www.nature.com/scientificreports OPEN The benefits of modified FOLFIRINOX for advanced pancreatic cancer and its induced Received: 29 September 2017 adverse events: a systematic review Accepted: 11 May 2018 Published: xx xx xxxx and meta-analysis Hongxuan Tong, Zhu Fan, Biyuan Liu & Tao Lu FOLFIRINOX has been one of the first-line options for advanced pancreatic cancer, even though it induces significant adverse effects. Several institutions have begun using modified FOLFIRINOX to decrease its side effects and increase its tolerability. We systematically investigated the outcome from patients who initially received modified FOLFIRINOX as a chemotherapy regimen for advanced pancreatic cancer. We used the random-model generic inverse variance method to analyse the binary data with 95% confidence intervals (CIs). Eleven studies were included in the meta-analysis with 563 total patients. The 6-month and 1-year overall survival (OS) rates of locally advanced pancreatic cancer (LAPC) were 90.9% and 76.2%. The 6-month and 1-year progression-free survival (PFS) rates of LAPC were 81.5% and 48.5%. The 6-month and 1-year OS rates of metastatic pancreatic cancer (MPC) were 79.7% and 47.6%. The 6-month and 1-year PFS rates of MPC were 56.3% and 20.6%. The following rates were also calculated: complete response rate (CR): 2.9%; partial response rate (PR): 35.9%; stable disease rate (SD): 41.2%; overall response rate (OR): 34.6%; disease control rate (DCR): 76.7%; progressive disease: 23.1%; and grade III/IV adverse events (AEs): neutropenia 23.1%, febrile neutropenia 4.8%, thrombocytopenia 4.8%, anaemia 5.7%, fatigue 11.5%, nausea 9.1%, diarrhoea 10.1%, vomiting 5.7%, neuropathy 3.8%, and increased ALT 5.7%. In conclusion, modified FOLFIRINOX could provide comparative survival benefits with fewer adverse events compared to the conventional dosage. Pancreatic cancer (PC) has one of the highest cancer mortality rates in the world . In 2017, the estimated num- ber of deaths from pancreatic cancer was 43,090 in the United States; further, the 5-year relative survival rate was only 8%, and that of the distant stage was only 3% . Pancreatic cancer is currently the third leading cause 3 4 of cancer-related deaths in the United States and will become the second leading cause in 2030 . Because most 5–8 cases are diagnosed at late stages as either metastatic or locally advanced , curative surgical resection can be 9,10 performed in only 15–20% of cases . Other than surgical resection, systemic chemotherapy is the only major treatment that can improve survival for patients with locally advanced or metastatic pancreatic cancer. Twenty years ago, gemcitabine (GEM) replaced 5-fluorouracil (5-FU) as the main chemotherapeutic drug for treating advanced pancreatic cancer because a modest survival increase (5.65 vs 4.41 months) and more clinical benefits were found in a Phase III clinical trial . Since then, gemcitabine monotherapy had been the gold standard for pancreatic cancer. Later, numerous clinical trials combined gemcitabine with other anti-tumour agents to increase the anti-tumour effects, but most such studies were unable to demonstrate the superiority of or a significant improvement in OS for gemcitabine combi- 5,6,12,13 nation therapy; only gemcitabine combined with capecitabine and erlotinib have shown promise . Recently, in the PRODIGE 4/ACCORD 11 randomized trials, a four-drug regimen called FOLFIRINOX, con- sisting of folinic acid, 5-u fl orouracil, irinotecan and oxaliplatin, was demonstrated to prolong overall survival compared to gemcitabine monotherapy (11.1 months vs 6.8 months). These results suggested that this combined School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 10029, China. Correspondence and requests for materials should be addressed to T.L. (email: email@example.com) Scientific Repo R ts | (2018) 8:8666 | DOI:10.1038/s41598-018-26811-9 1 www.nature.com/scientificreports/ regimen should be used in clinical practice as a first-line option for advanced pancreatic cancer patients . Shortly thereaer ft , a regimen of gemcitabine and albumin-bound paclitaxel was shown to have statistically significant sur - vival benet fi s in OS and PFS, thus providing another choice for treating advanced pancreatic cancer . However, FOLFIRINOX appears to be more effective than GEM/NAB-P . Although FOLFIRINOX is a first-line option for patients with metastatic pancreatic cancer, there is a controversy about whether the survival benefits of the four-drug combination regimen outweigh the associated toxicities . The significant adverse effects induced by this regimen include neutropenia, thrombocytopenia, febrile, diarrhoea neutropenia, febrile neutropenia, thrombocy- topenia, diarrhoea, and neuropathy, which limit its usage and require stopping chemotherapy during treatment. Therefore, FOLFIRINOX is usually prescribed for patients ≤ 76 years old who have a good performance status (ECOG 0 or 1) . To decrease the side effects and increase its tolerability, several institutions have used modified FOLFIRINOX. We conducted a systematic review and meta-analysis to assess the effectiveness and toxicities of modified FOLFIRINOX for patients with advanced pancreatic cancer compared to the conventional dosage. Methods Literature search. A systematic search was conducted to find eligible articles. Two investigators inde- pendently searched for prospective or retrospective studies (phase I-III trials, cohort studies, or case series) using Embase, PubMed, Web of Science, Scopus, and Cochrane without an upper-limit date until December 31, 2017. The search criteria included studies of advanced pancreatic cancer patients at any age who received any type of modified FOLFIRINOX in initial chemotherapy without language restrictions and no consideration of subse- quent treatment. The preceding original regimen of FOLFIRINOX contained oxaliplatin 85 mg/m , leucovorin 2 2 2 2 400 mg/m , irinotecan 180 mg/m , 5-fluorouracil (5-FU) bolus 400 mg/m and 5-fluorouracil (5-FU) 2400 mg/m . Modified FOLFIRINOX was defined as at least one of the drugs was reduced and/or the removal of 5-FU bolus in FOLFIRINOX . The search strategy was as follows: ((‘folinic acid’/exp AND fluorouracil/exp AND irinotecan/exp AND oxaliplatin/exp AND ‘drug combination’/exp) or (Folfirinox):ab,ti) and (‘pancreas cancer’/de OR ‘pancreas tumor’/de OR ‘pancreas adenoma’/de OR ‘pancreas adenocarcinoma’/de OR ‘pancreas carcinoma’/de OR ‘pan- creas islet cell carcinoma’/de OR (pancrea* NEAR/3 (cancer* OR neoplas* OR tumo* OR adenocarcinom* OR carcinom* OR adenom*)):ab,ti). For the detailed search strategy, see the supplement. After removing duplicate articles, two investigators independently reviewed the abstracts. Studies were excluded if the study type was a review/meta-analysis, case report, comment, letter to the editor, or irrelevant literature. Differences between the investigators were resolved by a third-party investigator’s opinion. Full articles were then selected for further assessment, and articles with only abstracts were excluded. Other exclusion crite- ria included studies that used a regimen other than modified FOLFIRINOX, did not include the initial usage of modified FOLFIRINOX or dose adjusted by physician’s judgement without a specific time or presented the same patient cohort in another study. For details of the excluded articles, see the Supplement. Data extraction. General information was extracted from the foregoing selected publications and included the name of article, first authors, the name of journal, year of publication, study design, participating cen- tres, country, observation sites, beginning and ending time, tumour stage, the composition of the modified FOLFIRINOX, its usage, number of patients, the ratio of males and females, average age, duration of follow-up, and performance status. Survival was evaluated by the OS (6-month and 1-year) and PFS (6-month and 1-year) for the LAPC and MPC groups, which were extracted from the selected publications. If the survival rates were not directly available from the articles or authors, Engauge Digitizer was used to pool survival data from the Kaplan–Meier survival curve in each selected publication, especially for advanced pancreatic cancer reports for which the OS and PFS rates were not provided . We chose the complete response (CR), partial response (PR), overall response (OR), stable disease (SD), disease control ratio (DCR), and progressive rate to evaluate the objective response to chemotherapy. The adverse events were calculated when they achieved grade III/IV. Grade III/IV toxicity includes neutropenia, febrile neutropenia, thrombocytopenia, anaemia, fatigue, vomiting, nausea, diarrhoea, neuropathy, and increased ALT. Statistical analysis. First, we used the Critical Appraisal Skill Program (CASP) to evaluate each study (sup- plement). The CASP is a critical appraisal tool that is used in observational studies to assess the methodological quality of the individual studies. Binary data were meta-analysed with the random-model generic inverse vari- ance method. We used random-effects rather than fixed-effects models because of the heterogeneity in the initial treatment of advanced pancreatic cancer. We used the odds ratio as the effect measure method and then changed 2 2 2 it to probability. The I statistics reflected the heterogeneity: I = 0% indicated no heterogeneity, I = (0%,25%) 2 2 indicated low heterogeneity, I = [25%,50%) indicated mild heterogeneity, I = [50%,75%) indicated moder- 2 19 ate heterogeneity, and I = [75%,100%] indicated high heterogeneity . All analyses were performed in Review Manager version 5.3 and Excel 2010. Results Study search. Figure 1 is a flow diagram that shows the selection process for the searched studies. We searched all databases that are available. There were 4772 related studies identified from the initial literature search; 2541 studies were eliminated because of duplications. Only 70 studies were eligible upon abstract screen- 20–30 ing. Aer f ft ull-text screening, only 11 studies remained, and they were included in the final analysis . In these 11 studies, there were 563 patients, including 333 MPC and 230 LAPC. The number of patients who were treated with modified FOLFIRINOX ranged from 10 to 137. The average age in each study ranged from 60 to 65 years old (Table 1). Most patients’ performance status was 0 or 1, and a small portion had a score of 2 . Most 2 2 27,29 of the studies removed the 5-FU bolus, but two studies reduced the dose from 400 mg/m to 300 mg/m . There Scientific Repo R ts | (2018) 8:8666 | DOI:10.1038/s41598-018-26811-9 2 www.nature.com/scientificreports/ Figure 1. Flow chart for study search (PRISMA diagram). 26,31 2 was an overlap of population in one study . The most usage of continuous infusion 5-FU was 2400 mg/m , 2 2 28 but one study increased it to 2800 mg/m or 3200 mg/m and eliminated the 5-FU bolus . The most frequently used dose of oxaliplatin was the same as the normal FOLFIRINOX regimen, but two studies used 63.75 mg/m 2 29,31 2 2 and 68 mg/m . The dosage of irinotecan ranged from 135 mg/m to 180 mg/m . For the detailed modified FOLFIRINOX regimens, see Table 2. Survival date. We divided advanced pancreatic cancer into LAPC and MPC to analyse the survival date because of the different prognoses between them. The pooled 6-month and 1-year OS rates of LAPC were 2 2 90.9 (95% CI 82.7–95.1%. I = 0%, P for Heterogeneity: 0.82) and 76.2% (95% CI 64.5–84.9%. I = 37%, P for Heterogeneity: 0.19). The pooled 6-month and 1-year PFS rates of LAPC were 81.5% (95% CI 69.3–89.6%. 2 2 I = 46%, P for Heterogeneity: 0.10) and 48.5% (95% CI 38.7–58.2%. I = 27%, P for Heterogeneity: 0.23). The pooled 6-month and 1-year OS rates of MPC were 79.7% (95% CI 74.6–84.1%. I = 0%, P for Heterogeneity: 0.56) and 47.6% (95% CI 36.3–58.8%. I = 68%, P for Heterogeneity: 0.004). The pooled 6-month and 1-year PFS rates of MPC were 56.3% (95% CI 49.2–63.1%. I = 26%, P for Heterogeneity: 0.23) and 20.6% (95% CI 13.8–29.1%. I = 54%, P for Heterogeneity: 0.04) (Fig. 2). Response rates. The pooled complete response rate (CR) was 2.9% (95% CI 1.0–10.7%. I = 37%, P for Heterogeneity: 0.21). The pooled partial response rate (PR) was 35.9% (95% CI 30.6–41.2%. I = 5%, P for Heterogeneity: 0.39). The pooled stable disease rate (SD) was 41.2% (95% CI 29.1–54.5%. I = 79%, P for Heterogeneity: <0.0001). The pooled overall response rate (OR) was 34.6% (95% CI 27.5–42.5%. I = 44%, P for Heterogeneity: 0.08). The pooled disease control rate (DCR) was 76.7% (95% CI 68.4–83.4%. I = 54%, P for Heterogeneity: 0.04). The pooled progressive disease was 23.1% (95% CI 16.7–31.5%. I = 54%, P for Heterogeneity: 0.04) (Fig. 3 and Table 3). Adverse events. There were 344 grade III/IV adverse events in our study (Table 4). Figure 4 shows the pooled event rates for grade III/IV adverse events. The pooled grade III/IV incidences of neutropenia, febrile neutropenia, thrombocytopenia, and anaemia were 23.1% (95% CI 11.5–41.2%. I = 89%, P for Heterogeneity: 2 2 <0.00001), 4.8% (95% CI 1.0–16%. I = 70%, P for Heterogeneity: 0.02), 4.8% (95% CI 2.9–8.3%. I = 0%, P for Heterogeneity: 0.88), and 5.7% (95% CI 2.9–9.9%. I = 36%, P for Heterogeneity: 0.18). Scientific Repo R ts | (2018) 8:8666 | DOI:10.1038/s41598-018-26811-9 3 www.nature.com/scientificreports/ Tumour Tumour Number Median location location Metastasis Metastasis Year of Start End of Males PS (%) age Head/ Body/ Number Number Metastasis Metastasis Metastasis in in lymph Author publication Country Time Time patients (%) 0/1/2 (range) Neck Tail of LAPC of MPC in liver in lungs in bones peritoneal nodes Stein 2016 USA 2011.11 2014.1 68 62% 47/53/0 62(46–79) 44 18 31 37 20 12 0 14 15 Vivaldi 2016 Italy 2008 2014 137 48% 67/33/0 60(33–75) 73 62 56 81 64 14 4 26 0 Mahaseth 2013 USA 2010.6 2012.6 56 57% 22/76/2 63(36–78) 42 18 20 36 NA Ghorani 2015 UK 2011.7 2014.5 18 44% 56/44/0 60(40–77) 10 1 3 15 NA Nanda 2015 USA 2010.6 2013.3 29 41% 14/62/24 62(36–77) 24 5 29 0 NA Vočka 2016 Czech 2013.1 2016.7 47 60% 57/43/0 62(40–72) 28 19 18 29 26 2 0 4 2 Liang* 2016 China 2014.4 2015.1 76 67% 61/39/0 61(38–75) NA NA 14 62 49 1 0 7 10 Chllamma 2016 Canada 2011.12 2014.7 66 NA NA 64(28–76) NA NA 22 44 NA Takeda 2015 Japan 2014.1 2015.7 10 40% 90/10/0 65(59–75) 4 6 2 8 NA Blazer 2014 USA 2011.1 2013.8 25 48% 100%/0 62(40–81) 9 16 25 0 NA Yoshida 2017 Japan 2014.1 2016.5 31 58% 81/19/0 64(49–72) 15 16 10 21 13 3 3 0 0 Total 563 230 333 172 32 7 51 27 Table 1. Summary of the included studies. *er Th e was an overlap in their study population. PS: ECOG performance status. Chemotherapy regimens Author Oxaliplatin Folinic acid Irinotecan 5-FU bolus 5-FU 27 2 2 2 2 2 Stein 85 mg/m 400 mg/m 135 mg/m 300 mg/m 2400 mg/m 2 2 2 2 85 mg/m 200 mg/m 150 mg/m None 2800 mg/m Vivaldi 2 2 2 2 85 mg/m 200 mg/m 165 mg/m None 3200 mg/m 21 2 2 2 2 Mahaseth 85 mg/m 400 mg/m 180 mg/m None 2400 mg/m 130–135 mg/ 20 2 2 2 Ghorani 85 mg/m 400 mg/m None 2400 mg/m 23 2 2 2 2 Nanda 85 mg/m 400 mg/m 180 mg/m None 2400 mg/m 29 2 2 2 2 Vočka 63.75 mg/m 300 mg/m 135 mg/m 300 1800 mg/m 26 2 2 2 2 Liang 68 mg/m 400 mg/m 135 mg/m None 2400 mg/m Chllamma No specific regimen 24 2 2 2 2 Takeda 85 mg/m 200 mg/m 150 mg/m None 2400 mg/m 30 2 2 2 2 Yoshida 85 mg/m 200 mg/m 150 mg/m None 2400 mg/m 22 2 2 2 Blazer 85 mg/m None 165 mg/m None 2400 mg/m Table 2. e det Th ailed regimens of modified FOLFIRINOX. Number of Author CR PR OR SD DCR patients Stein 0 18 18 43 61 66 Vivaldi 1 52 53 46 99 137 Ghorani 1 6 7 5 12 15 Vočka 2 13 15 12 27 41 Liang 0 23 23 16 39 54 Takeda 0 1 1 8 9 10 Blazer NA NA 2 NA NA 23 Yoshida 0 12 12 11 23 31 Total 4 125 131 141 270 377 Table 3. e c Th hemotherapy response to modified FOLFIRINOX. CR: complete response rate. PR: partial response rate. SD: stable disease rate. OR: overall response rate. DCR: disease control rate. e p Th ooled incidences of non-haematological AEs were as follows: fatigue 11.5% (95% CI 7.4–16.7%. I = 0%, P for Heterogeneity: 0.80), nausea 9.1% (95% CI 5.7–15.3%. I = 33%, P for Heterogeneity: 0.19), diarrhoea 10.1% 2 2 (95% CI 7.4–15.3%. I = 32%, P for Heterogeneity: 0.17), vomiting 5.7% (95% CI 2.9–12.3%. I = 66%, P for Heterogeneity: 0.008), neuropathy 3.8% (95% CI 2.0–7.4%. I = 10%, P for Heterogeneity: 0.35), and increased ALT 5.7% (95% CI 2.9–11.5%. I = 54%, P for Heterogeneity: 0.09) (Fig. 5). Scientific Repo R ts | (2018) 8:8666 | DOI:10.1038/s41598-018-26811-9 4 www.nature.com/scientificreports/ Figure 2. Meta-analysis for survival date. SE: standard error. IV: random-model generic inverse variance method. 95% CI: 95% confidence interval. Figure 3. Meta-analysis for objective response rate. SE: standard error. IV: random-model generic inverse variance method. 95% CI: 95% confidence interval. Discussion Our systematic review and meta-analysis considered 11 studies, which contained 563 patients with advanced pan- creatic cancer treated with modified FOLFIRINOX. Previously, FOLFIRINOX was used to treat advanced pan- creatic adenocarcinoma and demonstrated a better therapeutic benefit than gemcitabine (GEM) . Although the dosage of FOLFIRINOX was reduced, the 12-month survival rate was still much higher than those of gemcitabine Scientific Repo R ts | (2018) 8:8666 | DOI:10.1038/s41598-018-26811-9 5 www.nature.com/scientificreports/ Adverse events Stein Vivaldi Mahaseth Ghorani Nanda Vočka Chllamma Takeda Yoshida Liang Blazer Total patients Neutropenia 9 49 2 0 2 4 26 23 0 115 Thrombocytopenia 2 8 3 0 0 1 2 3 0 19 Febrile neutropenia 3 1 NA 1 NA NA 5 0 NA 10 Anaemia 4 4 NA 0 1 2 0 5 NA 16 Fatigue 9 NA 8 1 NA NA NA 0 4 22 Nausea NA 10 NA 4 4 2 1 NA 2 23 Diarrhoea 12 11 8 3 4 0 2 1 6 47 Vomiting 2 5 5 5 3 0 1 1 0 22 Neuropathy 2 3 3 0 1 NA 3 0 0 12 Increased ALT 3 6 NA 0 1 NA NA 9 NA 19 NA NA Asthenia NA 2 NA NA NA NA NA NA NA 2 Thromboembolic event 3 6 0 0 NA NA NA 0 NA 9 Stomatitis NA 9 NA NA NA NA NA NA NA 9 Gastrointestinal haemorrhage NA NA NA NA NA 1 NA NA NA 1 Anorexia NA 4 NA NA NA 0 2 NA NA 6 Allergic reaction NA NA 2 NA NA NA NA NA NA 2 Mucositis NA NA 1 NA NA NA 0 NA 0 1 Infection NA NA 3 NA NA NA NA 3 NA 6 Dysarthria NA NA NA 1 NA NA NA NA NA 1 Hyperbilirubinemia NA NA NA NA NA NA NA NA 2 2 Total events 49 118 35 15 NA 16 NA 10 42 45 14 344 Table 4. e ad Th verse events of modified FOLFIRINOX. Figure 4. Meta-analysis for adverse events of haematological AEs. SE: standard error. IV: random-model generic inverse variance method. 95% CI: 95% confidence interval. 11,33–36 and its combinational regimen, with the first at 76.2% in LAPC and 47.6% in MPC, compared to 18–37.2% . Since then, many clinical studies have been assessed the treatment of advanced pancreatic cancer by using mod- ified FOLFIRINOX. Compared to the preceding original regimen of FOLFIRINOX, the OS and PFS at 6 and 12 14,20,37,38 months for modified FOLFIRINOX were nearly equivalent . Similar to the data obtained for OS and PFS, as mentioned above, the response rate of modified FOLFIRINOX was also comparable to that of the original 14,20,37,38 regimen . Nevertheless, the favourable overall survival aer ft modified FOLFIRINOX might be partly attrib - utable to patient selection from many non-randomized studies. For the adverse events, the pooled rates of grade III/IV adverse events were lower than those of the 14,39,40 FOLFIRINOX group; some were even lower than the GEM group , such as anaemia, fatigue and vomiting. Concomitantly, a prospective phase II study of dose-attenuated treatment found that modified FOLFIRINOX could signic fi antly reduce the occurrence of vomiting and fatigue . As we know, in practice, when patients expe- rience serious adverse events during continuous FOLFIRINOX chemotherapy, the strategy for physicians is to reduce the dosage or even stop the chemotherapy. Therefore, modified FOLFIRINOX is a good choice at the begin- ning of therapy, particularly for those with poor performance status. Modified FOLFIRINOX provides a rela- tively mild intervention and thus induces lower adverse events, thereby ensuring the continuity of chemotherapy. Scientific Repo R ts | (2018) 8:8666 | DOI:10.1038/s41598-018-26811-9 6 www.nature.com/scientificreports/ Figure 5. Meta-analysis for adverse events of non-haematological AEs. SE: standard error. IV: random-model generic inverse variance method. 95% CI: 95% confidence interval. Interestingly, there was a great difference between the Asian group and Euromerican group in neutropenia (48.5% [20.6%, 77.4%] vs 10.7% [2.9%, 31.3%]). This may be due to different genetic traits between the ethnic groups. In general, the modified FOLFIRINOX regimen could provide good survival benefits for patients with advanced pancreatic cancer by increasing the OS and PFS and causing fewer adverse events. Our findings sug- gest that the dosage attenuation of initial FOLFIRINOX improves its tolerability without compromising its effi- cacy. Compared to the original regimen of FOLFIRINOX, modified FOLFIRINOX may be more applicable for patients with poor performance status. 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Annals of surgical oncology (2014). 41. Ginocchi, L. et al. Modified FOLFOXIRI in Advanced Pancreatic Cancer. Jop Journal of the Pancreas 23, 238–238 (2012). Author Contributions Hongxuan Tong designed the study and performed the literature search, analysis, quality evaluation, interpretation of data and drafting. Zhu Fan and Biyuan Liu performed the study search, quality evaluation and picture processing. Tao Lu contributed to general management. All authors reviewed and approved the final manuscript. Additional Information Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-018-26811-9. Competing Interests: The authors declare no competing interests. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre- ative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not per- mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2018 Scientific Repo R ts | (2018) 8:8666 | DOI:10.1038/s41598-018-26811-9 8
Scientific Reports – Springer Journals
Published: Jun 6, 2018
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