Attenuated FOLFIRINOX in the salvage treatment of gemcitabine-refractory advanced pancreatic cancer: a phase II study

Attenuated FOLFIRINOX in the salvage treatment of gemcitabine-refractory advanced pancreatic... Background: Combination therapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) chemo ‑ therapy drastically improves survival of advanced pancreatic cancer patients. However, the efficacy of FOLFIRINOX as a second‑ line treatment after gemcitabine failure has not been tested prospectively. We investigated the feasibility and safety of attenuated FOLFIRINOX in patients with gemcitabine‑ refractory advanced pancreatic cancer. Methods: A multicenter phase II prospective open‑ label, single‑ arm study was conducted at 14 hospitals. Patients with histologically proven invasive ductal pancreatic adenocarcinoma, a measurable or evaluable lesion, Eastern Cooperative Oncology Group performance status 0 or 1, adequate organ function, and aged 19 years or older were 2 2 2 eligible. Attenuated FOLFIRINOX consisted of oxaliplatin 65 mg/m , irinotecan 135 mg/m , and leucovorin 400 mg/m injected intravenously on day 1 and 5‑ fluorouracil 2000 mg/m continuously infused intravenously over 46 h on days 1–2, repeated every 2 weeks. The primary endpoint was progression‑ free survival from the initiation of FOLFIRINOX. Secondary endpoints were the objective response rate, disease control rate, overall survival, safety, and tolerability. We estimated overall survival and progression‑ free survival using the Kaplan–Meier methods. Results: We enrolled 39 patients from 14 institutions. The objective response rate was 10.3%, while the disease control rate was 64.1%. The 6‑ month and 1‑ year overall survival rates were 59.0% and 15.4%, respectively. Median progression‑ free survival and overall survival were 3.8 months (95% confidence interval [CI] 1.5–6.0 months) and 8.5 months (95% CI 5.6–11.4 months), respectively. Grade 3 or 4 adverse events were neutropenia (41.0%), nausea (10.3%), anorexia (10.3%), anemia (7.7%), mucositis (7.7%), pneumonia/pleural effusion (5.1%), and fatigue (5.1%). One treatment‑ related death attributable to septic shock occurred. Conclusion: Attenuated FOLFIRINOX may be promising as a second‑ line therapy for gemcitabine‑ refractory pancre‑ atic cancer. Keywords: Attenuated FOLFIRINOX, Second‑ line, Pancreatic cancer, Gemcitabine *Correspondence: newatp@naver.com Jung Hoon Kim and Sang‑ Cheol Lee contributed equally as first authors to this work Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University, 15 Jinju‑daero 816beon‑gil, Jinju 52727, Republic of Korea Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kim et al. Cancer Commun (2018) 38:32 Page 2 of 8 management, patent biliary stent, and adequate nutri- Background tional intake [15]. Gemcitabine-based chemotherapeutic Pancreatic cancer remains an obstinate disease despite regimens, which are used widely in clinical practice, are recent advances in diagnostic and therapeutic science still recommended as category 1 for most patients. and techniques. It is the fifth-leading cause of cancer- Fluoropyrimidine-based chemotherapy is recom- related deaths in Korea [1, 2], and its 5-year relative sur- mended as a second-line treatment for patients who have vival rate is approximately 7.6% across all stages [3]. Only progressed after gemcitabine-based first-line therapy. 10%–20% of patients are diagnosed with resectable dis- However, to our knowledge, no prospective investiga- ease at presentation [4–6]. A large proportion of patients tion has reported on whether FOLFIRINOX therapy can have advanced disease at initial presentation. Studies influence the outcomes of patients who maintain good aimed at developing an effective systemic treatment for performance status after gemcitabine failure. pancreatic cancer have elicited slow but steady advances uTh s, we conducted a single-arm phase II trial to in survival benefits. The greatest improvement in over - evaluate efficacy and safety of second-line dose-attenu - all survival (OS) was demonstrated by the randomized ated FOLFIRINOX for treating gemcitabine-refractory phase III PRODIGE 4/ACCORD 11 trial, which revealed patients with locally advanced unresectable or metastatic that combination therapy with oxaliplatin, irinotecan, pancreatic cancer in which curative therapy was not 5-fluorouracil, and leucovorin (FOLFIRINOX) was supe - feasible. rior to gemcitabine alone [7, 8]. The median progres - sion-free survival (PFS) and OS in the FOLFIRINOX Patients and methods group were 6.4 and 11.1 months, respectively (compared Study design with 3.3 and 6.8  months in the gemcitabine group). The This trial was a Korean, multicenter phase II prospective reported objective response rate was 31.6% versus 9.4% open-label, single-arm study. (FOLFIRINOX versus gemcitabine) [7]. The primary endpoint of our study was PFS. The defini - The trial with FOLFIRINOX was an important mile - tion of PFS was the time from initiation of FOLFIRINOX stone in the treatment of pancreatic cancer, although it until confirmation of progressive disease or death. Sec - raised a logical concern regarding toxicity and safety [9]. ondary endpoints were the objective response rate Grade 3 or 4 neutropenia occurred in 45.7% of patients (ORR), disease-control rate (DCR), OS, and safety and (75 in 164 patients), and one case of treatment-related tolerability of patients. ORR was defined as the propor - death due to febrile neutropenia was reported in the tion of patients who showed complete response (CR) or FOLFIRINOX arm, despite the investigators’ more rigor- partial response (PR), and DCR was defined as the pro - ous selection of participating patients than that reported portion of patients who showed stable disease (SD). in other studies [7]. A salvage systemic therapy for patients with advanced Patient selection pancreatic cancer refractory to the frontline regimen had Adult patients with histologically confirmed pancreatic not been established when we started the present study; adenocarcinoma on which curative treatment was not however, several investigators have, since then, con- feasible and who failed a gemcitabine-based palliative ducted pilot or phase II trials with combinations such as frontline chemotherapy or adjuvant gemcitabine within FOLFIRI [10], FOLFOX [11], and IROX [12]. Lee et  al. 6 months were eligible for inclusion. [13] investigated FOLFIRINOX as a second-line chemo- Additional eligibility criteria included the follow- therapy in patients with advanced pancreatic cancer who ing: at least one measurable or evaluable lesion based progressed on gemcitabine-based therapy, but the study on the response evaluation criteria in solid tumors was a retrospective analysis including only 18 patients. (RECIST) 1.1, adequate bone marrow (absolute neu- While our study was in progress, the results of a phase III trophil counts [ANC] ≥ 1.5 × 10 /L, number of study (CONKO-003 trial) comparing oxaliplatin, folinic thrombocytes ≥ 100 × 10 /L), hepatic function (total acid, and fluorouracil (OFF) with folinic acid and fluoro - bilirubin ≤ 1.5 × the upper limit of normal [ULN], uracil (FF) for gemcitabine-refractory pancreatic cancer or < 3.0 × ULN, in patients who underwent drainage were published; this work is the only phase III compara- procedure expecting normalization of the level, aspar- tive study to date that has verified survival benefits of tate transaminase (AST) and/or alanine transaminase second-line chemotherapy for advanced pancreatic can- (ALT) ≤ 3 × ULN [in case of liver metastasis, 5 × ULN]), cer [14]. renal function (serum creatinine ≤ 1.5  mg/dL or creati- Current guidelines recommend the application of FOL- nine clearance ≥ 50  mL/min), cardiac function (left ven- FIRINOX to a highly selective group of patients, such tricle ejection fraction ≥ 50% or age under 60  years old as patients with Eastern Cooperative Oncology Group without symptoms), and patent biliary stent for at least (ECOG) performance status (PS) of 0 or 1, good pain Kim et al. Cancer Commun (2018) 38:32 Page 3 of 8 2 months. The following patients were excluded: patients proportional hazards regression model was performed to who previously received irinotecan or oxaliplatin regi- identify prognostic factors to predict better PFS and OS. men, or any chemotherapy within 3 weeks prior to enrol- All tests were two-sided, and a p value < 0.05 was consid- ment, had uncontrolled brain metastases, or other types ered statistically significant. All analyses were performed of cancer except non-melanoma skin cancer, differen - using SPSS for Windows, version 19.0 (SPSS Inc, Chi- tiated thyroid carcinoma, cervix carcinoma in  situ, or cago, IL, USA). peripheral neuropathy limiting life activities. Results Patients’ characteristics Procedures Between October 2013 and February 2015, 41 patients Attenuated FOLFIRINOX consisted of oxaliplatin 65 mg/ 2 2 participated and fulfilled the criteria for examining our m , irinotecan 135  mg/m , and leucovorin 400  mg/ hypothesis without dropout. Two of the 41 patients could m injected intravenously on day 1 along with 5-FU not be evaluated; therefore, data on 39 patients were 2000  mg/m continuous intravenous infusion over 46  h ultimately analyzed. Baseline demographic and clini- on days 1–2. Each cycle was planned to be repeated cal characteristics are shown in Table  1. The median age every 2  weeks. We could not obtain dose-finding phase was 58  years (range 42–75  years). The numbers of men I data for FOLFIRINOX. Accordingly, we planned the doses of all drugs in our attenuated FOLFIRINOX to be 75% of the dose in the Prodige 4/Accord 11 study [7] and removed the bolus 5-FU. The plan was for chemother - Table 1 Baseline demographic and  clinical characteristics apy administration until observation of disease progres- of  39 evaluated patients with  gemcitabine-refractory sion or unacceptable toxicity. This study design did not advanced pancreatic cancer include any prophylactic granulocyte colony-stimulating Characteristic No. of patients % factor or antibiotics. Patient’s medical history, complete physical examina- Age tion, neurologic examination, ECOG performance status, ≤ 60 years 25 64.1 plain chest radiograph, complete blood counts, blood > 60 years 14 35.9 chemistry, and serum tumor markers were checked Sex within 7 days prior to enrollment. Abdomen-pelvis com- Male 29 74.4 puted tomography (CT) scan or magnetic resonance Female 10 25.6 imaging (MRI), metastatic organ CT, or bone scintigra- ECOG PS phy (in case of bone pain) was performed within 28 days 0 2 5.1 prior to enrollment. Baseline assessment of patients’ sta- 1 35 89.7 tus was repetitively performed within 3  days after every 2 2 5.1 cycle’s commencement. Response evaluation with CT Extent of disease scan or MRI was performed every three cycles. Tumor Locally advanced 7 17.9 response was assessed by investigators, based on RECIST Metastatic 32 82.1 v1.1. Toxicity profiles were determined using National Primary tumor location Cancer Institute Common Terminology Criteria for Head 18 46.1 Adverse Events, version 4.0. Body 9 23.1 Tail 12 30.8 Statistical analysis Metastatic site We used Simon’s 2-stage optimal design to determine Liver 17 43.6 the sample size. Assuming a PFS of 2.4  months (null Lung 7 17.9 hypothesis) with other 5-FU-based therapies and a tar- Distant lymph nodes 14 35.9 get PFS of 4.3  months reflecting clinical activity of the Peritoneum 7 17.9 FOLFIRINOX regimen, with an α error of 0.05, we calcu- Multiple organs 13 33.3 lated that a total of 45 patients would provide 80% power CA19‑9 value (U/mL) in detecting an effect on the primary outcome, assum - > 10 times of UNL 21 53.8 ing a 10% rate of dropouts or withdrawals. PFS and OS ≤ 10 times of UNL 18 46.2 were computed using the Kaplan–Meier method with Patients who received 3rd line 12 30.8 two-sided 95% confidence intervals (CIs). Censored sub - chemotherapy jects are indicated on the Kaplan–Meier curve as tick ECOG PS Eastern Cooperative Oncology Group Performance status, CA19-9 marks; these marks do not terminate the interval. Cox carbohydrate antigen 19-9, UNL upper normal limit Kim et al. Cancer Commun (2018) 38:32 Page 4 of 8 and women were 29 (74.4%) and 10 (25.6%), respec- calculated median relative dose intensities (ranges) of tively. ECOG performance status was usually 0 or 1, 5-FU, oxaliplatin, and irinotecan were 76.4% (38%– except among two participants. A major protocol viola- 100%), 79.5% (40.8%–100%), and 76.4% (40.6%–100%), tion occurred involving two enrolled patients who each respectively. The number and proportion of dose reduc - had an ECOG PS score of 2. The two patients completed tions and delays are summarized in Table  2, while the scheduled chemotherapy without life-threatening com- dose reduction protocol is presented in Table 3. plications and had evaluable outcomes; therefore, they Four patients achieved a partial response. Seven- were included in the final analysis. Seven patients (17.9%) teen patients (43.6%) had stable disease, and 14 patients had locally advanced unresectable disease, while other (35.9%) had progressive disease. The ORR was 10.3% (4 of patients had metastatic disease. The most frequent meta - 39 patients), and the DCR was 64.1% (25 of 39 patients). static site was the liver (43.6%), while 13 patients (33.3%) After a median follow-up period of 17.9  months, the had multiple metastatic organ involvement. Twelve median PFS was 3.8  months (95% CI 1.5–6.0  months) patients (30.8%) received 3rd-line palliative chemother- and the median OS was 8.5  months (95% CI 5.6– apy after being censored from the study. Median serum 11.4  months). The 6-month and 1-year overall survival carbohydrate antigen 19-9 (CA19-9) and carcinoem- rates were 59.0% and 15.4%, respectively (Fig.  1). Multi- bryonic antigen (CEA) values were 864.0  IU/mL (2.0– variate analysis revealed no significant difference in PFS 400,000.0  IU/mL) and 10.3  U/mL (0.0–1386.0  U/mL) in or OS according to age, sex, primary tumor location, 39 patients, respectively. liver metastasis, serum level of CA 19-9, presence of dose delays, or reductions of FOLFIRINOX (Table 4). Treatment and outcomes A total of 215 cycles were delivered to 39 patients with Toxicity data a median of 3 cycles/patient (range 1–17 cycles). The The most common grade 3 or 4 toxicity was neutropenia (16/39, 41.0%), but no patient experienced febrile neu- tropenia. Nausea and anorexia (both 10.3%) were the second most common adverse events. Toxicity data are Table 2 Summary of dose reductions and delays presented in Table 5. Septic shock with infection focus in Characteristic Number % the biliary tract occurred in a patient at 24 days after the 3rd cycle of FOLFIRINOX administration. The patient’s Dose reductions and delays per patient white blood cell count was 27,000/mm on admission. Number of patients 39 The patient died 11 days after presenting septic shock. Dose delays 24 61.5 Dose reductions 11 28.2 Discussion Dose reductions and delays per cycle The present study prospectively investigated the safety Number of cycles 215 and efficacy of an attenuated dose of FOLFIRINOX as a Dose delays 47 21.9 second-line therapy for advanced pancreatic cancer and Dose reductions showed encouraging length of progression-free survival 5‑Fluorouracil 33 15.3 and overall survival, but was accompanied by significant Oxaliplatin 39 18.1 toxicity. Irinotecan 46 21.4 Table 3 Summary of events that resulted in dose reductions and delays Toxicity Grade Oxaliplatin, 5-FU/Leucovorin Irinotecan Hemoglobin Any grade No reduction Neutropenia 3 (ANC 500–999/mm ) No reduction (1 week delay) 3) 4 (ANC ≤ 499/mm 25% reduction 25% reduction Febrile neutropenia 3 (ANC < 1000/mm and body tempera‑ 25% reduction 25% reduction ture ≥ 38.5 °C) 4 (grade 3 febrile neutropenia and life 50% reduction 50% reduction threatening sepsis) Thrombocytopenia 3 (25,000–50,000/mm ) 25% reduction 25% reduction 4 (< 25,000/mm ) 25% reduction ANC absolute neutrophil count Kim et al. Cancer Commun (2018) 38:32 Page 5 of 8 pancreatic cancer. The treatment regimen consisted of 2 2 oxaliplatin 85 mg/m , irinotecan 130–135 mg/m , folinic 2 2 acid 400  mg/m , and 5-FU infusion 2400  mg/m over 46  h, administered every 14  days. Their study included 15 patients with stage IV disease and indicated 47% ORR, with median PFS and OS of 7.2 and 9.3 months, respec- tively. The authors reported grade 3 or 4 neutropenia in 5.6% of their patients and non-hematologic adverse events (grade 3 or 4 vomiting: 27.8%). Blazer et  al. [17] and Lakatos et  al. [18] tested modified FOLFIRINOX in patients with locally advanced disease. Dose intensities varied between the research groups, but these studies reported a relatively low rate of adverse events along with meaningful disease control. Umemura et  al. [19] used a modified dose of FOL - FIRINOX to treat a small group of patients with unre- sectable locally advanced or metastatic pancreatic cancer who failed on gemcitabine- and S-1-based therapies. The authors designed the modified regimen with oxaliplatin 2 2 75  mg/m , irinotecan 150  mg/m , folinic acid 320  mg/ 2 2, m , 5-FU bolus 320 mg/m and 5-FU infusion 1920 mg/ m administered every 21 days. After a total of 114 cycles were delivered in 13 patients, the ORR obtained was 30.8% with no CR, and median PFS and OS were 137 and 176  days, respectively. Five patients (38.5%) experi- enced grade 3 or 4 neutropenia, but febrile neutropenia did not occur. The other common grade 3 or 4 adverse events were anorexia, vomiting, and diarrhea (3, 1, and 1 patients, respectively). The incidence of grade 3–4 diar - rhea in clinical trials in the Republic of Korea has been low compared with that reported in Western trials. Simi- lar incidence is reported in Japanese patients. Ethnic differences in the activity of enzymes that metabolize irinotecan appear to be the cause. In a phase II trial of modified FOLFIRI.3 compared with modified FOLFOX as a second-line treatment for advanced pancreatic can- cer conducted by Yoo et al. [11] in Korea, irinotecan dose was 140  mg/m every 2  weeks, and grade 3–4 diarrhea was observed in 7% of 31 patients. Kobayashi et  al. [20] reported no occurrence of grade 3–4 diarrhea in 18 Japa- Fig. 1 Kaplan–Meier curves of progression‑free survival (PFS) nese patients who were enrolled in a prospective phase and overall survival (OS) for 39 patients with pancreatic cancer. I/II study of FOLFIRINOX as a second-line treatment a The median PFS was 3.8 months (95% confidence interval for metastatic pancreatic cancer. The phase I trial was a [CI] 1.5–6.0 months). b The median OS was 8.5 months (95% CI dose-finding study for irinotecan in combination with 5.6–11.4 months) fixed-dose 5-FU, leucovorin and oxaliplatin. As a result, an irinotecan dose of 100 mg/m was recommended. This finding is consistent with the frequent dose reduction of Although several analyses on the efficacy and safety irinotecan in this study. The results of those two trials are of modified doses of FOLFIRINOX have been per - very similar to those of the current study. formed, conclusive evidence is still lacking. Ghorani In a small retrospective analysis of salvage treatment et al. [16] retrospectively analyzed data from their single- with FOLFIRINOX, Lee et  al. [13] reported a DCR of center experience in the United Kingdom with modi- 55.6%, with median PFS and OS of 2.8 and 8.4 months, fied FOLFIRINOX for chemotherapy-naïve advanced respectively. These findings are similar to the outcomes Kim et al. Cancer Commun (2018) 38:32 Page 6 of 8 Table 4 Prognostic factor analysis of 39 patients treated with FOLFIRINOX as a second-line treatment Variable Progression-free survival Overall survival Median, months (95% CI) Univariate Multivariate Median, months (95% CI) Univariate Multivariate (p value) hazard ratio (p (p value) hazard ratio (p value) value) Age ≤ 60 years 2.3 (0.89–3.71) 0.209 0.565 (0.193) 8.5 (3.39–13.61) 0.514 0.563 (0.209) > 60 years 4.83 (2.15–7.51) 8.63 (5.58–11.69) Sex Male 3.3 (1.28–5.32) 0.827 8.5 (4.49–12.51) 0.854 Female 3.73 (0–9.46) 8.83 (5.24–12.42) Extent of disease Locally advanced 1.77 (0–4.22) 0.465 1.318 (0.616) 9.67 (7.22–12.12) 0.14 0.379 (0.05) Metastatic 4.7 (1.86–7.54) 6.37 (3.56–9.18) Primary tumor location Head 4.7 (0.51–8.89) 0.332 0.711 (0.399) 8.83 (5.55–12.11) 0.569 0.862 (0.719) Body or tail 2.9 (1.44–4.36) 7.6 (1.74–13.46) Liver metastasis Yes 6.53 (2.04–11.02) 0.414 0.642 (0.29) 6.37 (2.94–9.8) 0.459 1.052 (0.897) No 2.9 (0–6.19) 8.67 (8.18–9.16) CA19‑9 value (U/mL) > 10 times of UNL 3.93 (1.52–6.35) 8.5 (5.51–11.49) 0.972 0.653 ≤ 10 times of UNL 3.77 (1.17–6.37) 8.83 (2.66–14.99) CA19-9 carbohydrate antigen 19-9, UNL upper normal limit obtained with our attenuated dose of FOLFIRINOX, These outcomes suggest the need for a triple combi - although the FOLFIRINOX regimen reported by Lee nation of drugs for gemcitabine-refractory pancreatic et  al. consisted of the same dose as that of the origi- cancer, despite concerns regarding their higher toxicity. nal PRODIGE/ACCORD 11 trial. Clinical outcomes of Attenuated FOLFIRINOX therapy in our study several studies with modified FOLFIRINOX as a front - achieved a meaningful OS benefit, although the ORR fell line treatment appeared not to be inferior to those of short of our expectations. However, this dose-modified the original dose [21, 22]. In the CONKO-003 trial, FOLFIRINOX regimen did not reduce toxicity either. which confirmed the survival benefit of salvage chem - Forty-one percent prevalence of grade 3 toxicities or neu- otherapy described above, the median OS was 5.9 tropenia and an event of treatment-related mortality still and 3.3  months, and time to progression was 2.9 and leave concerns regarding the safety of this regimen. The 2.0  months (OFF versus FF, respectively). The efficacy small size of the study population for subgroup analysis, of OFF regimen was not significantly different from the absence of biomarker evaluation, and the lack of an that of our attenuated FOLFIRINOX in terms of PFS assessment of the quality of life are also limitations of the but tends to be inferior in terms of OS. In this previous present study. There is increasing interest in the feasibil - study, 25% of the subjects received third-line therapy, ity and safety of FOLFIRINOX as a second-line treat- similarly to our series of patients. The results of a few ment. Before initiation of our study, gemcitabine-based single-arm studies with irinotecan, fluorouracil, and front-line therapy was doubted for its survival benefit leucovorin (FOLFIRI) as a second-line chemotherapy because only modest effects were observed when gemcit - for pancreatic cancer have also been published. Zani- abine in combination with erlotinib was compared with boni et  al. [10] reported that 36% of patients showed gemcitabine alone. DCR, with median PFS and OS of 3.2 and 5  months, Recently, a new regimen of albumin-bound paclitaxel respectively, using a FOLFIRI regimen in the GISCAD (nab-paclitaxel) plus gemcitabine was shown to be supe- multicenter phase II study. Yoo et  al. [12] stated that rior to gemcitabine alone for OS as a front-line treatment DCR was achieved in 23% of patients, with a median in a randomized phase III study; thus, nab-paclitaxel plus OS of 3.9  months in response to their modified FOL - gemcitabine is becoming one of the most widely used FIRI.3 chemotherapy in a randomized phase II study. options as a first-line treatment [23–26]. Accordingly, the Kim et al. Cancer Commun (2018) 38:32 Page 7 of 8 Authors’ contributions Table 5 Hematologic and  nonhematologic adverse JH Kang conceptualized and designed the study, coordinated and supervised events which ever occurred in  39 patients treated the data collection, and approved the final manuscript as submitted. JH Kim with FOLFIRINOX as a second-line treatment and S‑ CL analyzed the data, drafted and revised the manuscript. SYO, SYS, NL, EMN, SL, IGH, HRL, KTL, S‑BB, HJK, JSJ, DHL, HWL, SYK contributed to execute Adverse event Any grade Grade 3 or more clinical trial. All authors agreed to be responsible for all aspects of the study. All authors read and approved the final manuscript Number % Number % of patients of patients Author details Department of Internal Medicine, Institute of Health Sciences, Gyeongsang Hematologic National University, 15 Jinju‑daero 816beon‑gil, Jinju 52727, Republic of Korea. Neutropenia 18 46.2 16 41.0 Divsion of Hematology and Oncology, Department of Internal Medicine, Thrombocytopenia 7 17.9 1 2.6 Soonchunhyang University Hospital Cheonan, Cheonan 31151, Republic of Korea. Department of Internal Medicine, Dong‑A University Hospital, Anemia 23 59.0 3 7.7 Busan 49201, Republic of Korea. Department of Internal Medicine, Kangwon Nonhematologic National University School of Medicine, Chuncheon 24289, Republic of Korea. Nausea 23 59.0 4 10.3 Divsion of Hematology and Oncology, Department of Internal Medicine, Soonchunhyang University Hospital Seoul, Seoul 04401, Republic of Korea. Vomiting 3 7.7 1 2.6 Department of Internal Medicine, Ewha Womans University, College of Medi‑ Diarrhea 11 28.2 1 2.6 7 cine, Seoul 07985, Republic of Korea. Department of Internal Medicine, Fatigue 9 23.1 2 5.1 Dankook University Hospital, Cheonan 31116, Republic of Korea. Department of Internal Medicine, Chung‑Ang University, College of Medicine, Seoul 06973, Anorexia 21 53.8 4 10.3 Republic of Korea. Division of Hematology and Medical Oncology, Depart‑ Constipation 6 15.4 ment of Internal Medicine, Korea Cancer Hospital, Seoul 01812, Republic Mucositis 12 30.8 3 7.7 of Korea. Department of Hematology‑Oncology, Ajou University Hospital, Suwon 16499, Republic of Korea. Neuropathy 5 12.8 1 2.6 Septic shock 1 2.6 Acknowledgements Pneumonia/pleural effusion 2 5.1 We would like to thank Editage (https ://www.edita ge.co.kr) for English language editing. Abdominal distension 1 2.6 Alkaline phosphatase 1 2.6 Competing interests increased The authors declare that they have no competing interests. Hypokalemia 1 2.6 Availability of data and materials Glossopharyngeal neuralgia 1 2.6 The datasets obtained and analyzed during the present study are available Grade 5 (death) from the corresponding author on reasonable request. Consent for publication Not applicable. importance of salvage chemotherapy, which involves nei- Ethics approval and consent to participate ther gemcitabine nor taxane, is increasing. This trial was approved by the respective institutional review boards of all 14 participating centers and the Korea Food and Drug Administration (KFDA). It The higher DCR and longer OS observed in the current was conducted in accordance with the principles of Declaration of Helsinki study justify the triple combination of FOLFIRINOX over and the International Conference on Harmonization of Good Clinical Practice. doublet regimens such as FOLFIRI or FOLFOX, even in All participating patients provided written informed consent. heavily pretreated pancreatic cancer patients. To date, Funding only a handful of regimens apart from FOLFIRINOX The present study was supported by a research Grant from Hanmi Pharma‑ could obtain a median OS beyond 8  months from ini- ceutical Co. Ltd., and the Soonchunhyang University Research fund. tiation of second-line therapy for advanced pancreatic Received: 5 August 2017 Accepted: 5 January 2018 cancer [26]. Based on these findings, a phase III trial to confirm the survival benefits of modified FOLFIRINOX as a second-line treatment for advanced pancreatic can- cer is being planned. References 1. Bae JM, Jung KW, Won YJ. Estimation of cancer deaths in Korea for the upcoming years. J Korean Med Sci. 2002;17:611. 2. Kim SG, Hahm MI, Choi KS, Seung NY, Shin HR, Park EC. The eco‑ Conclusions nomic burden of cancer in Korea in 2002. Eur J Cancer Care (Engl). FOLFIRINOX is not only a front-line treatment of choice 2008;17:136–44. 3. Jung KW, Park S, Kong HJ, Won YJ, Boo YK, Shin HR, et al. Cancer statistics for advanced pancreatic cancer but can also be a prom- in Korea: incidence, mortality and survival in 2006–2007. 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Nagrial AM, Chin VT, Sjoquist KM, Pajic M, Horvath LG, Biankin AV, et al. uracil alone for gemcitabine‑refractory pancreatic cancer: outcomes from Second‑line treatment in inoperable pancreatic adenocarcinoma: a sys‑ the CONKO‑003 trial. J Clin Oncol. 2014;32:2423–9. tematic review and synthesis of all clinical trials. Crit Rev Oncol Hematol. 15. Seufferlein T, Bachet JB, Van Cutsem EF, Rougier P, Group on behalf of the 2015;96:483–97. EGW. Pancreatic adenocarcinoma: ESMO–ESDO clinical practice guide‑ lines for diagnosis, treatment and follow‑up. Ann Oncol. 2012;23:vii33–40. 16. Ghorani E, Wong HH, Hewitt C, Calder J, Corrie P, Basu B. Safety and effi‑ cacy of modified FOLFIRINOX for advanced pancreatic adenocarcinoma: a UK single‑ centre experience. Oncology. 2015;89:281–7. Ready to submit your research ? 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Attenuated FOLFIRINOX in the salvage treatment of gemcitabine-refractory advanced pancreatic cancer: a phase II study

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Biomedicine; Cancer Research; Oncology
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Abstract

Background: Combination therapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) chemo ‑ therapy drastically improves survival of advanced pancreatic cancer patients. However, the efficacy of FOLFIRINOX as a second‑ line treatment after gemcitabine failure has not been tested prospectively. We investigated the feasibility and safety of attenuated FOLFIRINOX in patients with gemcitabine‑ refractory advanced pancreatic cancer. Methods: A multicenter phase II prospective open‑ label, single‑ arm study was conducted at 14 hospitals. Patients with histologically proven invasive ductal pancreatic adenocarcinoma, a measurable or evaluable lesion, Eastern Cooperative Oncology Group performance status 0 or 1, adequate organ function, and aged 19 years or older were 2 2 2 eligible. Attenuated FOLFIRINOX consisted of oxaliplatin 65 mg/m , irinotecan 135 mg/m , and leucovorin 400 mg/m injected intravenously on day 1 and 5‑ fluorouracil 2000 mg/m continuously infused intravenously over 46 h on days 1–2, repeated every 2 weeks. The primary endpoint was progression‑ free survival from the initiation of FOLFIRINOX. Secondary endpoints were the objective response rate, disease control rate, overall survival, safety, and tolerability. We estimated overall survival and progression‑ free survival using the Kaplan–Meier methods. Results: We enrolled 39 patients from 14 institutions. The objective response rate was 10.3%, while the disease control rate was 64.1%. The 6‑ month and 1‑ year overall survival rates were 59.0% and 15.4%, respectively. Median progression‑ free survival and overall survival were 3.8 months (95% confidence interval [CI] 1.5–6.0 months) and 8.5 months (95% CI 5.6–11.4 months), respectively. Grade 3 or 4 adverse events were neutropenia (41.0%), nausea (10.3%), anorexia (10.3%), anemia (7.7%), mucositis (7.7%), pneumonia/pleural effusion (5.1%), and fatigue (5.1%). One treatment‑ related death attributable to septic shock occurred. Conclusion: Attenuated FOLFIRINOX may be promising as a second‑ line therapy for gemcitabine‑ refractory pancre‑ atic cancer. Keywords: Attenuated FOLFIRINOX, Second‑ line, Pancreatic cancer, Gemcitabine *Correspondence: newatp@naver.com Jung Hoon Kim and Sang‑ Cheol Lee contributed equally as first authors to this work Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University, 15 Jinju‑daero 816beon‑gil, Jinju 52727, Republic of Korea Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kim et al. Cancer Commun (2018) 38:32 Page 2 of 8 management, patent biliary stent, and adequate nutri- Background tional intake [15]. Gemcitabine-based chemotherapeutic Pancreatic cancer remains an obstinate disease despite regimens, which are used widely in clinical practice, are recent advances in diagnostic and therapeutic science still recommended as category 1 for most patients. and techniques. It is the fifth-leading cause of cancer- Fluoropyrimidine-based chemotherapy is recom- related deaths in Korea [1, 2], and its 5-year relative sur- mended as a second-line treatment for patients who have vival rate is approximately 7.6% across all stages [3]. Only progressed after gemcitabine-based first-line therapy. 10%–20% of patients are diagnosed with resectable dis- However, to our knowledge, no prospective investiga- ease at presentation [4–6]. A large proportion of patients tion has reported on whether FOLFIRINOX therapy can have advanced disease at initial presentation. Studies influence the outcomes of patients who maintain good aimed at developing an effective systemic treatment for performance status after gemcitabine failure. pancreatic cancer have elicited slow but steady advances uTh s, we conducted a single-arm phase II trial to in survival benefits. The greatest improvement in over - evaluate efficacy and safety of second-line dose-attenu - all survival (OS) was demonstrated by the randomized ated FOLFIRINOX for treating gemcitabine-refractory phase III PRODIGE 4/ACCORD 11 trial, which revealed patients with locally advanced unresectable or metastatic that combination therapy with oxaliplatin, irinotecan, pancreatic cancer in which curative therapy was not 5-fluorouracil, and leucovorin (FOLFIRINOX) was supe - feasible. rior to gemcitabine alone [7, 8]. The median progres - sion-free survival (PFS) and OS in the FOLFIRINOX Patients and methods group were 6.4 and 11.1 months, respectively (compared Study design with 3.3 and 6.8  months in the gemcitabine group). The This trial was a Korean, multicenter phase II prospective reported objective response rate was 31.6% versus 9.4% open-label, single-arm study. (FOLFIRINOX versus gemcitabine) [7]. The primary endpoint of our study was PFS. The defini - The trial with FOLFIRINOX was an important mile - tion of PFS was the time from initiation of FOLFIRINOX stone in the treatment of pancreatic cancer, although it until confirmation of progressive disease or death. Sec - raised a logical concern regarding toxicity and safety [9]. ondary endpoints were the objective response rate Grade 3 or 4 neutropenia occurred in 45.7% of patients (ORR), disease-control rate (DCR), OS, and safety and (75 in 164 patients), and one case of treatment-related tolerability of patients. ORR was defined as the propor - death due to febrile neutropenia was reported in the tion of patients who showed complete response (CR) or FOLFIRINOX arm, despite the investigators’ more rigor- partial response (PR), and DCR was defined as the pro - ous selection of participating patients than that reported portion of patients who showed stable disease (SD). in other studies [7]. A salvage systemic therapy for patients with advanced Patient selection pancreatic cancer refractory to the frontline regimen had Adult patients with histologically confirmed pancreatic not been established when we started the present study; adenocarcinoma on which curative treatment was not however, several investigators have, since then, con- feasible and who failed a gemcitabine-based palliative ducted pilot or phase II trials with combinations such as frontline chemotherapy or adjuvant gemcitabine within FOLFIRI [10], FOLFOX [11], and IROX [12]. Lee et  al. 6 months were eligible for inclusion. [13] investigated FOLFIRINOX as a second-line chemo- Additional eligibility criteria included the follow- therapy in patients with advanced pancreatic cancer who ing: at least one measurable or evaluable lesion based progressed on gemcitabine-based therapy, but the study on the response evaluation criteria in solid tumors was a retrospective analysis including only 18 patients. (RECIST) 1.1, adequate bone marrow (absolute neu- While our study was in progress, the results of a phase III trophil counts [ANC] ≥ 1.5 × 10 /L, number of study (CONKO-003 trial) comparing oxaliplatin, folinic thrombocytes ≥ 100 × 10 /L), hepatic function (total acid, and fluorouracil (OFF) with folinic acid and fluoro - bilirubin ≤ 1.5 × the upper limit of normal [ULN], uracil (FF) for gemcitabine-refractory pancreatic cancer or < 3.0 × ULN, in patients who underwent drainage were published; this work is the only phase III compara- procedure expecting normalization of the level, aspar- tive study to date that has verified survival benefits of tate transaminase (AST) and/or alanine transaminase second-line chemotherapy for advanced pancreatic can- (ALT) ≤ 3 × ULN [in case of liver metastasis, 5 × ULN]), cer [14]. renal function (serum creatinine ≤ 1.5  mg/dL or creati- Current guidelines recommend the application of FOL- nine clearance ≥ 50  mL/min), cardiac function (left ven- FIRINOX to a highly selective group of patients, such tricle ejection fraction ≥ 50% or age under 60  years old as patients with Eastern Cooperative Oncology Group without symptoms), and patent biliary stent for at least (ECOG) performance status (PS) of 0 or 1, good pain Kim et al. Cancer Commun (2018) 38:32 Page 3 of 8 2 months. The following patients were excluded: patients proportional hazards regression model was performed to who previously received irinotecan or oxaliplatin regi- identify prognostic factors to predict better PFS and OS. men, or any chemotherapy within 3 weeks prior to enrol- All tests were two-sided, and a p value < 0.05 was consid- ment, had uncontrolled brain metastases, or other types ered statistically significant. All analyses were performed of cancer except non-melanoma skin cancer, differen - using SPSS for Windows, version 19.0 (SPSS Inc, Chi- tiated thyroid carcinoma, cervix carcinoma in  situ, or cago, IL, USA). peripheral neuropathy limiting life activities. Results Patients’ characteristics Procedures Between October 2013 and February 2015, 41 patients Attenuated FOLFIRINOX consisted of oxaliplatin 65 mg/ 2 2 participated and fulfilled the criteria for examining our m , irinotecan 135  mg/m , and leucovorin 400  mg/ hypothesis without dropout. Two of the 41 patients could m injected intravenously on day 1 along with 5-FU not be evaluated; therefore, data on 39 patients were 2000  mg/m continuous intravenous infusion over 46  h ultimately analyzed. Baseline demographic and clini- on days 1–2. Each cycle was planned to be repeated cal characteristics are shown in Table  1. The median age every 2  weeks. We could not obtain dose-finding phase was 58  years (range 42–75  years). The numbers of men I data for FOLFIRINOX. Accordingly, we planned the doses of all drugs in our attenuated FOLFIRINOX to be 75% of the dose in the Prodige 4/Accord 11 study [7] and removed the bolus 5-FU. The plan was for chemother - Table 1 Baseline demographic and  clinical characteristics apy administration until observation of disease progres- of  39 evaluated patients with  gemcitabine-refractory sion or unacceptable toxicity. This study design did not advanced pancreatic cancer include any prophylactic granulocyte colony-stimulating Characteristic No. of patients % factor or antibiotics. Patient’s medical history, complete physical examina- Age tion, neurologic examination, ECOG performance status, ≤ 60 years 25 64.1 plain chest radiograph, complete blood counts, blood > 60 years 14 35.9 chemistry, and serum tumor markers were checked Sex within 7 days prior to enrollment. Abdomen-pelvis com- Male 29 74.4 puted tomography (CT) scan or magnetic resonance Female 10 25.6 imaging (MRI), metastatic organ CT, or bone scintigra- ECOG PS phy (in case of bone pain) was performed within 28 days 0 2 5.1 prior to enrollment. Baseline assessment of patients’ sta- 1 35 89.7 tus was repetitively performed within 3  days after every 2 2 5.1 cycle’s commencement. Response evaluation with CT Extent of disease scan or MRI was performed every three cycles. Tumor Locally advanced 7 17.9 response was assessed by investigators, based on RECIST Metastatic 32 82.1 v1.1. Toxicity profiles were determined using National Primary tumor location Cancer Institute Common Terminology Criteria for Head 18 46.1 Adverse Events, version 4.0. Body 9 23.1 Tail 12 30.8 Statistical analysis Metastatic site We used Simon’s 2-stage optimal design to determine Liver 17 43.6 the sample size. Assuming a PFS of 2.4  months (null Lung 7 17.9 hypothesis) with other 5-FU-based therapies and a tar- Distant lymph nodes 14 35.9 get PFS of 4.3  months reflecting clinical activity of the Peritoneum 7 17.9 FOLFIRINOX regimen, with an α error of 0.05, we calcu- Multiple organs 13 33.3 lated that a total of 45 patients would provide 80% power CA19‑9 value (U/mL) in detecting an effect on the primary outcome, assum - > 10 times of UNL 21 53.8 ing a 10% rate of dropouts or withdrawals. PFS and OS ≤ 10 times of UNL 18 46.2 were computed using the Kaplan–Meier method with Patients who received 3rd line 12 30.8 two-sided 95% confidence intervals (CIs). Censored sub - chemotherapy jects are indicated on the Kaplan–Meier curve as tick ECOG PS Eastern Cooperative Oncology Group Performance status, CA19-9 marks; these marks do not terminate the interval. Cox carbohydrate antigen 19-9, UNL upper normal limit Kim et al. Cancer Commun (2018) 38:32 Page 4 of 8 and women were 29 (74.4%) and 10 (25.6%), respec- calculated median relative dose intensities (ranges) of tively. ECOG performance status was usually 0 or 1, 5-FU, oxaliplatin, and irinotecan were 76.4% (38%– except among two participants. A major protocol viola- 100%), 79.5% (40.8%–100%), and 76.4% (40.6%–100%), tion occurred involving two enrolled patients who each respectively. The number and proportion of dose reduc - had an ECOG PS score of 2. The two patients completed tions and delays are summarized in Table  2, while the scheduled chemotherapy without life-threatening com- dose reduction protocol is presented in Table 3. plications and had evaluable outcomes; therefore, they Four patients achieved a partial response. Seven- were included in the final analysis. Seven patients (17.9%) teen patients (43.6%) had stable disease, and 14 patients had locally advanced unresectable disease, while other (35.9%) had progressive disease. The ORR was 10.3% (4 of patients had metastatic disease. The most frequent meta - 39 patients), and the DCR was 64.1% (25 of 39 patients). static site was the liver (43.6%), while 13 patients (33.3%) After a median follow-up period of 17.9  months, the had multiple metastatic organ involvement. Twelve median PFS was 3.8  months (95% CI 1.5–6.0  months) patients (30.8%) received 3rd-line palliative chemother- and the median OS was 8.5  months (95% CI 5.6– apy after being censored from the study. Median serum 11.4  months). The 6-month and 1-year overall survival carbohydrate antigen 19-9 (CA19-9) and carcinoem- rates were 59.0% and 15.4%, respectively (Fig.  1). Multi- bryonic antigen (CEA) values were 864.0  IU/mL (2.0– variate analysis revealed no significant difference in PFS 400,000.0  IU/mL) and 10.3  U/mL (0.0–1386.0  U/mL) in or OS according to age, sex, primary tumor location, 39 patients, respectively. liver metastasis, serum level of CA 19-9, presence of dose delays, or reductions of FOLFIRINOX (Table 4). Treatment and outcomes A total of 215 cycles were delivered to 39 patients with Toxicity data a median of 3 cycles/patient (range 1–17 cycles). The The most common grade 3 or 4 toxicity was neutropenia (16/39, 41.0%), but no patient experienced febrile neu- tropenia. Nausea and anorexia (both 10.3%) were the second most common adverse events. Toxicity data are Table 2 Summary of dose reductions and delays presented in Table 5. Septic shock with infection focus in Characteristic Number % the biliary tract occurred in a patient at 24 days after the 3rd cycle of FOLFIRINOX administration. The patient’s Dose reductions and delays per patient white blood cell count was 27,000/mm on admission. Number of patients 39 The patient died 11 days after presenting septic shock. Dose delays 24 61.5 Dose reductions 11 28.2 Discussion Dose reductions and delays per cycle The present study prospectively investigated the safety Number of cycles 215 and efficacy of an attenuated dose of FOLFIRINOX as a Dose delays 47 21.9 second-line therapy for advanced pancreatic cancer and Dose reductions showed encouraging length of progression-free survival 5‑Fluorouracil 33 15.3 and overall survival, but was accompanied by significant Oxaliplatin 39 18.1 toxicity. Irinotecan 46 21.4 Table 3 Summary of events that resulted in dose reductions and delays Toxicity Grade Oxaliplatin, 5-FU/Leucovorin Irinotecan Hemoglobin Any grade No reduction Neutropenia 3 (ANC 500–999/mm ) No reduction (1 week delay) 3) 4 (ANC ≤ 499/mm 25% reduction 25% reduction Febrile neutropenia 3 (ANC < 1000/mm and body tempera‑ 25% reduction 25% reduction ture ≥ 38.5 °C) 4 (grade 3 febrile neutropenia and life 50% reduction 50% reduction threatening sepsis) Thrombocytopenia 3 (25,000–50,000/mm ) 25% reduction 25% reduction 4 (< 25,000/mm ) 25% reduction ANC absolute neutrophil count Kim et al. Cancer Commun (2018) 38:32 Page 5 of 8 pancreatic cancer. The treatment regimen consisted of 2 2 oxaliplatin 85 mg/m , irinotecan 130–135 mg/m , folinic 2 2 acid 400  mg/m , and 5-FU infusion 2400  mg/m over 46  h, administered every 14  days. Their study included 15 patients with stage IV disease and indicated 47% ORR, with median PFS and OS of 7.2 and 9.3 months, respec- tively. The authors reported grade 3 or 4 neutropenia in 5.6% of their patients and non-hematologic adverse events (grade 3 or 4 vomiting: 27.8%). Blazer et  al. [17] and Lakatos et  al. [18] tested modified FOLFIRINOX in patients with locally advanced disease. Dose intensities varied between the research groups, but these studies reported a relatively low rate of adverse events along with meaningful disease control. Umemura et  al. [19] used a modified dose of FOL - FIRINOX to treat a small group of patients with unre- sectable locally advanced or metastatic pancreatic cancer who failed on gemcitabine- and S-1-based therapies. The authors designed the modified regimen with oxaliplatin 2 2 75  mg/m , irinotecan 150  mg/m , folinic acid 320  mg/ 2 2, m , 5-FU bolus 320 mg/m and 5-FU infusion 1920 mg/ m administered every 21 days. After a total of 114 cycles were delivered in 13 patients, the ORR obtained was 30.8% with no CR, and median PFS and OS were 137 and 176  days, respectively. Five patients (38.5%) experi- enced grade 3 or 4 neutropenia, but febrile neutropenia did not occur. The other common grade 3 or 4 adverse events were anorexia, vomiting, and diarrhea (3, 1, and 1 patients, respectively). The incidence of grade 3–4 diar - rhea in clinical trials in the Republic of Korea has been low compared with that reported in Western trials. Simi- lar incidence is reported in Japanese patients. Ethnic differences in the activity of enzymes that metabolize irinotecan appear to be the cause. In a phase II trial of modified FOLFIRI.3 compared with modified FOLFOX as a second-line treatment for advanced pancreatic can- cer conducted by Yoo et al. [11] in Korea, irinotecan dose was 140  mg/m every 2  weeks, and grade 3–4 diarrhea was observed in 7% of 31 patients. Kobayashi et  al. [20] reported no occurrence of grade 3–4 diarrhea in 18 Japa- Fig. 1 Kaplan–Meier curves of progression‑free survival (PFS) nese patients who were enrolled in a prospective phase and overall survival (OS) for 39 patients with pancreatic cancer. I/II study of FOLFIRINOX as a second-line treatment a The median PFS was 3.8 months (95% confidence interval for metastatic pancreatic cancer. The phase I trial was a [CI] 1.5–6.0 months). b The median OS was 8.5 months (95% CI dose-finding study for irinotecan in combination with 5.6–11.4 months) fixed-dose 5-FU, leucovorin and oxaliplatin. As a result, an irinotecan dose of 100 mg/m was recommended. This finding is consistent with the frequent dose reduction of Although several analyses on the efficacy and safety irinotecan in this study. The results of those two trials are of modified doses of FOLFIRINOX have been per - very similar to those of the current study. formed, conclusive evidence is still lacking. Ghorani In a small retrospective analysis of salvage treatment et al. [16] retrospectively analyzed data from their single- with FOLFIRINOX, Lee et  al. [13] reported a DCR of center experience in the United Kingdom with modi- 55.6%, with median PFS and OS of 2.8 and 8.4 months, fied FOLFIRINOX for chemotherapy-naïve advanced respectively. These findings are similar to the outcomes Kim et al. Cancer Commun (2018) 38:32 Page 6 of 8 Table 4 Prognostic factor analysis of 39 patients treated with FOLFIRINOX as a second-line treatment Variable Progression-free survival Overall survival Median, months (95% CI) Univariate Multivariate Median, months (95% CI) Univariate Multivariate (p value) hazard ratio (p (p value) hazard ratio (p value) value) Age ≤ 60 years 2.3 (0.89–3.71) 0.209 0.565 (0.193) 8.5 (3.39–13.61) 0.514 0.563 (0.209) > 60 years 4.83 (2.15–7.51) 8.63 (5.58–11.69) Sex Male 3.3 (1.28–5.32) 0.827 8.5 (4.49–12.51) 0.854 Female 3.73 (0–9.46) 8.83 (5.24–12.42) Extent of disease Locally advanced 1.77 (0–4.22) 0.465 1.318 (0.616) 9.67 (7.22–12.12) 0.14 0.379 (0.05) Metastatic 4.7 (1.86–7.54) 6.37 (3.56–9.18) Primary tumor location Head 4.7 (0.51–8.89) 0.332 0.711 (0.399) 8.83 (5.55–12.11) 0.569 0.862 (0.719) Body or tail 2.9 (1.44–4.36) 7.6 (1.74–13.46) Liver metastasis Yes 6.53 (2.04–11.02) 0.414 0.642 (0.29) 6.37 (2.94–9.8) 0.459 1.052 (0.897) No 2.9 (0–6.19) 8.67 (8.18–9.16) CA19‑9 value (U/mL) > 10 times of UNL 3.93 (1.52–6.35) 8.5 (5.51–11.49) 0.972 0.653 ≤ 10 times of UNL 3.77 (1.17–6.37) 8.83 (2.66–14.99) CA19-9 carbohydrate antigen 19-9, UNL upper normal limit obtained with our attenuated dose of FOLFIRINOX, These outcomes suggest the need for a triple combi - although the FOLFIRINOX regimen reported by Lee nation of drugs for gemcitabine-refractory pancreatic et  al. consisted of the same dose as that of the origi- cancer, despite concerns regarding their higher toxicity. nal PRODIGE/ACCORD 11 trial. Clinical outcomes of Attenuated FOLFIRINOX therapy in our study several studies with modified FOLFIRINOX as a front - achieved a meaningful OS benefit, although the ORR fell line treatment appeared not to be inferior to those of short of our expectations. However, this dose-modified the original dose [21, 22]. In the CONKO-003 trial, FOLFIRINOX regimen did not reduce toxicity either. which confirmed the survival benefit of salvage chem - Forty-one percent prevalence of grade 3 toxicities or neu- otherapy described above, the median OS was 5.9 tropenia and an event of treatment-related mortality still and 3.3  months, and time to progression was 2.9 and leave concerns regarding the safety of this regimen. The 2.0  months (OFF versus FF, respectively). The efficacy small size of the study population for subgroup analysis, of OFF regimen was not significantly different from the absence of biomarker evaluation, and the lack of an that of our attenuated FOLFIRINOX in terms of PFS assessment of the quality of life are also limitations of the but tends to be inferior in terms of OS. In this previous present study. There is increasing interest in the feasibil - study, 25% of the subjects received third-line therapy, ity and safety of FOLFIRINOX as a second-line treat- similarly to our series of patients. The results of a few ment. Before initiation of our study, gemcitabine-based single-arm studies with irinotecan, fluorouracil, and front-line therapy was doubted for its survival benefit leucovorin (FOLFIRI) as a second-line chemotherapy because only modest effects were observed when gemcit - for pancreatic cancer have also been published. Zani- abine in combination with erlotinib was compared with boni et  al. [10] reported that 36% of patients showed gemcitabine alone. DCR, with median PFS and OS of 3.2 and 5  months, Recently, a new regimen of albumin-bound paclitaxel respectively, using a FOLFIRI regimen in the GISCAD (nab-paclitaxel) plus gemcitabine was shown to be supe- multicenter phase II study. Yoo et  al. [12] stated that rior to gemcitabine alone for OS as a front-line treatment DCR was achieved in 23% of patients, with a median in a randomized phase III study; thus, nab-paclitaxel plus OS of 3.9  months in response to their modified FOL - gemcitabine is becoming one of the most widely used FIRI.3 chemotherapy in a randomized phase II study. options as a first-line treatment [23–26]. Accordingly, the Kim et al. Cancer Commun (2018) 38:32 Page 7 of 8 Authors’ contributions Table 5 Hematologic and  nonhematologic adverse JH Kang conceptualized and designed the study, coordinated and supervised events which ever occurred in  39 patients treated the data collection, and approved the final manuscript as submitted. JH Kim with FOLFIRINOX as a second-line treatment and S‑ CL analyzed the data, drafted and revised the manuscript. SYO, SYS, NL, EMN, SL, IGH, HRL, KTL, S‑BB, HJK, JSJ, DHL, HWL, SYK contributed to execute Adverse event Any grade Grade 3 or more clinical trial. All authors agreed to be responsible for all aspects of the study. All authors read and approved the final manuscript Number % Number % of patients of patients Author details Department of Internal Medicine, Institute of Health Sciences, Gyeongsang Hematologic National University, 15 Jinju‑daero 816beon‑gil, Jinju 52727, Republic of Korea. Neutropenia 18 46.2 16 41.0 Divsion of Hematology and Oncology, Department of Internal Medicine, Thrombocytopenia 7 17.9 1 2.6 Soonchunhyang University Hospital Cheonan, Cheonan 31151, Republic of Korea. Department of Internal Medicine, Dong‑A University Hospital, Anemia 23 59.0 3 7.7 Busan 49201, Republic of Korea. Department of Internal Medicine, Kangwon Nonhematologic National University School of Medicine, Chuncheon 24289, Republic of Korea. Nausea 23 59.0 4 10.3 Divsion of Hematology and Oncology, Department of Internal Medicine, Soonchunhyang University Hospital Seoul, Seoul 04401, Republic of Korea. Vomiting 3 7.7 1 2.6 Department of Internal Medicine, Ewha Womans University, College of Medi‑ Diarrhea 11 28.2 1 2.6 7 cine, Seoul 07985, Republic of Korea. Department of Internal Medicine, Fatigue 9 23.1 2 5.1 Dankook University Hospital, Cheonan 31116, Republic of Korea. Department of Internal Medicine, Chung‑Ang University, College of Medicine, Seoul 06973, Anorexia 21 53.8 4 10.3 Republic of Korea. Division of Hematology and Medical Oncology, Depart‑ Constipation 6 15.4 ment of Internal Medicine, Korea Cancer Hospital, Seoul 01812, Republic Mucositis 12 30.8 3 7.7 of Korea. Department of Hematology‑Oncology, Ajou University Hospital, Suwon 16499, Republic of Korea. Neuropathy 5 12.8 1 2.6 Septic shock 1 2.6 Acknowledgements Pneumonia/pleural effusion 2 5.1 We would like to thank Editage (https ://www.edita ge.co.kr) for English language editing. Abdominal distension 1 2.6 Alkaline phosphatase 1 2.6 Competing interests increased The authors declare that they have no competing interests. Hypokalemia 1 2.6 Availability of data and materials Glossopharyngeal neuralgia 1 2.6 The datasets obtained and analyzed during the present study are available Grade 5 (death) from the corresponding author on reasonable request. Consent for publication Not applicable. importance of salvage chemotherapy, which involves nei- Ethics approval and consent to participate ther gemcitabine nor taxane, is increasing. This trial was approved by the respective institutional review boards of all 14 participating centers and the Korea Food and Drug Administration (KFDA). It The higher DCR and longer OS observed in the current was conducted in accordance with the principles of Declaration of Helsinki study justify the triple combination of FOLFIRINOX over and the International Conference on Harmonization of Good Clinical Practice. doublet regimens such as FOLFIRI or FOLFOX, even in All participating patients provided written informed consent. heavily pretreated pancreatic cancer patients. To date, Funding only a handful of regimens apart from FOLFIRINOX The present study was supported by a research Grant from Hanmi Pharma‑ could obtain a median OS beyond 8  months from ini- ceutical Co. Ltd., and the Soonchunhyang University Research fund. tiation of second-line therapy for advanced pancreatic Received: 5 August 2017 Accepted: 5 January 2018 cancer [26]. Based on these findings, a phase III trial to confirm the survival benefits of modified FOLFIRINOX as a second-line treatment for advanced pancreatic can- cer is being planned. References 1. Bae JM, Jung KW, Won YJ. Estimation of cancer deaths in Korea for the upcoming years. J Korean Med Sci. 2002;17:611. 2. Kim SG, Hahm MI, Choi KS, Seung NY, Shin HR, Park EC. The eco‑ Conclusions nomic burden of cancer in Korea in 2002. Eur J Cancer Care (Engl). FOLFIRINOX is not only a front-line treatment of choice 2008;17:136–44. 3. Jung KW, Park S, Kong HJ, Won YJ, Boo YK, Shin HR, et al. Cancer statistics for advanced pancreatic cancer but can also be a prom- in Korea: incidence, mortality and survival in 2006–2007. 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Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

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Cancer CommunicationsSpringer Journals

Published: Jun 4, 2018

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