Forty patients (62.5%) required dose reductions. Fewer patients required dose reduction in the resected group than in the non-resected group (33.3% (5/15) vs 71.4% (35/49), respectively, P = .013), although cRDIs did not differ between groups (71.8% vs 69.6%, respectively). Nineteen patients were not suited for resection and required further SBRT, and resection was achieved in 2 additional patients after SBRT (Table 2). The overall response and disease control rates were much higher in the resected group than in the non-resected group (32.7% and 8.2% vs. 100% and 66.7%, P < .001, respectively) (Table 3).
Adverse effects are summarized in Table 4. There were no statistical differences between the resected and non-resected groups in terms of adverse effects, although the non-resected group showed a higher rate of non-hematologic adverse effects. Ten out of 64 patients (15.6%) experienced febrile neutropenia, which did not differ between the groups. However, grade 4 febrile neutropenia was observed in 3 patients of the non-resected group, among whom 2 experienced mortality due to sepsis, even after schedule and dose modification of FOLFIRINOX and use of G-CSF.
3.3 Surgical and long-term outcomes
Table 5 summarizes the clinical data for 15 patients who underwent surgery for LAPC after neoadjuvant FOLFIRINOX. The median time to resection was 6.7 months (3.2–14.3 months). Among the 15 patients, 8 patients received pancreaticoduodenectomy and 7 received distal pancreatectomy. Eleven patients achieved R0 resection following FOLFIRINOX therapy (73.3%), 9 patients had lymph nodes metastases, and 1 patient achieved pathologic complete response. Twelve patients received adjuvant chemotherapy (gemcitabine-based chemotherapy in 11 patients). One patient, who displayed a systemic erythematous lupus disorder, died of postoperative complication of acute mesenteric artery thrombosis, despite heparinization after surgery.
During a median follow-up time of 9.4 months after resection (1.8–35.5 months) and 23.1 months after diagnosis (15.0–46.1 months), 4 patients observed recurrences in 3.3, 5.1, 13.9, and 15.7 months, respectively, after resection. The cumulative recurrence rate was 14.3% at 6 months and 28.5% at 18 months after resection. Among this cohort, 2 patients remained alive 20.2 months and 35.5 months, respectively, after resection (26.3 and 43.4 months after diagnosis, respectively). Ten patients did not experience recurrence during the median follow-up time of 20.3 months after resection (10.7 – 35.5 months) and 23.9 months after diagnosis (15.0–46.1 months).
The median OS for all enrolled patients was 17.0 months (1.9–46.1 months). The 1-year survival rate for all patients was 70.3% and the 2-year survival rate was 34.7%. The median OS of the resected group was unable to be accurately calculated because > 50% of patients remain alive (> 40 months) but was clearly better than that of the non-resected group (13.0 months) (Fig. 2).
3.4 Predictors associated with resectability
As shown in Table 6, the presence of dose reduction was associated with the failure to convert to resectability in univariate and multivariate logistic regression. The patients who received reduced dose intensity in each cycle had lower probability of subsequent resection compared with patients who received standard dose of FOLFIRINOX (P = .024), although cRDIs did not display statistically significant differences between the groups (P = .639). None of the other factors included in the regression analyses were associated with resectability.
This study presents outcomes of a large series of patients with LAPC who received neoadjuvant FOLFIRINOX chemotherapy as a naïve treatment in a single institution. Our data show that 23.4% of patients with LAPC became resectable and surgical candidates, and R0 resection was achieved in 73.3% of patients after adequate FOLFIRINOX chemotherapy, in agreement with a report from the western countries (25.9% and 78.4%, respectively). Furthermore, our data demonstrate that, for obtaining resectability, it is advantageous to administer FOLFIRINOX without dose reduction, if tolerated by the patient.
According to the meta-analysis released in 2012, after gemcitabine-based neoadjuvant chemotherapy in patients with LAPC, resection was performed in 27% of cases and the R0 resection ratio was only 23%. In contrast, our data show that around 1/4th of patients with LAPC can undergo resection, of which about 75% are R0 resections, and this is in accordance with a recent systematic review of FOLFIRINOX. In agreement with our results, patients with LAPC who underwent surgery after neoadjuvant FOLFIRINOX can expect median OS of > 3 years, which is much longer than the median OS (∼24 months) of patients with resected pancreatic cancer. Therefore, the treatment strategy for patients with LAPC should be changed to curative intent, rather than palliation, in the era of FOLFIRINOX.
While methodologies and influential factors towards achieving higher resection rate have not been well described, we found that patients who maintain planned dose of FOLFIRINOX are more likely to convert to displaying a resectable tumor than those who do not, despite similar total administered dosage of FOLFIRINOX during treatments. In other words, interval modification may confer more resectability outcomes than dose modification, and we suggest to 1st consider interval modification, and whether dose or schedule should be inevitably modified due to variable reasons. Our results are supported by a recent study, which found that increasing the number of full-dose neoadjuvant FOLFIRINOX treatments was significantly associated with increased survival.
FOLFIRINOX displays adverse effects. Recently published eastern data show much higher rates of grade 3 or 4 febrile neutropenia in comparison with a report from the Western countires (15.6% of our institution / 22.2% of Japanese patients vs. 5% of Western patients).[10,14,15] In this study, 2 patients died of neutropenic fever and accompanying complications after FOLFIRINOX, despite the use of G-CSF and adequate dose and interval modification. This observation suggests that there may be interracial differences, especially since there were no treatment-related mortalities (0/355) in a recent systematic review from Western country. Clinicians face a dilemma of how to maintain dose intensity while avoiding febrile neutropenia in patients with LAPC who are treated with FOLFIRINOX, especially in Asian populations. We do not observe febrile neutropenia after the use of pegylated G-CSF. Based on our experience and recent study showing preventive effect of pegylated G-CSF against neutropenia during FOLFIRINOX, we would suggest that pegylated G-CSF can be an option for keeping FOLFIRINOX dose intensity, although it requires further investigation.
The role of radiotherapy in patients with LAPC remains a controversial issue. Nineteen patients had SBRT with FOLFIRINOX and 2 patients achieved resectability (2/19, 10%). This suggests that SBRT increases resectability when resectable status is not achieved, even after adequate administration of FOLFIRINOX in patients with LAPC. Although SBRT has theoretical advantages, such as short duration of radiation, delivery of more ablative doses to the tumor, and minimization of interrupting systemic chemotherapy, the role of SBRT in patients with LAPC requires further clarification in the future.
This study was limited to a single center retrospective analysis; however, our data can be considered valuable because 64 patients with LAPC who received FOLFIRINOX from a single center represent one of the largest cohorts in the world, particularly in Asian populations. Although we discovered that FOLFIRINOX without dose modification provides a higher rate of subsequent resectability in patients with LAPC, prospective studies should be conducted to further clarify this finding.
In conclusion, FOLFIRINOX should be considered as an active regimen in patients with LAPC, since this therapy provides an acceptable resection rate and promising R0 resection rate. If patients tolerate this treatment, the administration of FOLFIRINOX without dose reduction is associated with achieving resectability.
These data were presented in part at the ASCO Gastrointestinal Cancer Symposium 2017, San Francisco, California.
Conceptualization: Jaihwan Kim, Jin-Hyeok Hwang.
Data curation: Jongchan Lee, Jong-chan Lee, Hyoung Woo Kim.
Formal analysis: Jongchan Lee, Jin-Hyeok Hwang.
Investigation: Jongchan Lee, Hyoung Woo Kim, Jin-Hyeok Hwang.
Methodology: Jongchan Lee, Jaihwan Kim, Jin-Hyeok Hwang.
Project administration: Jongchan Lee.
Resources: Jinwon Kim, Jaihwan Kim.
Software: Jong-chan Lee.
Supervision: Jin-Hyeok Hwang.
Validation: Jong-chan Lee, Jin-Hyeok Hwang.
Visualization: Jongchan Lee.
Writing – original draft: Jongchan Lee.
Writing – review & editing: Jongchan Lee, Mark A. Gromski, Jin-Hyeok Hwang.
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Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
dose intensity; FOLFIRINOX; locally advanced pancreatic cancer; R0 resection; toxicity