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Superior therapeutic efficacy of nab-paclitaxel over cremophor-based paclitaxel in locally advanced and metastatic models of human pancreatic cancer.

ABSTRACT: Albumin-bound paclitaxel (nab-paclitaxel, nab-PTX) plus gemcitabine (GEM) combination has demonstrated efficient antitumour activity and statistically significant overall survival of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) compared with GEM monotherapy. This regimen is currently approved as a standard of care treatment option for patients with metastatic PDAC. It is unclear whether cremophor-based PTX combined with GEM provide a similar level of therapeutic efficacy in PDAC.We comprehensively explored the antitumour efficacy, effect on metastatic dissemination, tumour stroma and survival advantage following GEM, PTX and nab-PTX as monotherapy or in combination with GEM in a locally advanced, and a highly metastatic orthotopic model of human PDAC.Nab-PTX treatment resulted in significantly higher paclitaxel tumour plasma ratio (1.98-fold), robust stromal depletion, antitumour efficacy (3.79-fold) and survival benefit compared with PTX treatment. PTX plus GEM treatment showed no survival gain over GEM monotherapy. However, nab-PTX in combination with GEM decreased primary tumour burden, metastatic dissemination and significantly increased median survival of animals compared with either agents alone. These therapeutic effects were accompanied by depletion of dense fibrotic tumour stroma and decreased proliferation of carcinoma cells. Notably, nab-PTX monotherapy was equivalent to nab-PTX plus GEM in providing survival advantage to mice in a highly aggressive metastatic PDAC model, indicating that nab-PTX could potentially stop the progression of late-stage pancreatic cancer.Our data confirmed that therapeutic efficacy of PTX and nab-PTX vary widely, and the contention that these agents elicit similar antitumour response was not supported. The addition of PTX to GEM showed no survival advantage, concluding that a clinical combination of PTX and GEM may unlikely to provide significant survival advantage over GEM monotherapy and may not be a viable alternative to the current standard-of-care nab-PTX plus GEM regimen for the treatment of PDAC patients.

SUBMITTER: Rajeshkumar NV

PROVIDER: S-EPMC4985357 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Superior therapeutic efficacy of nab-paclitaxel over cremophor-based paclitaxel in locally advanced and metastatic models of human pancreatic cancer.

Rajeshkumar N V NV Yabuuchi Shinichi S Pai Shweta G SG Tong Zeen Z Hou Shihe S Bateman Scott S Pierce Daniel W DW Heise Carla C Von Hoff Daniel D DD Maitra Anirban A Hidalgo Manuel M

British journal of cancer 20160721 4

<h4>Background</h4>Albumin-bound paclitaxel (nab-paclitaxel, nab-PTX) plus gemcitabine (GEM) combination has demonstrated efficient antitumour activity and statistically significant overall survival of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) compared with GEM monotherapy. This regimen is currently approved as a standard of care treatment option for patients with metastatic PDAC. It is unclear whether cremophor-based PTX combined with GEM provide a similar level of therap ...[more]

PMID: 27441498

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Project description:Background and purposeA phase 2 study LAPACT indicated nab-paclitaxel plus gemcitabine (AG) improved outcomes of patients with locally advanced pancreatic cancer (LAPC). Conventional radiotherapy failed to show benefit, indicating high dose to volume with high risk of recurrence is needed. The high dose can be delivered through hypofractionated tomotherapy with simultaneous integrated boost (SIB). However, there is a lack of such prospective trials and more data are needed to validate the role of AG plus hypofractionated tomotherapy with SIB in patients with LAPC.Materials and methodsPatients with LAPC receiving AG plus tomotherapy at the Nanjing Drum Tower Hospital between 2018 and 2021 were retrospectively analyzed. The treatment was scheduled as follows: nab-paclitaxel 125 mg/m2 plus gemcitabine 1,000 mg/m2 on days 1 and 8 every three weeks for at least two cycles, followed by hypofractionated tomotherapy with SIB (high dose field: 50 Gy/10 fractions, the remainder: 30 Gy/10 fractions). Then patients were given AG until intolerance or disease progression.ResultsOverall, 22 patients completing the chemoradiotherapy were included. The median follow-up was 15.2 months. After the chemoradiotherapy, 5 patients achieved a partial response (PR), 15 had a stable disease (SD), and another 2 patients were with progressive disease (PD). The median progression-free survival (PFS) and overall survival (OS) were 12.8 months (95% confidence interval [CI] 4.3-21.3 months) and 16.3 months (95% CI 10.9-21.6 months), respectively. The optimal carbohydrate antigen (CA) 19-9 response and chemotherapy cycles ≥6 were correlated with favorable PFS and OS. The most common recurrent pattern was peritoneal dissemination (22.7%) and the locoregional recurrence rate was relatively low (4.5%). Treatments were well-tolerated. The most common grade ≥3 adverse event was thrombocytopenia (13.6%).ConclusionThis study demonstrated the feasibility of AG followed by hypofractionated tomotherapy with SIB in patients with LAPC. The hypofractionated tomotherapy with SIB was safe and showed high local control rate. Further study with a larger population to validate our data is underway.

Project description:BACKGROUND:Combination chemotherapy regimens including fluoropyrimidines as well as albumin-bound paclitaxel have shown promising results in patients with metastatic pancreatic adenocarcinoma (mPC). Based on the recently described excellent therapeutic index of capecitabine plus nab-paclitaxel in metastatic breast cancer, the present phase II trial was initiated. METHODS:Patients with previously untreated mPC were treated with capecitabine (825 mg/m(2) orally bid on days 1-15) and nab-paclitaxel (125 mg/m(2) intravenously on days 1 and 8) every 3 weeks. In patients without clinically relevant adverse reactions after the 1st treatment course (? grade 2 toxicities according to NCI-CTC vs. 4.0, exuding alopecia and fatigue of any degree) and adequate bone marrow function, the nab-paclitaxel dose was escalated to 100 mg/m(2) on days 1, 8 and 15 of each cycle; this intra-individual dose escalation was maintained during subsequent treatment courses if tolerated. The primary endpoint was objective response rate (ORR) according to RECIST criteria, assessed by an independent radiological review committee with evaluation performed every 2 months. RESULTS:Between 12/2013 and 01/2015, 30 patients were entered in this monocentric academic phase II trial. All patients had an ECOG performance status of 0-1, 80% had liver metastases and 23% had biliary stents in place at time of study initiation. Median CA19-9 was 1,004 U/mL (0.9-100.000 U/mL). In all patients except 2, a dose escalation of nab-paclitaxel after the 1st treatment course could be accomplished. The most common grade 3 adverse events (AEs) included transient sensory neuropathy (23%), (afebrile) neutropenia (17%), hand-foot-syndrome (13%) and phototoxic skin reaction (10%). Among 29 RECIST-response assessable patients, the ORR was 41.4% and stable disease (SD) was noted in 34.5%, resulting in a disease control rate (DCR) of 76%. After a median follow-up duration of 10.3 months (range, 1.9-19.0 months), 13/30 patients (43.3%) are presently being alive. CONCLUSIONS:The combination of capecitabine + nab-paclitaxel at these doses and scheduling was well tolerated and showed substantial antitumor efficacy.

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Superior therapeutic efficacy of nab-paclitaxel over cremophor-based paclitaxel in locally advanced and metastatic models of human pancreatic cancer.

Publications

Superior therapeutic efficacy of nab-paclitaxel over cremophor-based paclitaxel in locally advanced and metastatic models of human pancreatic cancer.

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