584 Review article

Taxanes: impact on pancreatic cancer E. Gabriela Chioreana and Daniel D. Von Hoffb Taxanes are core therapeutic components for several advanced malignancies, and have been studied extensively in pancreatic adenocarcinomas with mixed results. Although the triplet combination FOLFIRINOX improves outcomes for patients with metastatic disease, it is compounded by significant toxicity, and novel regimens, rationally designed and based on thorough mechanistic activity on the tumor targets, are clearly needed. Solventbased taxanes, docetaxel and paclitaxel, have little activity as single agents, but combinations with fluoropyrimidines and gemcitabine show efficacy, albeit they have not undergone testing in phase III trials. Pancreatic cancer is characterized by an abundant desmoplastic, fibroinflammatory and hypoperfused stroma, which has been blamed for its overall chemoresistance. Nanoparticle bound paclitaxel (nab-paclitaxel) has been pharmacologically designed as a novel water-soluble agent, with improved therapeutic index compared with the cremophor-based formulation, capable of achieving higher systemic exposure. In preclinical systems, when combined with gemcitabine, nab-paclitaxel increased intratumoral gemcitabine delivery, possibly due to inducing stromal ‘collapse’ and through inhibition of the

gemcitabine-catabolizing enzyme cytidine deaminase. Most recently, the combination of nab-paclitaxel and gemcitabine demonstrated significant survival benefit with good tolerability in metastatic pancreatic cancer in the phase III trial MPACT, and now represents one of the gold-standard regimens for this disease. Although taxanes are overall potent chemotherapeutics for various cancers, it is clear that for meaningful results in pancreatic adenocarcinomas, rationally designed combinations and novel technologies for drug delivery are likely to be most c 2014 successful. Anti-Cancer Drugs 25:584–592 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Introduction

an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor [8]. Although significant statistically, erlotinib only conferred 12 days in median survival advantage in combination with gemcitabine versus gemcitabine alone (6.2 vs. 5.9 months). These results did not represent a step forward in bettering pancreatic cancer survival rates and were not practice changing.

In the past few decades paclitaxel, docetaxel and most recently, nanoparticle albumin-bound paclitaxel (nabpaclitaxel), have been studied in the treatment of one of the most chemoresistant malignant tumors, pancreatic adenocarcinoma, with few remarkable results, until recently. Among the 45 200 patients diagnosed annually with pancreatic cancer [1], 50% have metastatic disease at the outset, and another 30% have localized but unresectable disease. Overall survival ranges between 6 and 12 months for those with systemic metastases, and 11 and 16 months for those with locally advanced, but inoperable cancers. In the past three decades, the standard therapies for pancreatic cancer consisted of fluoropyrimidines like 5-fluorouracil (5-FU), and the antimetabolite drug gemcitabine. In 1996 gemcitabine was found to be superior to 5-FU in clinical benefit response (24 vs. 5%) as well as overall efficacy (overall survival of 5.6 vs. 4.4 months, and 1-year survival rates of 18 vs. 2%) [2]. Many combination regimens with other chemotherapies and/or biologically targeted agents were built on these backbones but had dismayingly negative results [3–7]. In 2005, the first significant survival improvement of a gemcitabine combination was noted with c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-4973

Anti-Cancer Drugs 2014, 25:584–592 Keywords: docetaxel, nanoparticle bound paclitaxel, paclitaxel, pancreatic cancer, taxanes a

Department of Medicine, University of Washington, Seattle, Washington and Translational Genomics Research Institute (TGen)/Virginia Piper Cancer Center, Scottsdale, Arizona, USA

b

Correspondence to E. Gabriela Chiorean, MD, Department of Medicine, University of Washington, 825 Eastlake Ave East, G4830, Seattle, WA 98109, USA Tel: + 1 206 288 6248; fax: + 1 206 288 2047; e-mail: [email protected] Received 15 November 2013 Revised form accepted 12 December 2013

The excessive chemoresistance that characterizes pancreatic cancer has been studied in both xenograft and genetically engineered Kras LSL-G12D/ + ; Trp53LSL-R172H/ + ; Cre (KPC) mouse models [9]. These preclinical models, as well as several human clinical studies helped demonstrate that the dense desmoplastic tumor stroma, mostly devoid of functional vasculature, and infiltrated by an immunosuppressive environment contributes to poor access by therapeutics, and confers chemoradiotherapy and radiotherapy resistance [10]. Targeting the tumor stroma has become an area of intense research [11,12]. Taxanes stabilize microtubules by increasing their polymerization, and induce cell cycle arrest at the G2/M phase, resulting in cell death [13]. Docetaxel and paclitaxel differ in molecular pharmacology, with docetaxel thought to achieve higher intracellular concentrations, partly because of better escape efflux mechanisms relative to paclitaxel [14]. Because of preclinical evidence DOI: 10.1097/CAD.0000000000000073

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Taxanes in pancreatic cancer Chiorean and Von Hoff 585

of activity in pancreatic tumor models, taxanes have been tested in the several clinical trials, both as single agents or in combination, in early stage and in advanced or metastatic disease. Importantly, taxanes are not crossresistant with most major drug classes, which may influence practice in a variety of tumors. Despite promising activity in vivo, as single agents, the solventbased taxanes, docetaxel and paclitaxel, have not proven significant superiority compared with gemcitabine for pancreatic cancer. Nab-paclitaxel, a water-soluble compound, showed enhanced distribution properties within the tumor microenvironment. In addition, nab-paclitaxel demonstrated the ability to increase intratumoral gemcitabine concentration in pancreatic cancer mouse models [15], and in clinical trials it showed significant survival benefit when combined with gemcitabine [16,17]. The nab-paclitaxel with gemcitabine combination represents a new gold-standard treatment for advanced metastatic pancreatic cancer, and the first gemcitabinebased chemotherapy combination to benefit patients.

Docetaxel Pancreatic cancer is characterized by complex genetic alterations in protein-coding genes like KRAS (> 95%), p16/CDKN2A (95%), TP53 (50–75%), and DPC4/SMAD4 (55%), as demonstrated by Jones et al. [18]. In-vitro studies tested chemosensitivity profiles in several Table 1

genetically defined pancreatic cancer cell lines [19]. In these models, in contrast with gemcitabine, irinotecan, cisplatin or mitomycin C, docetaxel showed remarkable cytotoxicity among all the cell lines tested, irrespective of the genetic inactivation/mutation. Docetaxel has been tested extensively in patients with pancreatic adenocarcinomas. Below we review its use in advanced pancreatic cancers for first line and the refractory disease setting, as well as for localized disease (Table 1).

First-line therapy locally advanced or metastatic disease

As single agent, docetaxel has been used in doses of 60 mg/m2 [20] or 100 mg/m2 every 3 weeks in small phase II trials [21,22], with modest activity at high doses: response rates 6–15%, time to progression 2–5 months, and median survival of 7–8.5 months. Toxicity had been mostly myelosuppression (grade 3/4 neutropenia 36–95%, grade 3/4 anemia 9–16%) and fatigue (grade 3/4 11–33%). Preclinical data suggest synergistic effects between docetaxel and paclitaxel with capecitabine, because of the upregulation of the thymidine phosphorylase (TP) enzyme via enhancing intratumoral tumor necrosis factora levels [46]. In clinical studies, the effects on TP activity seemed durable (> 10 days), but the combination therapy resulted in significant myelotoxicity, especially with docetaxel dosed every 3 weeks [47]. On the basis

Clinical trials of docetaxel in pancreatic cancer

References First-line therapy Okada et al. [20] Androulakis et al. [21] Rougier et al. [22] Cascinu et al. [23] Stathopoulos et al. [24] Ryan et al. [25] Schneider et al. [26] Shepard et al. [27] Lutz et al. [28] Ridwelski et al. [29] Kulke et al. [30] Burtness et al. [31] Fine and colleagues [32,33] Hill et al. [34] De Jesus-Acosta et al.b [35] Xenidis et al. [36] Reni et al. [37] Second-line therapy Cereda and Reni [38] Saif et al.b [39] Ignatiadis et al. [40] Brell et al. [41] Carvajal et al. [42] Ko et al. [43] Katopodis et al. [44] Dakik et al.b [45] De Jesus-Acosta et al.b [35]

Number of patients

Treatment

Response rate (%)

PFS/TTP (months)

OS (months)

21 33 43 24 54 34 40 32 49 47 68 65 37 43 21 79 40 53

Docetaxel Docetaxel Docetaxel Docetaxel + gemcitabine Docetaxel + gemcitabine Docetaxel + gemcitabine Docetaxel + gemcitabine Docetaxel + gemcitabine Docetaxel + gemcitabine Docetaxel + cisplatin Docetaxel + gemcitabine Docetaxel + gemcitabine Docetaxel + irinotecan GTX GTX GTX GTX PDXG

0 3 15 1 13 18 27 12.5 19.4 23.5 18.6 7 27 22 11 11 40 60

1a 5a 2a 3a 7.5a 3.8 N/A N/A 3.9 2.8 N/A 4.1a N/A 6.9 5.8 N/A 6 7.4

6 8.5 7 5.4 6.1 8.9 7 4.7 7.4 7.1 9 6.4 9.4 14.5 7.4 11.6 9 10.7

10 17 26 41 10 14 31 59 75

Docetaxel Docetaxel Docetaxel + gefitinib Docetaxel + gefitinib Docetaxel + flavopiridol Docetaxel + irinotecan Docetaxel + capecitabine GTX GTX

0 0 0 2 0 0 10 0 3

1.5 2 2 1.8 N/A 1 2.4 2 N/A

4 4 3 4.5 4.2 4.5 6.3 4.2 5.7

GTX, gemcitabine, docetaxel, capecitabine; N/A, not available; OS, overall survival; PDXG, cisplatin, docetaxel, capecitabine, gemcitabine; PFS, progression-free survival; TTP, time to progression. a Time to progression. b Retrospective study.

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586 Anti-Cancer Drugs 2014, Vol 25 No 5

of pharmacobiologic studies, to maintain sustained elevated TP levels and reduce toxicities, weekly docetaxel at 35–36 mg/m2 in combination with capecitabine has been the regimen mostly used in phase II studies for solid tumors [48]. Additive, synergistic or even antagonistic properties were noted for docetaxel with gemcitabine in various cancer cell lines, but it is unclear whether the administration sequence or dosing is important, or whether their properties are strictly dependent on the cancer type [49,50]. Several preclinical models have documented synergism when taxanes, docetaxel and paclitaxel, were combined with cisplatin or carboplatin, with one putative mechanism being downregulation of the multidrug resistant proteins, resulting in accumulation of intracellular platinum-glutathione complexes [51,52]. Phase I and II studies have tested the safety and efficacy of docetaxel seeking synergism when combined with other chemotherapy agents. In combination with gemcitabine, docetaxel dosed at 70–100 mg/m2 every 2–3 weeks caused increased toxicity, mostly hematologic [23,24,27], but weekly doses of 30–40 mg/m2  2 every 3 weeks were better tolerated and were used in most phase II studies [26,29,30]. The combination of docetaxel with gemcitabine yielded variable response rates of 1–27%, median progression-free survival (PFS) rates of B3–4 months, and median overall survival (OS) rates of 6–9 months (Table 1). These doublet therapy trials, including those randomized performed by EORTC [28] and CALGB [30] did not show meaningful benefit compared with single agent gemcitabine. Docetaxel was also studied in combination with cisplatin [28], or irinotecan [31] with similar response rates of 24% and median survival of 7–9 months, comparable to other docetaxel combinations. One of the most studied triplet regimens in pancreatic adenocarcinoma incorporating docetaxel with gemcitabine and capecitabine (GTX), was developed after preclinical data showed apoptotic synergism with increased Bax, Bak and decreased Bcl-2 and Bcl-XL expression, as well as MEK inhibitory effects in pancreatic cancer cell lines [32,53]. Retrospective analyses of GTX noted response rates between 11 and 40%, and median OS of B11 months [35,53], but superior OS of 25 months was seen in patients with locally advanced disease [35]. Prospective phase II studies confirmed responses up to 40% and median OS ranging from 7 to 14.5 months, and a preliminary correlation with benefit in patients with high pMEK expression [32–34,36]. The GTX regimen, while used extensively and with variable dosing schedules in the community, is limited by increased toxicity [grade 3/4 neutropenia (29%), fatigue, diarrhea, mucositis, and hand-foot skin reaction (8% each)]. Another docetaxelcontaining multidrug regimen with gemcitabine, capecitabine and cisplatin (PDXG) also demonstrated high responses of 60%, and median OS of B11 months [37].

These multidrug combinations confer significant response rates in advanced pancreatic cancer, but no randomized phase III trials have been performed to demonstrate survival benefit over gemcitabine alone. Second-line therapy metastatic disease

At least 50% of patients with pancreatic cancer whose tumors progress on first-line treatment are candidates for further salvage therapy, and standard regimens may include fluoropyrimidines and taxanes. In a few small phase II and retrospective studies docetaxel single agent or in combination with various chemotherapies or biologically targeted agents, has shown minimal activity, with response rates of 0–15% and overall median OS of 4–5 months [35,39–45]. A recent report of docetaxel with oxaliplatin shows conflicting results, with a modest response rate of 16% and median PFS of 7 weeks, but an OS of 8.3 months, suggesting benefit from further therapy beyond progression on second-line treatment [54].

Neoadjuvant therapy for borderline resectable pancreatic cancer

Because of the high response rates noted in the metastatic setting, GTX has been used as induction regimen followed by chemoradiotherapy in several small neoadjuvant trials for patients with borderline resectable pancreatic adenocarcinomas. Median PFS rates varied between 11 and 26 months, and OS between 16 and 33 months, likely because of small sample sizes and eligibility criteria differences [55,56]. Docetaxel-based chemoradiotherapy for localized resectable and unresectable disease

Taxanes have radiosensitizing properties [57], and therefore they have been tested in combination with radiotherapy in patients with resectable or unresectable disease. Neoadjuvant docetaxel 30 mg/m2 weekly with radiotherapy was studied in 34 patients with operable pancreatic cancer, and confered a resectability rate of only 50%, and a median survival of 32 months among those successfully operated [58]. In locally advanced disease, docetaxel plus 5-FU-based chemoradiation was limited by toxicity and a median PFS of only 4 months leading to study discontinuation [59]. These modest results did not lead to advancing docetaxel-based chemoradiotherapy in phase III studies in pancreatic cancer.

Paclitaxel Paclitaxel is a widely used taxane in cancer treatment, and contrary to docetaxel, which manifests higher affinity to b-tubulin causing cell damage by affecting centrosome organization in the S phase, it causes mitotic arrest in the G2 and M phases of the cell cycle [60]. Because of its poor water solubility, paclitaxel is formulated in Cremophor, a castor oil solvent [61], but this causes an increase in systemic drug exposure due to reduced cellular uptake

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Taxanes in pancreatic cancer Chiorean and Von Hoff 587

Table 2

Clinical trials of paclitaxel in pancreatic cancer

References First-line therapy Gebbia and Gebbia [63] Whitehead et al. [64] Lam et al. [65] Von Hoff et al. [16] Von Hoff et al. [17] Ko et al. [66] Leichman et al. [67] El-Khoueiry et al. [68] Lohr et al. [69] Saif et al. [70] Second-line therapy Oettle et al.b [71] Shukuya et al.b [72] Maeda et al.b [73] Kim et al. [74] Hosein et al. [75] Ernani et al.b [76]

Number of patients

Treatment

Response rate (%)

PFS/TTP (months)

OS (months)

14 39 43 67 431 15 19 29 156 56

Paclitaxel Paclitaxel Paclitaxel + bryostatin Nab-paclitaxel + gemcitabine Nab-paclitaxel + gemcitabine Nab-paclitaxel + gemcitabine + capecitabine Nab-paclitaxel + gemcitabine + erlotinib Nab-paclitaxel + gemcitabine + vandetanib EndoTAG + gemcitabine Paclitaxel polymeric micelle

0 8 0 46 23 14 46 28 14 7

N/A N/A 1.9 7.9 5.5 N/A 5.3 5.3 4.4 2.8

7.2 5 1.9 12.2 8.5 7.5 9.3 8.2 8.7 6.5

Paclitaxel Paclitaxel Paclitaxel Paclitaxel + 5-fluorouracil Nab-paclitaxel Nab-paclitaxel + gemcitabine

5 0 10 10 5 22

N/A 1.7 3.6 2.5a 1.6 3

4 3.4 6.7 7.6 7.3 N/A

18 23 30 28 19 10

N/A, not available; OS, overall survival; PFS, progression-free survival; TTP, time to progression. a Time to progression. b Retrospective study.

of the drug from large spherical micellar-like structures with a highly hydrophobic interior [62]. The draw-back of Cre-paclitaxel is the toxicity profile (i.e. hypersensitivity reactions) and a possibly lower clinical efficacy than expected with a hydrophilic formulation. Several clinical trials tested paclitaxel and its newer nanoparticle-based formulations, in advanced and early-stage pancreatic cancer (Table 2). Therapy for advanced disease

Paclitaxel administered weekly at 80–90 mg/m2, or every 3 weeks at 175–250 mg/m2, has no significant activity in the first-line treatment of advanced pancreatic cancer. In several phase II trials response rates were 0–8% and the median survival was 5–7 months [63–65]. Similarly disappointing results were noted with paclitaxel in gemcitabine-refractory disease, as single agent or in combination with 5-FU (response rates 0–10%, OS 2–7.6 months) [71–74]. Paclitaxel-based chemoradiotherapy localized resectable and unresectable disease

When used as radiosensitizer in the neoadjuvant setting for patients with resectable disease, paclitaxel was associated with prohibitive toxicity [77], whereas for unresectable patients it conferred response rates of 26% and median OS of 8–11 months [78,79], comparable with other standard gemcitabine-based or fluoropyrimidinebased regimens.

Nanoparticle-based paclitaxel Novel paclitaxel formulations, designed with the goal to improve bioavailability, tumor tissue penetration, and enhance the therapeutic index, are based on nanotechnology and include polymeric nanoparticles, liposomes, and albumin-based nanoparticles [62]. Nanoparticles, by definition,

are synthetic materials with a size between 1 and 1000 nm, which can facilitate the transport of cancer therapeutics against negatively charged endothelial membranes, and selectively delivering them to target tumor tissues. First-line therapy metastatic disease

Liposome encapsulated paclitaxel, or EndoTAG-1 (ET) contains paclitaxel within the cationic liposome membrane. Paclitaxel can be selectively delivered to negatively charged intratumoral endothelial cells through positively charged liposomes [80]. Preclinically, this methodology showed activity in pancreatic cancer [81]. ET in combination with gemcitabine was studied among 212 patients with advanced pancreatic cancer in a randomized phase II study. Although gemcitabine alone conferred the expected OS of 6.8 months, the combination regimen using escalating doses of ET (11, 22, and 44 mg/m2 twice weekly), was associated with survival rates of 8.1–9.3 months [69]. The toxicity profile of gemcitabine with ET was overall mild, but included infusion-related chills, pyrexia (16 and 8%, respectively, grade 3/4), and thrombocytopenia (16% grade 3/4). Polymeric nanoparticles represent the largest category of vehicles for carrying drug ‘payloads’, with core-shell particles (material surrounding the drug payload) and polymeric micelles (non-crosslinked particles around a hydrophobic drug) [82] being the most common subtypes. Paclitaxel-loaded polymeric micelle (GenexolPM) [83], showed modest efficacy as monotherapy in metastatic pancreatic cancer (response rate of 6.7% and median survival of 6.5 months) [70]. The toxicity profile was predominantly grade 3 neutropenia (40%), fatigue (18%), infection and neuropathy (13% each), not markedly different from Cre-paclitaxel. Protein nanoparticles containing paclitaxel (nab-paclitaxel) were initially developed to avoid the toxicities associated

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588 Anti-Cancer Drugs 2014, Vol 25 No 5

with Cremophor EL in soluble paclitaxel [84,85]. Nabpaclitaxel, formulated with human serum albumin, upon injection, dissolves into soluble albumin–paclitaxel complexes, and allows a three-fold higher systemic exposure of unbound paclitaxel compared with the Cremophor ELsoluble paclitaxel [86]. Nab-paclitaxel reaches the tumors’ microenvironment across endothelial cells by the enhanced permeation and retention effect, as well as through receptor-mediated transcytosis [87]. A putative mechanism for the tumor accumulation of nab-paclitaxel is the presence of albumin-binding proteins such as gp60 and secreted protein acidic and rich in cysteine (SPARC/ ostenectin) in the tumor proximity [88]. Although SPARC expression seems to correlate with worse outcomes in pancreatic cancer [89], treatment of SPARC expressing tumors with nab-paclitaxel may confer improved efficacy [16,90,91]. Pancreatic ductal adenocarcinomas are characterized by an almost universal desmoplastic reaction, featuring a fibrotic stroma, and dysfunctional hypoperfused vasculature [92]. This altered extracellular matrix has been implicated in the poor sensitivity of pancreatic cancer to chemotherapeutics. SPARC has been associated with stromal formation, invasion, and metastasis [89], and by binding nab-paclitaxel, it has been postulated to facilitate its intratumoral delivery. In a preclinical study using patient-derived xenografts, nab-paclitaxel induced stromal collapse and led to a three-fold increase in intratumoral gemcitabine concentration [16]. The stromal disrupting effects of nab-paclitaxel have also been noted in a small neoadjuvant study for resectable pancreatic cancer patients [93]. Among 10 pancreatic cancer patients who underwent surgical resection, treatment with two 4-week cycles of nab-paclitaxel and gemcitabine before surgery did not induce objective radiological responses, but caused increased ‘tumor softness’ by endoscopic ultrasound-based elastography, and histopathologically resulted in one complete pathological response, six major pathological responses (a few isolated malignant cells left), and one partial response (large residual tumor). Compared with untreated controls, nab-paclitaxel with gemcitabine was associated with less abundant collagen matrix infiltration around tumor glands, and a decreased number of cancer-associated fibroblasts. A more recently described mechanism of nabpaclitaxel synergism with gemcitabine in mouse models involves the inactivation by nab-paclitaxel of the gemcitabine catabolizing enzyme cytidine deaminase, by the production of destabilizing reactive oxygen species [15]. Interestingly, because nab-paclitaxel is formulated with human albumin, repeated administration in mice has not been feasible because of analphylactic reactions, therefore the effects on stromal ‘collapse’, which requires longer-term follow-up, may not have not been observed. The mechanisms of nab-paclitaxel activity on pancreatic adenocarcinoma stroma are still being elucidated, and

novel biomarkers and functional imaging are being intensely explored. The most significant efficacy to date in pancreatic cancer with nab-paclitaxel has been reported in the setting of advanced disease. In a preliminary phase I/II trial of 67 patients with metastatic pancreatic adenocarcinoma treated with nab-paclitaxel and gemcitabine, Von Hoff et al. [16] tested escalating doses of nab-paclitaxel 100, 125, and 150 mg/m2 in combination with gemcitabine 1000 mg/m2 weekly  3 every 4 weeks. Dose-limiting toxicity was neutropenic sepsis at 150 mg/m2, thus the maximum tolerated dose was declared 125 mg/m2 weekly. Among 44 patients treated at the maximum tolerated dose, the response rate was 48%, and the median OS reached 12.2 months. Stromal SPARC staining by immunohistochemistry identified high-level and low-level SPARC subgroups of patients, with differential survival of 17.8 and 8.1 months, respectively (P = 0.0431). These encouraging data formed the basis for the phase III study of nab-paclitaxel plus gemcitabine in metastatic pancreatic adenocarcinoma clinical trial MPACT [17]. This international randomized study among 861 patients, demonstrated a significant response (23 vs. 7%, P < 0.001), PFS (5.5 vs. 3.7 months, P < 0.001), and OS (8.5 vs. 6.7 months, P < 0.001) benefit with nab-paclitaxel plus gemcitabine compared with gemcitabine alone. Overall, the combination treatment was well tolerated, and the most significant toxicities of grade 3 or higher were neutropenia (38%), fatigue and neuropathy (17% each), and thrombocytopenia (13%). These results led to nab-paclitaxel approval by the FDA on 6 September 2013 for metastatic pancreatic cancer. In this trial, archival tumor biopsies have been collected to analyze the role of stromal and tumor SPARC expression, both as prognostic and predictive marker of benefit. The results are highly anticipated. Although earlier studies proposed SPARC as a prognostic marker for worse outcomes in many cancers, and possibly a predictive biomarker of benefit from nab-paclitaxel-based chemotherapies, recent preclinical data in genetically engineered mouse pancreatic cancer models indicated SPARC independent desmoplasia, and intratumoral paclitaxel levels no different among SPARC + / + (positive) and SPARC – / – (negative) tumors [94]. Nevertheless, decreased toxicity with water-soluble nab-paclitaxel led to higher tolerated doses compared with cremophor-based paclitaxel, which resulted in significantly higher neoplastic cell death. The role of circulating SPARC is controversial, but it has been proposed that it may be linked to higher intravascular nab-paclitaxel levels [94]. Given potential synergy in preclinical models, nabpaclitaxel and gemcitabine combined with capecitabine was analyzed by Ko et al. [66] but likely due to lower administered doses (gemcitabine 750 mg/m2, nab-paclitaxel 100 mg/m2 on day 4, and capecitabine 750 mg/m2 twice daily days 1–7, every 14 days), response rates were

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Taxanes in pancreatic cancer Chiorean and Von Hoff 589

only 14% and the median survival was 7.5 months. Small clinical trials reported on nab-paclitaxel plus gemcitabine with the addition of biologically targeted agents such as erlotinib, an EGFR inhibitor [67], or vandetanib, a VEGFR2, EGFR, RET inhibitor [68], with median PFS of 5.3 months and OS of 8–9 months, no different from the results with chemotherapy alone. FOLFIRINOX is another standard regimen for metastatic pancreatic cancer associated with response rates of 30% and OS of 11 months [95]. With the goal of increasing the 1-year survival for metastatic pancreatic cancer patients above 70% (1-year survival with nab-paclitaxel-gemcitabine is 35%, and with FOLFIRINOX it is 48%), an ongoing phase II trial is testing induction therapy with six 4-week cycles of nab-paclitaxel/gemcitabine followed by consolidation FOLFIRINOX for 12 2-week cycles. To date, response rates to induction therapy were 50%, but complete results will only be available once the study follow-up matures [96]. Many investigations are planned or ongoing using the backbone of nab-paclitaxel with or without gemcitabine, with the addition of other chemotherapeutics such as cisplatin (NCT01893801), cisplatin plus capecitabine (PAXG) (NCT01730222), or molecularly targeted agents including the JAK2/STAT3 inhibitor ruxolitinib (NCT01822756), the Smac-mimetic LCL161 (NCT01934634), or the WNT pathway inhibitor OMP-59R5 (NCT01647828). Rational combinations are still needed, and one with anticipated synergism is the addition of the stromal disrupting agent pegylated recombinant human hyaluronidase, PEGPH20, which has been shown to reduce the high interstitial pressure within the pancreatic tumor stroma [11], and is therefore expected to enhance nab-paclitaxel and gemcitabine delivery (NCT01839487). Promising results with PEGPH20 have already been observed when combined with gemcitabine alone (response rates 33%), particularly for patients with high content of hyaluronic acid in the tumor stroma (response rates 56%) [97]. Second-line/salvage therapy metastatic disease

Nab-paclitaxel has been tested as monotherapy or in combination with gemcitabine in the second-line treatment of advanced pancreatic cancer. In a phase II trial, single agent nab-paclitaxel showed low response rates (5%) and PFS of 1.7 months, but the OS of 7.3 months suggests benefit from additional lines of therapy [75]. An additional retrospective analysis of nab-paclitaxel showed PFS rates of 2 months, and a median OS of 3 months [98]. Similarly, gemcitabine plus nab-paclitaxel demonstrated modest benefit in the salvage setting, with median PFS of only 3 months [76].

pathological response rates were noted (30–70%); however, long-term survival data are not available [93,99]. A phase III trial with nab-paclitaxel and gemcitabine is planned for patients with resected pancreatic adenocarcinoma, and smaller studies integrating chemoradiotherapy either gemcitabine-based or nab-paclitaxel-based are planned or ongoing. Conclusion and future directions

It is now clear that well designed, mechanistically driven clinical trials with agents targeting key components in pancreatic cancers are needed for meaningful strides in this disease. Highly cytotoxic chemotherapy combinations seem to have efficacy, but at the cost of increased toxicity (e.g. FOLFIRINOX, GTX, PDXG), and from this stand-point, nab-paclitaxel with gemcitabine represents a step forward balancing increased survival rates with overall good tolerability. Nevertheless, despite these improvements, we need to continue identifying critical biomarkers to personalize the most appropriate regimen to individual patients. It is equally important to enhance current gold-standard backbone regimens with rational molecularly targeted therapies. Taxanes have several known chemoresistance mechanisms, such as ABC transporter-mediated multidrug resistance [100,101], tubulin mutations [102], epigenetic silencing of proapoptotic genes [103], the expression of gamma-secretase complexes, which can inhibit the taxane-induced apoptosis [104], and chromosomal instability [105], which should also be exploited to improve efficacy. Innovative technologies in drug development, such as those that are nanoparticle-based, are making a significant impact in improving the pharmacologic parameters and increasing the therapeutic index for taxanes, and are likely to further advance clinical benefits with these widely used anticancer therapies [106–108].

Acknowledgements E. Gabriela Chiorean and Daniel D. Von Hoff had previously received research grant support from Celgene Pharmaceuticals. Conflicts of interest

E. Gabriela Chiorean and Daniel D. Von Hoff served as consultants on Celgene Pharmaceuticals Scientific Advisory Board.

References Neoadjuvant and adjuvant therapy early-stage disease

Given high response rates in advanced disease, several small clinical trials noted activity of nab-paclitaxel with gemcitabine in the preoperative setting. Whereas radiological responses with two to three cycles of neoadjuvant therapy have ranged between 0 and 16%, higher

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Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63:11–30. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15:2403–2413. Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus

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capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 2009; 27:5513–5518. Heinemann V, Vehling-Kaiser U, Waldschmidt D, Kettner E, Marten A, Winkelmann C, et al. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ’Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104). Gut 2013; 62:751–759. Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schonekas H, Rost A, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 2006; 24:3946–3952. Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2009; 27:3778–3785. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 2010; 28:3617–3622. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25:1960–1966. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005; 7:469–483. Komar G, Kauhanen S, Liukko K, Seppanen M, Kajander S, Ovaska J, et al. Decreased blood flow with increased metabolic activity: a novel sign of pancreatic tumor aggressiveness. Clin Cancer Res 2009; 15:5511–5517. Provenzano PP, Hingorani SR. Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br J Cancer 2013; 108:1–8. Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, et al. Stromal biology and therapy in pancreatic cancer. Gut 2011; 60:861–868. Fuchs DA, Johnson RK. Cytologic evidence that taxol, an antineoplastic agent from Taxus brevifolia, acts as a mitotic spindle poison. Cancer Treat Rep 1978; 62:1219–1222. Gligorov J, Lotz JP. Preclinical pharmacology of the taxanes: implications of the differences. Oncologist 2004; 9 (Suppl 2):3–8. Frese KK, Neesse A, Cook N, Bapiro TE, Lolkema MP, Jodrell DI, et al. nabPaclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov 2012; 2:260–269. Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011; 29:4548–4554. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369:1691–1703. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321:1801–1806. Cui Y, Brosnan JA, Blackford AL, Sur S, Hruban RH, Kinzler KW, et al. Genetically defined subsets of human pancreatic cancer show unique in vitro chemosensitivity. Clin Cancer Res 2012; 18:6519–6530. Okada S, Sakata Y, Matsuno S, Kurihara M, Sasaki Y, Ohashi Y, et al. Phase II study of docetaxel in patients with metastatic pancreatic cancer: a Japanese cooperative study. Cooperative Group of Docetaxel for Pancreatic Cancer in Japan. Br J Cancer 1999; 80:438–443. Androulakis N, Kourousis C, Dimopoulos MA, Samelis G, Kakolyris S, Tsavaris N, et al. Treatment of pancreatic cancer with docetaxel and granulocyte colony-stimulating factor: a multicenter phase II study. J Clin Oncol 1999; 17:1779–1785. Rougier P, Adenis A, Ducreux M, de Forni M, Bonneterre J, Dembak M, et al. A phase II study: docetaxel as first-line chemotherapy for advanced pancreatic adenocarcinoma. Eur J Cancer 2000; 36:1016–1025. Cascinu S, Gasparini G, Catalano V, Silva RR, Pancera G, Morabito A, et al. A phase I–II study of gemcitabine and docetaxel in advanced pancreatic cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Ann Oncol 1999; 10:1377–1379. Stathopoulos GP, Mavroudis D, Tsavaris N, Kouroussis C, Aravantinos G, Agelaki S, et al. Treatment of pancreatic cancer with a combination of

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30

31

32

33

34

35

36

37

38

39

40

41

42

43

docetaxel, gemcitabine and granulocyte colony-stimulating factor: a phase II study of the Greek Cooperative Group for Pancreatic Cancer. Ann Oncol 2001; 12:101–103. Ryan DP, Kulke MH, Fuchs CS, Grossbard ML, Grossman SR, Morgan JA, et al. A phase II study of gemcitabine and docetaxel in patients with metastatic pancreatic carcinoma. Cancer 2002; 94:97–103. Schneider BP, Ganjoo KN, Seitz DE, Picus J, Fata F, Stoner C, et al. Phase II study of gemcitabine plus docetaxel in advanced pancreatic cancer: a Hoosier Oncology Group study. Oncology 2003; 65:218–223. Shepard RC, Levy DE, Berlin JD, Stuart K, Harris JE, Aviles V, et al. Phase II study of gemcitabine in combination with docetaxel in patients with advanced pancreatic carcinoma (E1298). A trial of the Eastern Cooperative Oncology Group. Oncology 2004; 66:303–309. Lutz MP, Van Cutsem E, Wagener T, Van Laethem JL, Vanhoefer U, Wils JA, et al. Docetaxel plus gemcitabine or docetaxel plus cisplatin in advanced pancreatic carcinoma: randomized phase II study 40984 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group. J Clin Oncol 2005; 23:9250–9256. Ridwelski K, Fahlke J, Kuhn R, Hribaschek A, Kettner E, Greiner C, et al. Multicenter phase-I/II study using a combination of gemcitabine and docetaxel in metastasized and unresectable, locally advanced pancreatic carcinoma. Eur J Surg Oncol 2006; 32:297–302. Kulke MH, Tempero MA, Niedzwiecki D, Hollis DR, Kindler HL, Cusnir M, et al. Randomized phase II study of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in patients with metastatic pancreatic cancer: CALGB 89904. J Clin Oncol 2009; 27:5506–5512. Burtness B, Thomas L, Sipples R, McGurk M, Salikooti S, Christoforou M, et al. Phase II trial of weekly docetaxel/irinotecan combination in advanced pancreatic cancer. Cancer J 2007; 13:257–262. Fine R, Lee Y, Sherman WH, Gulati AP, Oberstein PE, Chu K, et al. Prospective phase II trial of GTX in metastatic pancreatic cancer: laboratory and clinical studies [Gastrointestinal Cancers Symposium abstracts]. J Clin Oncol 2012; 34 (Suppl):209. Fine RL, Moorer G, Sherman W, Chu K, Maurer M, Chabot J, et al. Phase II trial of GTX chemotherapy in metastatic pancreatic cancer [ASCO meeting abstracts]. J Clin Oncol 2009; 27 (Suppl):4623. Hill ME, Li X, Kim S, Campbell A, Culler K, Bloomston M, et al. A phase I study of the biomodulation of capecitabine by docetaxel and gemcitabine (mGTX) in previously untreated patients with metastatic adenocarcinoma of the pancreas. Cancer Chemother Pharmacol 2011; 67:511–517. De Jesus-Acosta A, Oliver GR, Blackford A, Kinsman K, Flores EI, Wilfong LS, et al. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol 2012; 69:415–424. Xenidis N, Chelis L, Amarantidis K, Chamalidou E, Dimopoulos P, Courcoutsakis N, et al. Docetaxel plus gemcitabine in combination with capecitabine as treatment for inoperable pancreatic cancer: a phase II study. Cancer Chemother Pharmacol 2012; 69:477–484. Reni M, Cereda S, Rognone A, Belli C, Ghidini M, Longoni S, et al. A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen). Cancer Chemother Pharmacol 2012; 69:115–123. Cereda S, Reni M. Weekly docetaxel as salvage therapy in patients with gemcitabine-refractory metastatic pancreatic cancer. J Chemother 2008; 20:509–512. Saif MW, Syrigos K, Penney R, Kaley K. Docetaxel second-line therapy in patients with advanced pancreatic cancer: a retrospective study. Anticancer Res 2010; 30:2905–2909. Ignatiadis M, Polyzos A, Stathopoulos GP, Tselepatiotis E, Christophylakis C, Kalbakis K, et al. A multicenter phase II study of docetaxel in combination with gefitinib in gemcitabine-pretreated patients with advanced/metastatic pancreatic cancer. Oncology 2006; 71:159–163. Brell JM, Matin K, Evans T, Volkin RL, Kiefer GJ, Schlesselman JJ, et al. Phase II study of docetaxel and gefitinib as second-line therapy in gemcitabine pretreated patients with advanced pancreatic cancer. Oncology 2009; 76:270–274. Carvajal RD, Tse A, Shah MA, Lefkowitz RA, Gonen M, Gilman-Rosen L, et al. A phase II study of flavopiridol (Alvocidib) in combination with docetaxel in refractory, metastatic pancreatic cancer. Pancreatology 2009; 9:404–409. Ko AH, Dito E, Schillinger B, Venook AP, Bergsland EK, Tempero MA. Excess toxicity associated with docetaxel and irinotecan in patients with metastatic, gemcitabine-refractory pancreatic cancer: results of a phase II study. Cancer Invest 2008; 26:47–52.

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Taxanes in pancreatic cancer Chiorean and Von Hoff 591

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Katopodis O, Polyzos A, Kentepozidis N, Giassas S, Rovithi M, Bozionelou V, et al. Second-line chemotherapy with capecitabine (Xeloda) and docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial. Cancer Chemother Pharmacol 2011; 67:361–368. Dakik HK, Moskovic DJ, Carlson PJ, Tamm EP, Qiao W, Wolff RA, et al. The use of GTX as second-line and later chemotherapy for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol 2012; 69:425–430. Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, Ishitsuka H. Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 1998; 4:1013–1019. Maher JF, Villalona-Calero MA. Taxanes and capecitabine in combination: rationale and clinical results. Clin Breast Cancer 2002; 2:287–293. Nadella P, Shapiro C, Otterson GA, Hauger M, Erdal S, Kraut E, et al. Pharmacobiologically based scheduling of capecitabine and docetaxel results in antitumor activity in resistant human malignancies. J Clin Oncol 2002; 20:2616–2623. Smorenburg CH, Sparreboom A, Bontenbal M, Verweij J. Combination chemotherapy of the taxanes and antimetabolites: its use and limitations. Eur J Cancer 2001; 37:2310–2323. Dumez H, Louwerens M, Pawinsky A, Planting AS, de Jonge MJ, Van Oosterom AT, et al. The impact of drug administration sequence and pharmacokinetic interaction in a phase I study of the combination of docetaxel and gemcitabine in patients with advanced solid tumors. Anticancer Drugs 2002; 13:583–593. Engblom P, Rantanen V, Kulmala J, Helenius H, Grenman S. Additive and supra-additive cytotoxicity of cisplatin–taxane combinations in ovarian carcinoma cell lines. Br J Cancer 1999; 79:286–292. Maeda S, Sugiura T, Saikawa Y, Kubota T, Otani Y, Kumai K, et al. Docetaxel enhances the cytotoxicity of cisplatin to gastric cancer cells by modification of intracellular platinum metabolism. Cancer Sci 2004; 95:679–684. Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, et al. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol 2008; 61:167–175. Ettrich T, Goetz VW, Gress T, Michl P, Geissler M, Hebart H, et al. DOCOX: a phase II trial with docetaxel and oxaliplatin as a second-line systemic therapy for patients with advanced and/or metastatic adenocarcinoma of the pancreas [ASCO meeting abstracts]. J Clin Oncol 2013; 31 (Suppl):4034. Inoue Y, Koh W, Sinanan M, Byrd DR, Park JO, Mann GN, et al. Multimodality neoadjuvant therapy for resectable pancreas cancer. Gastrointestinal Cancers Symposium 2010; abstract #261. Patel M, Hoffe S, Malafa M, Hodul P, Klapman J, Centeno B, et al. Neoadjuvant GTX chemotherapy and IMRT-based chemoradiation for borderline resectable pancreatic cancer. J Surg Oncol 2011; 104:155–161. Liebmann J, Cook JA, Fisher J, Teague D, Mitchell JB. In vitro studies of Taxol as a radiation sensitizer in human tumor cells. J Natl Cancer Inst 1994; 86:441–446. Turrini O, Ychou M, Moureau-Zabotto L, Rouanet P, Giovannini M, Moutardier V, et al. Neoadjuvant docetaxel-based chemoradiation for resectable adenocarcinoma of the pancreas: new neoadjuvant regimen was safe and provided an interesting pathologic response. Eur J Surg Oncol 2010; 36:987–992. Oberic L, Viret F, Baey C, Ychou M, Bennouna J, Adenis A, et al. Docetaxeland 5-FU-concurrent radiotherapy in patients presenting unresectable locally advanced pancreatic cancer: a FNCLCC-ACCORD/0201 randomized phase II trial’s pre-planned analysis and case report of a 5.5-year disease-free survival. Radiat Oncol 2011; 6:124. Pazdur R, Kudelka AP, Kavanagh JJ, Cohen PR, Raber MN. The taxoids: paclitaxel (Taxol) and docetaxel (Taxotere). Cancer Treat Rev 1993; 19:351–386. Rowinsky EK, Cazenave LA, Donehower RC. Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst 1990; 82:1247–1259. Ten Tije AJ, Verweij J, Loos WJ, Sparreboom A. Pharmacological effects of formulation vehicles: implications for cancer chemotherapy. Clin Pharmacokinet 2003; 42:665–685. Gebbia N, Gebbia V. Single agent paclitaxel in the treatment of unresectable and/or metastatic pancreatic adenocarcinoma. Eur J Cancer 1996; 32 A:1822–1823. Whitehead RP, Jacobson J, Brown TD, Taylor SA, Weiss GR, Macdonald JS. Phase II trial of paclitaxel and granulocyte colonystimulating factor in patients with pancreatic carcinoma: a Southwest Oncology Group study. J Clin Oncol 1997; 15:2414–2419.

65

66

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68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

Lam AP, Sparano JA, Vinciguerra V, Ocean AJ, Christos P, Hochster H, et al. Phase II study of paclitaxel plus the protein kinase C inhibitor bryostatin-1 in advanced pancreatic carcinoma. Am J Clin Oncol 2010; 33:121–124. Ko AH, Truong TG, Kantoff E, Jones KA, Dito E, Ong A, et al. A phase I trial of nab-paclitaxel, gemcitabine, and capecitabine for metastatic pancreatic cancer. Cancer Chemother Pharmacol 2012; 70:875–881. Leichman LP, O’Neil BH, Berlin J, Weekes CD, Ames P, McKinley M, et al. A phase IB study of erlotinib in combination with gemcitabine and nabpaclitaxelin patients with previously untreated advanced pancreatic cancer: an academic GI cancer consortium (AGICC) [ASCO meeting abstracts]. J Clin Oncol 2012; 30 (Suppl):4052. El-Khoueiry AB, Iqbal S, Lenz H, Gitlitz BJ, Yang D, Cole S, et al. A phase I study of two different schedules of nab-paclitaxel with ascending doses of vandetanib with expansion in patients with pancreatic cancer [ASCO meeting abstracts]. J Clin Oncol 2011; 29 (Suppl):4124. Lohr JM, Haas SL, Bechstein WO, Bodoky G, Cwiertka K, Fischbach W, et al. Cationic liposomal paclitaxel plus gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: a randomized controlled phase II trial. Ann Oncol 2012; 23:1214–1222. Saif MW, Podoltsev NA, Rubin MS, Figueroa JA, Lee MY, Kwon J, et al. Phase II clinical trial of paclitaxel loaded polymeric micelle in patients with advanced pancreatic cancer. Cancer Invest 2010; 28:186–194. Oettle H, Arnold D, Esser M, Huhn D, Riess H. Paclitaxel as weekly second-line therapy in patients with advanced pancreatic carcinoma. Anticancer Drugs 2000; 11:635–638. Shukuya T, Yasui H, Boku N, Onozawa Y, Fukutomi A, Yamazaki K, et al. Weekly paclitaxel after failure of gemcitabine in pancreatic cancer patients with malignant ascites: a retrospective study. Jpn J Clin Oncol 2010; 40:1135–1138. Maeda S, Motoi F, Onogawa T, Morikawa T, Shigeru O, Sakata N, et al. Paclitaxel as second-line chemotherapy in patients with gemcitabinerefractory pancreatic cancer: a retrospective study. Int J Clin Oncol 2011; 16:539–545. Kim YJ, Bang S, Park JY, Park SW, Chung JB, Song SY. Phase II study of 5fluorouracil and paclitaxel in patients with gemcitabine-refractory pancreatic cancer. Cancer Chemother Pharmacol 2009; 63:529–533. Hosein PJ, de Lima Lopes G Jr, Pastorini VH, Gomez C, Macintyre J, Zayas G, et al. A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. Am J Clin Oncol 2013; 36:151–156. Ernani V, Akunyili II, Hosein P, Macintyre J, Rocha Lima CMS. Gemcitabine and nab-paclitaxel in patients with refractory advanced pancreatic cancer [Gastrointestinal Cancers Symposium meeting abstracts]. J Clin Oncol 2012; 30 (Suppl 4):373. Pisters PW, Wolff RA, Janjan NA, Cleary KR, Charnsangavej C, Crane CN, et al. Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome. J Clin Oncol 2002; 20:2537–2544. Safran H, Moore T, Iannitti D, Dipetrillo T, Akerman P, Cioffi W, et al. Paclitaxel and concurrent radiation for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2001; 49:1275–1279. Rich T, Harris J, Abrams R, Erickson B, Doherty M, Paradelo J, et al. Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12. Am J Clin Oncol 2004; 27:51–56. Schmitt-Sody M, Strieth S, Krasnici S, Sauer B, Schulze B, Teifel M, et al. Neovascular targeting therapy: paclitaxel encapsulated in cationic liposomes improves antitumoral efficacy. Clin Cancer Res 2003; 9:2335–2341. Eichhorn ME, Ischenko I, Luedemann S, Strieth S, Papyan A, Werner A, et al. Vascular targeting by EndoTAG-1 enhances therapeutic efficacy of conventional chemotherapy in lung and pancreatic cancer. Int J Cancer 2010; 126:1235–1245. Schroeder A, Heller DA, Winslow MM, Dahlman JE, Pratt GW, Langer R, et al. Treating metastatic cancer with nanotechnology. Nat Rev Cancer 2012; 12:39–50. Kim TY, Kim DW, Chung JY, Shin SG, Kim SC, Heo DS, et al. Phase I and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clin Cancer Res 2004; 10:3708–3716. Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 2005; 23:7794–7803. Ibrahim NK, Desai N, Legha S, Soon-Shiong P, Theriault RL, Rivera E, et al. Phase I and pharmacokinetic study of ABI-007, a cremophor-free,

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

592

86 87

88

89

90

91

92 93

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Anti-Cancer Drugs 2014, Vol 25 No 5

protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res 2002; 8:1038–1044. Yardley DA. nab-Paclitaxel mechanisms of action and delivery. J Control Release 2013; 170:365–372. Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res 2006; 12:1317–1324. Sato N, Fukushima N, Maehara N, Matsubayashi H, Koopmann J, Su GH, et al. SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor–stromal interactions. Oncogene 2003; 22:5021–5030. Infante JR, Matsubayashi H, Sato N, Tonascia J, Klein AP, Riall TA, et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol 2007; 25:319–325. Yardley DA, Daniel BR, Inhorn RC, Vazquez ER, Trieu VN, Motamed K, et al. SPARC microenvironment signature analysis of a phase II trial of neoadjuvant gemcitabine, epirubicin, and nab-paclitaxel in locally advanced breast cancer [ASCO meeting abstracts]. J Clin Oncol 2010; 28 (Suppl):10574. Markovic S, Suman V, Trieu VN, Liu X, Yeh W, Hwang L, et al. Tumor SPARC microenvironment signature and plasma levels in a phase II trial of unresectable stage IV melanoma treated with nab-paclitaxel and carboplatin: a translational study of NCCTG trial N057E [ASCO meeting abstracts]. J Clin Oncol 2010; 28 (Suppl):8578. Mahadevan D, Von Hoff DD. Tumor–stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther 2007; 6:1186–1197. Alvarez R, Musteanu M, Garcia-Garcia E, Lopez-Casas PP, Megias D, Guerra C, et al. Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br J Cancer 2013; 109:926–933. Neesse A, Frese KK, Chan DS, Bapiro TE, Howat WJ, Richards FM, et al. SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. Gut 2013 [Epub ahead of print]. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364:1817–1825. Ramanathan R, Lee P, Leach JW, Anthony SP, Weiss GJ, Rosen PJ, et al. Phase II study of induction therapy with gemcitabine and nab-paclitaxel followed by consolidation with mFOLFIRINOX in patients with metastatic pancreatic cancer [Gastrointestinal Cancers Symposium abstracts]. J Clin Oncol 2012; 30 (Suppl):233.

97

98

99

100

101

102

103

104

105

106 107

108

Hingorani SR, Harris WP, Beck T, Berdov BA, Wagner SA, Pshevlotsky EM, et al. A phase Ib study of gemcitabine plus PEGPH20 (pegylated recombinant human hyaluronidase) in patients with stage IV previously untreated pancreatic cancer [ASCO meeting abstracts]. J Clin Oncol 2013; 31 (Suppl):4010. Ramfidis VS, Syrigos KN, Saif MW. New therapeutic strategies in the second line setting of advanced or metastatic pancreatic adenocarcinoma. JOP 2013; 14:344–346. MacKenzie S, Zeh H, McCahill LE, Sielaff TD, Bahary N, Gribbin TE, et al. A pilot phase II multicenter study of nab-paclitaxel and gemcitabine as preoperative therapy for potentially resectable pancreatic cancer [ASCO meeting abstracts]. J Clin Oncol 2013; 31 (Suppl):4038. Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control 2003; 10:159–165. Zhou WJ, Zhang X, Cheng C, Wang F, Wang XK, Liang YJ, et al. Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein. Br J Pharmacol 2012; 166:1669–1683. Giannakakou P, Sackett DL, Kang YK, Zhan Z, Buters JT, Fojo T, et al. Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. J Biol Chem 1997; 272:17118–17125. Ramachandran K, Miller H, Gordian E, Rocha-Lima C, Singal R. Methylation-mediated silencing of TMS1 in pancreatic cancer and its potential contribution to chemosensitivity. Anticancer Res 2010; 30:3919–3925. Tasaka T, Akiyoshi T, Yamaguchi K, Tanaka M, Onishi H, Katano M. Gammasecretase complexes regulate the responses of human pancreatic ductal adenocarcinoma cells to taxanes. Anticancer Res 2010; 30:4999–5010. McClelland SE, Burrell RA, Swanton C. Chromosomal instability: a composite phenotype that influences sensitivity to chemotherapy. Cell Cycle 2009; 8:3262–3266. Ma WW, Hidalgo M. The winning formulation: the development of paclitaxel in pancreatic cancer. Clin Cancer Res 2013; 19:5572–5579. Hrkach J, Von Hoff D, Mukkaram Ali M, Andrianova E, Auer J, Campbell T, et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci Transl Med 2012; 4:128ra39. Von Hoff DD, Mita M, Eisenberg P, LoRusso P, Weiss G, Sachdev J, et al. A phase 1 study of BIND-014, a PSMA-targeted nanoparticle containing docetaxel, in patients with refractory solid tumors [AACR meeting abstracts]. Proc Am Assoc Cancer Res 2013; LBA203.

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