The main finding of the present study was that nal-IRI + 5-FU/l-LV therapy was considered to be a useful regimen as second-line or later treatment for unresectable advanced pancreatic cancer, even in clinical practice. An NLR of ≥ 2.7 was a significant predictive factor for the OS.
In a systematic review of 71 studies in patients with unresectable advanced pancreatic cancer who received various second-line treatments, the median OS among all treatments ranged from 4.0 to 5.4 months [19]. Oxaliplatin has been investigated as a second-line treatment for patients with metastatic pancreatic cancer [20, 21]. In the CONKO-3 trial, the median OS was 5.9 months for oxaliplatin + 5-FU/folinic acid as second-line treatment after first-line gemcitabine monotherapy [20]. In the PANCREOX phase 3 study, the median OS was 6.1 months for biweekly modified FOLFOX6 as second-line treatment after first-line gemcitabine monotherapy [21]. In the present study, the median OS was 9.0 months, which was considered to be satisfactory in comparison with the previous regimen of second-line treatment.
The median OS and PFS were reported to be 6.2 (95% CI 4.8-8.4) months and 3.1 (95% CI 2.7-4.2) months, respectively, in the NAPOLI-1 study [11, 12]. A phase II trial in Japan also demonstrated a similar median OS and PFS of 6.3 and 2.7 months, respectively, with a tolerable safety profile [13]. The median OS and PFS in the current study seemed to be slightly better than those in NAPOLI-1 study and the phase II trial in Japan. The ORR and DCR were previously reported to be 17% and 52%, respectively, in the NAPOLI-1 study [11, 12], and a phase II trial in Japan demonstrated a similar ORR (17.5%) and DCR (52.5%) calculated based on the best response [13]. In the present study, the ORR and DCR were 5.3% and 44.7%, respectively, which were slightly worse than those values in previous reports. The American Society of Clinical Oncology Clinical Practice Guidelines for the treatment of metastatic pancreatic cancer recommend nal-IRI + 5-FU/l-LV as second-line therapy in patients previously treated with gemcitabine plus nab-paclitaxel [22], and the current National Comprehensive Cancer Network guidelines for the treatment of pancreatic cancer recommend nal-IRI + 5-FU/l-LV as category 1 second-line therapy for metastatic disease [23].
The NLR showed a significant difference as a predictive factor for the OS and response in the present study. Inflammation has recently been considered to play an essential role in cancer progression. A number of inflammation-based prognostic factors have been developed, including the GPS, mGPS, PLR, NLR, CRP/Alb ratio and PNI [16–18, 24–26]. Iwai et al. [27]. reported that a high NLR might be an independent indicator of a poor prognosis in patients with unresectable pancreatic cancer. In their study, the NLR was the best predictive factor among the GPS, mGPS, PLR, CRP/Alb ratio and PNI [27]. Although all of these inflammation-based prognostic factors reached statistical significance in their study [27], only the NLR and CRP/Alb ratio reached statistical significance in the present study. In their receiver operator characteristic analyses for the OS at six-month follow-up, the AUC area was the greatest for the NLR, followed in descending order by the CRP/Alb ratio, GPS, PNI, mGPS and PLR [27]. The sequence of the AUC area in the present study was similar to the previous report: NLR, CRP/Alb ratio, mGPS, PNI and PLR. If the number of patients were increased in our study, not only the NLR and CRP/Alb ratio but also other factors, namely the mGPS, PNI and PLR, might have also shown statistical significance.
The mechanism underlying the relationship between the NLR and prognosis in patients with unresectable pancreatic cancer remains to be clarified. Neutrophils inhibit the immune response by lymphocytes, natural killer cells or activated T cells [28, 29], while lymphocytes reflect the immune response of the host to either infection or cancer. Tumor-infiltrating lymphocytes are reported to be associated with a good prognosis in patients with pancreatic ductal adenocarcinoma [30]. Baseline characteristics associated with long-term survivors who survived for more than one year in the NAPOLI-1 study [11, 12] were a younger age, better performance status, lower NLR, lower CA19-9 level and absence of liver metastases. Six of the 44 patients survived for more than one year from start of nal-IRI + 5-FU/LV treatment in the present study. Although the number of long-term survivors in our study was small, a lower NLR and lower CA19-9 level seemed to be associated with a long-term survival.
AEs were manageable, although gastrointestinal symptoms and blood cell AEs were observed. The most common grade ≥3 AE in this study was neutropenia (20.0%), followed by leukopenia (9.1%) and anemia (6.1%). In the NAPOLI-1 trial, grade ≥3 AEs included neutropenia (15.4%), a decreased white blood cell count (12.0%) and diarrhea (9.4%) [11, 12].
The current study had several limitations. First, this was a retrospective study, and the number of patients was relatively small. Because the number of patients with prior irinotecan-based therapy was small, the effect of a history of irinotecan-based therapy could not be analyzed. Future studies should explore this point.
In conclusion, nal-IRI + 5-FU/l-LV therapy was considered to be a useful regimen as second-line or later treatment for unresectable advanced pancreatic cancer, even in clinical practice. An NLR of ≥2.7 was a significant predictive factor. Nal-IRI + 5-FU/l-LV therapy showed a good response with manageable AEs.