Background
Pancreatic ductal adenocarcinoma (PDAC) remains an intractable illness due to late stage of presentation, a propensity to metastasize, relative resistance to cytotoxic treatment and the lack of effective targeted agents. In 2017, an estimated 53,670 new cases of pancreatic cancer were diagnosed [
1]. The majority of patients have either regional (11.5%) or distant (52%) spread at presentation. With a low 5-year survival rate of only 8.2%, PDAC ranks as the 3rd leading cause of cancer deaths, with an estimated 43,090 patient deaths in 2017. It is estimated that PDAC will rise to the second leading cause of cancer mortality by 2030 [
2].
The treatment landscape for advanced PDAC has significantly changed since 2010. Randomized phase III trials have demonstrated significant survival benefits of FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) [
3] or nab-paclitaxel + gemcitabine (nab-P + Gem) [
4] compared with the prior standard of care, single agent gemcitabine, for frontline treatment. Nanoliposomal irinotecan (nal-IRI) is a novel formulation of irinotecan, encapsulating drug molecules within long-circulating liposome-based nanoparticles with resulting favorable pharmacokinetic and biodistribution properties [
5]. Recently, the randomized phase III NAPOLI-1 trial demonstrated significant survival benefit of nal-IRI with fluorouracil/leucovorin (nal-IRI + 5-FU/LV) compared with 5-FU alone after disease-progression on gemcitabine-based chemotherapy, progression-free survival (PFS) of 3.1 vs 1.5 months, respectively (
p = 0.0001) and overall survival (OS) of 6.1 vs 4.2 months (
p = 0.012). Nal-IRI received FDA approval on October 22nd, 2015.
Due to the aggressiveness of this disease, and, until recently, the dearth of effective therapies, the majority of patients receive only a single line of chemotherapy [
6,
7]. With the current availability of several lines of active combination therapy, studies describing outcomes of sequential therapy are greatly needed. In particular, evidence for how to best integrate nal-IRI + 5-FU/LV into the treatment algorithm is needed and to understand the dosing schedule of the regimen. This retrospective, single institution analysis was conducted to address these questions.
Discussion
Treatment options for advanced PDAC are expanding but nonetheless finite. Although PDAC remains a challenging disease, the last decade has seen the development of three new and effective combination chemotherapy regimens. The current study is the first report of post-approval, real-world analysis of nal-IRI + 5-FU/LV for the treatment of patients with advanced PDAC. This is also the first study reporting outcomes for patients in an era where two active, combination chemotherapy regimens, FOLFIRINOX and nab-P + Gem, are available for treating patients in the frontline/neoadjuvant settings, and an active, combination chemotherapy regimen, nal-IRI + 5-FU/LV, is available in the second-line setting.
The optimal sequencing of therapy remains undefined, and in practice, is largely defined by patient performance status, age, patient and physician preference. Molecular biomarkers, such as mutations in BRCA1/2 or microsatellite instability, to guide therapy are found in only a small minority of our patients [
15]. For patients receiving FOLFIRINOX in the frontline setting, treatment with nab-P + Gem has been studied in a number of cohort studies. One of the largest was performed by the French AGEO (Association des Gastro-Entérologues Oncologues), [
16] which studied a similarly sized cohort (
N = 57) as our current study. Portal and colleagues found reasonable PFS (5.1 mo), OS (8.8 mo) and an encouraging median OS of 18 months from the beginning of advanced disease therapy. For patients receiving nab-P + Gem chemotherapy in the frontline setting, a number of 5-FU-based chemotherapy regimens have been studied. Chiorean and colleagues performed a retrospective analysis of patients enrolled in the pivotal MPACT study to evaluate 2nd therapy received [
6]. In patients who received 2nd-line therapy, primarily 5-FU-based, after frontline nab-P + Gem, overall survival was 12.8 mo. The most common 5-FU-based regimens administered contained oxaliplatin. Irinotecan-based chemotherapy was uncommon, and none of these individuals received nal-IRI + 5-FU/LV.
Before the approval of nal-IRI + 5-FU/LV, the most common regimens for treatment after failure of gemcitabine-based chemotherapy were FOLFIRI and FOLFOX. The activity of FOLFIRI has been studied in a number of single arm studies. In one of the largest such studies, Zaniboni and colleagues found PFS and OS of 3.2 and 5 mo, respectively [
17]. No randomized studies have been performed to support the efficacy of FOLFIRI in the 2nd line. Two randomized studies investigating the activity of 5-FU and oxaliplatin combinations report conflicting results. The randomized phase III CONKO-003 trial demonstrated a benefit of OFF, a 5-FU and oxaliplatin regimen commonly administered in Europe, compared to 5-FU alone, with PFS of 2.9 v 2.0 mo (
p = 0.019), respectively, and OS of 5.9 v 3.3 mo (
p = 0.010), respectively [
18]. By contrast, the PANCREOX trial demonstrated no benefit of mFOLFOX6 compared with 5-FU, with PFS of 3.1 v 2.9 mo, and surprisingly a detriment in OS, 6.1 v 9.9 mo (
p = 0.02) [
19]. A single randomized phase II study has compared second line therapy with FOLFIRI to FOLFOX [
20]. Both regimens performed similarly, with PFS of 1.9 and 1.4 mo, respectively, and OS of 3.8 and 3.4 mo, respectively. Overall survival from beginning of frontline therapy was 10.8 mo for both groups. A recent meta-analysis performed by Sonbol and colleagues comparing second-line therapies concluded that although both oxaliplatin and irinotecan improved PFS compared with 5-FU alone, only irinotecan appeared to improve OS [
21].
Nal-IRI is a liposomal encapsulated formulation of irinotecan with favorable pharmacokinetic properties as demonstrated in preclinical [
5] and preliminary clinical studies [
22]. These results led to a phase II trial, [
23] then the randomized phase III NAPOLI-1 trial. [
8] NAPOLI-1 was a global study which enrolled 417 patients who previously received Gem-based chemotherapy. Patients were initially randomized to receive either nal-IRI monotherapy dosed at 120 mg/m
2 every 3 weeks or 5-FU/LV monotherapy dosed at 2000 mg/m
2/continuous infusion over 24 h weekly for 4 out of every 6-week cycle. A third arm, nal-IRI + 5-FU/LV, dosed at nal-IRI (70 mg/m
2) with 5-FU/LV (2400 mg/m
2/continuous infusion over 46 h), was added once the phase II dose of the combination was established. As previously discussed, NAPOLI-1 demonstrated both PFS (3.1 vs 1.5 mo,
p = 0.0001) and OS benefit (6.1 vs 4.2 mo,
p = 0.012) of nal-IRI + 5-FU/LV compared with 5-FU. In our current study, PFS (2.88 mo) for all patients treated with similar to that seen in the NAPOLI-1 study. A number of key factors were significantly associated with longer survival, including earlier line of therapy, non-progression on prior irinotecan-based chemotherapy, and dose-reductions while on treatment. In this real-world study, safety was comparable to that seen in the NAPOLI-1 study. The main toxicities seen were fatigue, gastrointestinal toxicities and cytopenias. The incidence of grade 3 or 4 toxicities was low. As part of the NAPOLI-1 study, patients found to be homozygous for the UGT1A1*28 allele were dosed at 50 mg/m
2, then dose escalated to 70 mg/m
2 in the absence of toxicity. Reassuringly, a separate safety analysis of the NAPOLI-1 study found that patients homozygous for the UGT1A1*28 allele (7/117) experienced similar treatment toxicity compared to those without [
24]. Patients treated at our institution are not routinely tested for UGT1A1 genotype. Of note, the median starting dose administered of 55 mg/m
2 is below that used in the NAPOLI-1 trial. This pre-emptive dose reduction represents real-world practice patterns and likely played a major role in the low rate of serious adverse events seen. Neither starting dose, nor dose reductions were associated with worse outcomes with regards to PFS or OS. This observation has been made in other regimens used for the treatment of advanced PDAC. For example, Ahn and colleagues found improved safety and promising efficacy when nab-P + Gem was administered at a lower, every other week, frequency [
25]. Similarly, FOLFIRINOX with a variety of dose modifications is currently being studied. Two studies have found that dose reductions result in improved safety and similar [
26] if not improved [
27] efficacy. Lee and colleagues have developed a tool to optimize dose intensity for both toxicity and efficacy and applied their approach to FOLFIRINOX. [
28] Studies to systematically examine this and other strategies to improve patient tolerance and outcomes should be undertaken.
With the increased prevalence of tumor somatic and patient germline sequencing, our ability to study the relationship between genomics and treatment response and survival will grow. A number of prior studies have studied gene mutations in KRAS, CDKN2A, TP53 and SMAD4 with regards to survival with mixed results. Hayashi and colleagues found that fewer numbers of mutations in these 4 key genes were associated with better prognosis [
29]. Other studies have similarly found low p53 expression, [
30] mutations in p16 and TP53, [
31] and SMAD4 [
32] as predictive of poor prognosis. While mutations in these genes did not correlate with overall survival from advanced stage disease in our patient cohort, there was a correlation between TP53 mutation status and PFS on nal-IRI + 5-FU/LV treatment, with a trend seen for CDKN2A and SMAD4. One preclinical study has previously demonstrated a relationship between TP53 mutation status and irinotecan sensitivity [
33]. While no definitive conclusions can be drawn from a study of this size, our results suggest an interesting pharmacogenomic signal that merits further study and validation in larger, controlled patient cohorts.
The overall survival seen across all sequences of treatment was encouraging. In particular, patients receiving frontline nab-P + Gem followed by 2nd line nal-IRI + 5-FU/LV (
Sequence 2) experienced an OS of 23.0 mo from the time of advanced disease diagnosis. Patients treated with FOLFIRINOX and nab-P + Gem prior to nal-IRI + 5-FU/LV (
Sequence 1) also experienced excellent OS (25.5 mo), however, this was not significantly longer. This study represents the first published experience documenting survival in a patient population receiving treatment with access to all modern, FDA-approved chemotherapeutic agents. Given the toxicities experienced by some patients receiving FOLFIRINOX, the excellent survival seen in patients who did not receive FOLFIRINOX (
Sequence 2) is encouraging and further studies to explore optimal sequencing are warranted. Overall advanced disease survival seen in our study compares favorably to OS reported with sequential nab-P + Gem then 5-FU-based chemotherapy (13.5 mo) [
6] and sequential FOLFIRINOX and nab-P + Gem (18 mo). [
16] Patient selection is likely a critical issue. Further studies are warranted to confirm the prolonged OS outcomes seen in this study. Patients who received nal-IRI + 5-FU/LV in the frontline metastatic setting experienced prolonged mPFS (10.82 mo) and mOS (not reached), however, the number of patients was very small. The use of nal-IRI for the frontline treatment of patients deserves further evaluation, and an ongoing study (
ClinicalTrials.gov Identifier NCT02551991) will hopefully provide a definitive answer to this question.
As a single institution, retrospective analysis, the current study has limitations. Only patients without significant deterioration after prior gemcitabine-based chemotherapy and remained eligible for nal-IRI + 5-FU/LV chemotherapy were included. Patients treated at our tertiary referral center may not experience the same outcomes as patients treated in the community. Nevertheless, our results are encouraging and support continued utilization and study of the nal-IRI + 5-FU/LV regimen to treat patients with advanced pancreatic cancer, and to further optimize selection of patients most likely to benefit.