6)8 (23.5)4 (11.7)11 (32.3)
Anemia28 (82.3)8 (23.5)11 (32.3)9 (26.4)
Thrombocytopenia17 (50.0)11 (32.3)1 (2.9)5 (14.7)
Non-hematopoietic adverse eventsAll gradesGrade 1Grade 2Grade 3–4
Febrile neutropenia3 (8.8)0 (0.0)0 (0.0)3 (8.8)
Liver enzyme elevation8 (23.5)5 (14.7)3 (8.8)0 (0.0)
Azotemia4 (11.7)4 (11.7)0 (0.0)0 (0.0)
Emesis11 (32.3)8 (23.5)3 (8.8)0 (0.0)
Anorexia6 (17.6)3 (8.8)2 (5.8)1 (2.9)
Diarrhea8 (23.5)5 (14.7)2 (5.8)1 (2.9)
Stomatitis6 (17.6)3 (8.8)2 (5.8)1 (2.9)
Sensory neuropathy8 (23.5)4 (11.7)2 (5.8)2 (5.8)
mFOLFIRINOX, modified FOLFIRINOX.
Table
Table 3. Changes in the quality of life of the patients, presented as absolute values.
Table 3. Changes in the quality of life of the patients, presented as absolute values.
ItemsBaselineBest ResponseProgression
Mean ± SDMean ± SDpMean ± SDp
Physical function9.52 ± 3.788.24 ± 3.630.00811.19 ± 3.750.012
Role function4.14 ± 1.903.71 ± 1.820.1174.81 ± 2.040.035
Emotional function7.14 ± 1.606.29 ± 1.620.0157.88 ± 2.850.260
Cognitive function2.95 ± 0.922.62 ± 0.800.0953.56 ± 1.310.053
Social function3.24 ± 1.093.24 ± 1.090.8674.13 ± 1.670.016
Symptom scale21.95 ± 6.4119.67 ± 4.680.03124.06 ± 6.290.013
Financial scale1.67 ± 0.581.48 ± 0.600.1571.75 ± 0.580.480
Global health status10.67 ± 8.408.95 ± 1.400.4709.06 ± 2.050.521
Biliary symptom36.00 ± 6.2833.00 ± 5.040.13438.94 ± 6.800.046
SD, standard deviation.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Lee, Y.-P.; Oh, S.Y.; Kim, K.M.; Go, S.-I.; Kim, J.H.; Huh, S.J.; Kang, J.H.; Ji, J.H. Modified FOLFIRINOX as a Second-Line Treatment for Patients with Gemcitabine-Failed Advanced Biliary Tract Cancer: A Prospective Multicenter Phase II Study. Cancers 2022, 14, 1950. https://doi.org/10.3390/cancers14081950

AMA Style

Lee Y-P, Oh SY, Kim KM, Go S-I, Kim JH, Huh SJ, Kang JH, Ji JH. Modified FOLFIRINOX as a Second-Line Treatment for Patients with Gemcitabine-Failed Advanced Biliary Tract Cancer: A Prospective Multicenter Phase II Study. Cancers. 2022; 14(8):1950. https://doi.org/10.3390/cancers14081950

Chicago/Turabian Style

Lee, Yong-Pyo, Sung Yong Oh, Kwang Min Kim, Se-Il Go, Jung Hoon Kim, Seok Jae Huh, Jung Hun Kang, and Jun Ho Ji. 2022. "Modified FOLFIRINOX as a Second-Line Treatment for Patients with Gemcitabine-Failed Advanced Biliary Tract Cancer: A Prospective Multicenter Phase II Study" Cancers 14, no. 8: 1950. https://doi.org/10.3390/cancers14081950

APA Style

Lee, Y. -P., Oh, S. Y., Kim, K. M., Go, S. -I., Kim, J. H., Huh, S. J., Kang, J. H., & Ji, J. H. (2022). Modified FOLFIRINOX as a Second-Line Treatment for Patients with Gemcitabine-Failed Advanced Biliary Tract Cancer: A Prospective Multicenter Phase II Study. Cancers, 14(8), 1950. https://doi.org/10.3390/cancers14081950

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop