Current frontline systemic treatment options and limitation

Gemcitabine has been the mainstay of chemotherapy for metastatic PDAC for the past three decades, since Moore et al demonstrated that gemcitabine is superior to 5-fluorouracil (5-FU) in terms of quality of life and overall improvement in survival from 4.41 months to 5.56 months, compared to 5-FU.20 Since 2010, two combination therapies, FOLFIRINOX (a combination of oxaliplatin, irinotecan, folinic acid, and fluorouracil), and nab-paclitaxel and gemcitabine have been widely accepted as frontline systemic treatments. In a phase III randomized clinical trial, FOLFIRINOX has been shown to prolong overall median survival to 11.1 months compared to 6.8 months in a group treated with gemcitabine alone. However, this combination should be used in selected patients, such as younger (age <65) patients with limited comorbidities and those with good performance status.21 Another new combination, nab-paclitaxel and gemcitabine, improved median overall survival, from 6.6 to 8.7 months, compared to gemcitabine monotherapy alone. Furthermore, this combination has been widely used with manageable adverse effects and is currently the standard of care in most community practices.22

Refractory pancreatic cancer

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Despite new chemotherapeutic regimens, in many patients with metastatic pancreatic cancer, unfortunately chemotherapy fails and there is disease progression. Nagrial et al demonstrated through a meta-analysis of PDAC trials that approximately 43% of patients who progressed on first-line therapy went on to second-line treatment.23 This number has increased in recent years due to availability of newer therapeutic options and improved supportive care for advanced pancreatic cancer patients.24 Therefore, research into defining and improving the sequence of optimal therapy remains an important consideration for patients with good performance status and who are motivated to pursue additional therapy to control their disease.

Results from a randomized phase III trial for second-line treatment of PDAC (CONKO-003), suggested that the use of a weekly regimen called OFF, a combination of oxaliplatin and 5-FU/LV, could be beneficial in PDAC patients refractory to gemcitabine. When compared to 5-FU/LV alone, OFF extended the duration of OS from 3.3 months to 5.9 months and PFS from 2.0 months to 2.9 months. OFF was found to be associated with significantly increased neurotoxicity and myelosuppression.25However, a recent randomized phase III study (PANCREOX) failed to prove the benefit of 5-FU and oxaliplatin over 5-FU/LV alone. In this study, median OS and PFS for FOLFOX (folinic acid, 5-FU and oxaliplatin) was 6.1 and 3.1 months compared with 9.9 months and 2.9 months for 5-FU alone. Furthermore, the overall incidence of grade 3 or 4 adverse events was significantly higher in the FOLFOX arm at 63% compared to 11% in the control arm without additional clinical benefit. The most common adverse effects were hematological toxicities including neutropenia and thrombocytopenia, followed by paresthesia and peripheral neuropathy.26

A single institute retrospective study was conducted to test the efficacy of gemcitabine and nab-paclitaxel after FOLFIRINOX failure in 12 enrolled patients with metastatic pancreatic adenocarcinoma. The overall response rate was 30% and disease control rate was 60%. The gemcitabine and nab-paclitaxel combination therapy after FOLFIRINOX failure were later further investigated in other studies which showed inconsistent results. The efficacy of the gemcitabine and nab-paclitaxel combination therapy after FOLFIRINOX needs to be further evaluated in larger studies.27

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Irinotecan is a prodrug, metabolized primarily in liver and colon tissue to the active form, SN-38.28Yoo et al did a randomized phase II trial comparing oxaliplatin and 5-FU/LV (FOLFOX) with free irinotecan and 5-FU/LV (FOLFIRI) in PDAC patients. Median overall survival only marginally increased to 3.9 months with FOLFIRI, from 3.5 months with FOLFOX.29 Multiple prospective and retrospective studies of using FOLFIRI-based regimens were subsequently performed but they are all limited in terms of small sample sizes and were of single-arm design; therefore, the potential benefit of FOLFIRI is still unclear in refractory pancreatic cancer.29–34

Liposomal carriers are widely utilized in cancer therapy to enhance anticancer activity of drugs.35 The liposomal formulation shelters the drug from unwanted early metabolism, keeping it in plasma circulation and in tissues longer and increasing delivery into tumors. Therefore, this prolongs intratumoral levels of the drug, and theoretically increases antineoplastic activity.36 In preclinical settings, the nanoliposomal formulation of irinotecan, has been shown to have advantageous pharmacokinetics and roughly 5–6-fold higher level of its active metabolite, SN-38 in tumors, when compared with the free, traditional form of the drug.37 Ideally, this allows for increased active drug delivery to the tumor and increased antitumor effects and efficacy. Furthermore, irinotecan works by inhibiting topoisomerase activity in tumors, and subsequently halting rapid cell division.38

A phase II trial with PDAC patients showed nal-IRI produced median overall and median PFS rates of 5.2 and 2.4 months, respectively.39 These findings led to a large randomized, phase III clinical trial called NAPOLI-1. This study involved 417 patients at 76 sites in 14 countries. Wang-Gillan et al demonstrated that nal-IRI, when paired with 5-FU/LV, improved overall survival in patients who progressed on prior gemcitabine-based treatment.19 They compared three patient groups, nal-IRI +5-FU/LV, nal-IRI monotherapy, and 5-FU/LV as a control. It was shown that median OS was significantly increased in patients receiving nal-IRI +5-FU/LV compared with 5-FU/LV alone (6.6 months vs 4.0 months). Median overall survival did not differ between nal-IRI monotherapy and 5-FU/LV. In addition, PFS increased to 3.1 months in patients receiving nal-IRI +5-FU/LV from 1.5 months with 5-FU/LV alone. Nal-IRI with 5-FU/LV improved objective tumor response, time to treatment failure, and CA 19–9 tumor marker response showing its activities against pancreatic cancer.19 Detailed descriptions of patient characteristics and survival are summarized in Table 1.

Glassman et al at Memorial Sloan Kettering Cancer Center retrospectively examined their experiences with nal-IRI in 56 patients with advanced PDAC who received nal-IRI +5-FU/LV. The results showed median OS and PFS were 5.3 and 2.9 months, respectively. However, patients who progressed previously on irinotecan-based chemotherapy experienced worse outcomes on nal-IRI compared to those who were irinotecan naïve. Specifically, patients with prior irinotecan had median OS of 3.9 months, compared to 7.7 months in irinotecan naïve patients. PFS was also worse in patients with prior irinotecan, with PFS falling from 5.7 to 2.2 months.40 Petrelli et al did a meta-analysis comparing oxaliplatin and irinotecan therapies for PDAC treatment after administering gemcitabine. They found that second-line irinotecan-based regimens improved overall survival by 5.5 months, whereas patients who received oxaliplatin-based regimens improved OS by 5.3 months.41 These data suggest that additional cytotoxic agents might have a value in refractory pancreatic cancer patients.

Pelzer et al presented an interpretation of the NAPOLI-1 data for quality of life. Through statistical analysis of data, they presented Q-TWiST, which integrates quality and quantity of survival, by dividing periods into periods of treatment and toxicity (TOX). The authors evaluated treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). This analysis also penalizes treatments with increased toxicities or shorter times to disease progression (REL) and rewarding those with lower TOX and longer PFS times. Q-TWiST data may help inform physicians in discussing quality of life issues in patients with pancreatic cancer when considering second-line chemotherapy. Patients with nal-IRI +5-FU/LV treatment had significantly more mean time in TWiST (3.4 vs 2.4) and TOX (1.0 vs 0.3), but similar REL (2.5 vs 2.7). Nal-IRI +5-FU/LV had 1.3 months greater Q-TWiST (5.1 vs 3.9). These data show that nal-IRI +5-FU/LV provided significantly greater quality-adjusted survival time compared to 5-FU/LV alone. In summary, treatment with nal-IRI with 5-FU/LV in patients refractory to gemcitabine would benefit regardless of their functional status, but the decision should be made individually based on physician’s discretion and shared decision-making.42 This study is particularly important, as quality of life decisions and data are particularly important since most of the patients are given cancer therapy to palliate their symptoms and to improve OS.