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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 10  |  Page : 730-735

Evaluation of the use of nab-paclitaxel and gemcitabine in clinical practice


Hospital Pharmacy Service, Estructura Organizativa de Gestión Integrada de Vigo – Hospital, Álvaro Cunqueiro, Vigo, Pontevedra, Spain

Date of Web Publication24-Sep-2018

Correspondence Address:
Cristina Casanova-Martinez
Casanova-Martínez, Camiño dos Cañotais 44, 36212 Vigo, Pontevedra
Spain
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.188292

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 > Abstract 


Context: Pancreatic cancer in a common tumor in our country for which there are various treatment alternatives.
Objective: Evaluate the effectiveness and safety of nab-paclitaxel and gemcitabine in everyday clinical practice.
Settings and Design: Observational, retrospective study at a tertiary university hospital.
Subjects and Methods: We included patients diagnosed of metastatic or locally advanced pancreatic cancer that were being treated with nab-paclitaxel and gemcitabine. We recorded response, progression-free survival (PFS), and overall survival (OS) rates together with toxicities.
Statistical Analysis Used: We used SPSS program for Windows. We conducted descriptive statistics using averages, medians, standard deviations or ranges, and percentages.
Results: We included 15 patients. At 3 months, there were no complete responses; 20% showed partial responses, and in 60% of patients, the disease stabilized. The median PFS was 8.9 months and the OS was 9.6. The most important adverse reactions were neutropenia, fatigue, and nausea/vomiting.
Conclusions: The treatment regimen leads to increased survival in these patients with an acceptable toxicity profile.

Keywords: Effectiveness and treatment exposure, nab-paclitaxel, pancreatic cancer, toxicity


How to cite this article:
Casanova-Martinez C, Romero-Ventosa EY, González-Costas S, Arroyo-Conde C, Piñeiro-Corrales G. Evaluation of the use of nab-paclitaxel and gemcitabine in clinical practice. J Can Res Ther 2018;14, Suppl S3:730-5

How to cite this URL:
Casanova-Martinez C, Romero-Ventosa EY, González-Costas S, Arroyo-Conde C, Piñeiro-Corrales G. Evaluation of the use of nab-paclitaxel and gemcitabine in clinical practice. J Can Res Ther [serial online] 2018 [cited 2020 Oct 21];14:730-5. Available from: https://www.cancerjournal.net/text.asp?2018/14/10/730/188292




 > Introduction Top


Pancreatic cancers still have a dismal prognosis. According to the EUROCARE-5 study, the overall 1-year survival rate in Europe ranges from ~11% in Malta to 28.3% in Belgium; >95% of those affected die of the disease. The high mortality rate, in most cases, is due to late diagnosis, early metastasis, and poor response to chemotherapy and radiotherapy.[1] Surgical resection offers the only chance of cure. However, only 15–20% of patients have resectable disease at first diagnosis; the majority have either locally advanced or metastatic cancer. Median survival is 8–12 months for patients with locally advanced unresectable disease, and only 3–6 months for those who present with metastases (National Comprehensive Cancer Network [NCCN] guidelines version 1, 2015). In the metastatic setting, fluorouracil-based chemotherapy, as compared with best supportive care alone, improves survival by approximately 3 months.[2] In 1996, a study comparing gemcitabine with fluorouracil in patients with advanced pancreatic cancer showed an improvement in overall survival (OS) of 1 month among patients receiving gemcitabine.[3] Over the following 10 years, multiple randomized studies compared single-agent gemcitabine with combination therapy but did not show a consistent improvement in survival. In one exception, the addition of the epidermal growth factor receptor inhibitor erlotinib was associated with a significant improvement in OS of approximately 2 weeks.[4] Because of its limited effect and added toxicity, adoption of this regimen has not been widespread. Recently, two clinical trials changed the standard of care from single-agent gemcitabine to combination chemotherapy.[2] In the first study, FOLFIRINOX (irinotecan plus fluorouracil plus oxaliplatin), as compared with gemcitabine alone, was associated with a significant improvement in median survival.[5] In the second study, nab-paclitaxel and gemcitabine, as compared with gemcitabine alone, were also associated with prolongation of OS.[6] At present, FOLFIRINOX or combination of gemcitabine and nab-paclitaxel is considered the standard treatment for patients with good performance status who do not have coexisting conditions (NCCN guidelines version 1, 2015).[7]

The albumin-bound paclitaxel (nab-paclitaxel [Abraxane®], Celgene) particles showed antitumor activity in combination with gemcitabine in monodose synergistic models of pancreatic cancer.[8] The Food and Drug Administration (FDA) approved this in combination with gemcitabine for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas on September 6, 2013, and the European Medicines Agency on November 22, 2013.

We performed this study, at one academic center, in advanced/metastatic pancreatic cancer patients. All patients were treated with the nab-paclitaxel and gemcitabine combination therapy, and we evaluated the effectiveness and safety of this combination in everyday clinical practice.


 > Subjects and Methods Top


Unicentric, observational, and retrospective study of patients diagnosed with metastatic or locally advanced pancreatic cancer treated with a regimen of nab-paclitaxel and gemcitabine between May 2013 and December 2014 at a tertiary university hospital. The closing date of the study was on February 23, 2015, and the patients were analyzed by intention to treat.

The data needed for the study were obtained from the electronic patient clinical record database (IANUS® v. 04.20.0503) and from the registry of the “chemotherapy program software” of the pharmacy service (Oncofarm 2013.0.20.0).

The variables collected were the general data of the patient (medical record number, date of birth, sex, and Eastern Cooperative Oncology Group Performance Status [ECOG PS]);[9] data from comorbidities (tobacco, diabetes mellitus, and prior pancreatic disease); and data related to the disease (date of diagnosis, basal value of carbohydrate antigen tumor marker [CA19-9], stage at diagnosis, tumor location, presence, number, and location of metastases, and prior surgery and/or radiotherapy). With regard to the treatment for locally advanced or metastatic disease, we recorded the total number of lines received, the start date, and the ECOG PS before each of them. In addition, we recorded the number of doses received with nab-paclitaxel, the number of reductions, delays, adverse reactions observed with this drug, and date of progression and/or exitus. To estimate the effectiveness, we measured the response rates using Response Evaluation Criteria in Solid Tumors criteria,[10] the progression-free survival (PFS), and OS using the Kaplan–Meier method.[11] To assess safety, we evaluated toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

We performed all statistical analyses using the SPSS program for Windows, version 15 (Copyright© SPSS Inc., 1989–2002, Chicago, IL, USA). We conducted descriptive statistics for quantitative variables using averages or medians as fitting, and standard deviations (SDs) or ranges, respectively. We expressed the qualitative variables as absolute percentages.

This study was adapted to the standards and recommendations of the Declaration of Helsinki (Edinburgh Amendment) and the Oviedo Convention and followed the standards of Good Clinical Practice in humans, as well as the provisions of Act 14/2007, July 3, on biomedical research. This study does not involve any exposure, carrying out further tests or extra visits. The data collected do not reveal the patients' identities.


 > Results Top


Characteristics of the study population

We included 15 patients diagnosed with locally advanced or metastatic pancreatic cancer that were being treated with nab-paclitaxel and gemcitabine during the study period (19 months). The demographic, clinical, and tumor baseline characteristics of the patients are listed in [Table 1].
Table 1: Characteristics of the patients demographic, clinical, and tumor at baseline

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Treatment of locally advanced or metastatic disease

All patients received chemotherapy for locally advanced or metastatic disease; 66.7% of the patients received a single line of treatment.

The time from diagnosis until the start of the first line of treatment was 7.8 (SD: 22.2) months.

We noted that 93.4% of the patients were ECOG PS 0–1 before the beginning of the first line of treatment and the remaining 6.6% ECOG PS 2. Combined nab-paclitaxel and gemcitabine was given as a first-line treatment (including the ECOG PS 2 patient) in 93.4% of the patients, and FOLFIRINOX therapy was used in the remaining 6.6%.

On finishing the study, 26.7% of patients continued with the first-line treatment, whereas this was stopped in 73.3% due to: progression (63.6%), toxicity or allergy (27.3%), or according to the wishes of the patient (9.1%).

The second line of treatment with different schemes was given to 33.3% of the patients: monotherapy with irinotecan, XELOX (capecitabine and oxaliplatin), XELIRI (capecitabine and irinotecan), capecitabine plus radiation therapy, or gemcitabine plus nab-paclitaxel (the latter in the patient who received FOLFIRINOX as a first-line). At the end of the study, only 1 of 5 patients continued with the second line of treatment and the remaining four had stopped due to progression or toxicity.

Effectiveness of treatment

Response to treatment at 3 months

We evaluated the response at 3 months by computerized axial tomography. We did not find any complete responses (CRs). The disease control rate was 80% (20% of partial responses and 60% of stable disease [SD]). We observed that 20% of patients progressed at 3 months.

Survival analysis

During the study period, 66.7% of the patients progressed. Of these, 80% were exitus. The median OS was 9.6 months (95% confidence interval [CI]: 6.8–12.4), and the median PFS was 8.9 months (95% CI: 0.1–17.6). The survival curves are shown in [Figure 1] and [Figure 2].
Figure 1: Overall survival by Kaplan–Meier curve

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Figure 2: Progression-free survival by Kaplan–Meier curve

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Serum concentrations of CA19-9 marker

The average level of CA19-9 tumor marker before the start of treatment with nab-paclitaxel and gemcitabine was 1563.3 IU/ml (SD: 2766.5). In 26.7% of the patients, the marker level was determined during treatment. This gave an average of 163.0 IU/ml (SD: 120.8). After treatment, the average marker level for 60% of the patients that were analyzed was 1662.8 (SD: 3176.1).

Treatment exposure

The median duration of treatment was 3.5 months (range: 0.23–10.7), with 33.4% of patients receiving treatment for at least 6 months.

The nab-paclitaxel dose was reduced in 53.4% of the patients. In total, 52% of all nab-paclitaxel doses administered, during the study, were at the full dose of 125 mg/m2.

The relative dose intensity (proportion of the administered cumulative dose relative to the planned cumulative dose) in our study was 84.52%.

Adverse reactions

[Table 2] gives the main adverse reactions; we observed in the patients in our study.
Table 2: Common adverse events

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We observed that 93.4% of the patients suffered some hematologic adverse events. Neutropenia forced to reduce the dose in 26.7% of the patients (75% of them, presented neutropenia of a grade ≥3) and delay it in 33.4% (80% presented neutropenia of ≥3). Thrombocytopenia forced to reduce and delay doses in 13.4% of the patients.

The more frequent nonhematological adverse events related to treatment were fatigue, nausea and vomiting, peripheral neuropathy, and liver toxicity; only fatigue reaching grade 3 (13.4%). Only peripheral neuropathy forced to reduce the dose of nab-paclitaxel in 13.4% of the patients. One patient (6.7%) delayed the dose due to diarrhea.


 > Discussion Top


Metastatic or locally advanced pancreatic cancer is a very aggressive tumor with few treatment options. Over recent decades, the standard treatment given to patients provided a modest clinical benefit, but not without toxicity. Currently, the main guides of clinical practice (NCCN,[7] Canadian Agency for Drugs and Technologies in Health)[8] proposed the association of nab-paclitaxel and gemcitabine as a first-line treatment for metastatic pancreatic cancer. Our single-centered study, which was carried out in a tertiary care hospital, shows that the demographic characteristics of our population are similar to those found in other studies.[12],[13],[14],[15] In most of the studies analyzed, the age of the patients is similar to the ages of our patients.[6],[8],[14],[16]

In our study, the primary tumor was mainly found either at the level of the tail of the pancreas or in more than one location. This differed from other works[6],[12] that highlighted the location at the level of the head of the pancreas. Giordano et al., 2015,[17] determined that there was an association between the location of the primary tumor in the head and worse prognosis in terms of OS and PFS; therefore, the location of the tumor is important in determining the prognosis of the disease.

In all the studies analyzed, the majority of the patients treated with this chemotherapy regimen had metastases. Of these, 84–85% were at the hepatic level,[6],[12],[14],[16] with the exception of one Spanish study,[18] where the percentage was much lower. In our study, the locations of the majority of the metastases were similar to those reported in the majority of the studies (69% in liver).

The general status (ECOG PS) of the patients analyzed is mostly 0–1, which is consistent with the value obtained in other works, ranging between 82.2% to 87%.[16],[17],[18] Some authors only included ECOG PS 0–1 patients in their studies,[8] and others employed different assessment scales.[6],[12]

Nab-paclitaxel and gemcitabine therapy has shown to be a combination that provides clinical benefit, both in response rates and survival in patients unfit to receive FOLFIRINOX. In our study, the rate of disease control was very high, 5% higher than that cited in other works.[16] However, no CR was found. We only found one study that included 118 patients, where CR was observed in 4 of them.[17] In terms of survival, our PFS data are greater than those found in the bibliography.[16],[18],[19] The OS is above the value, we observed in two papers[16],[17] and in Phase I–II trial.[8] This could be due to the fact that in Phase I–II trials, the patients are more stringently selected than in routine clinical practice.

The average duration of treatment with nab-paclitaxel and gemcitabine was lower in our work in comparison with the pivotal trial. This could be because clinical trials have more stringent inclusion criteria than those used in general health care. The relative dose intensity was slightly higher in our study than the pivotal trial (84.5% vs. 81%).[8] This tells us that both groups of patients received about the same total amount of nab-paclitaxel.

The most frequent toxicities reported in the studies are hematologic adverse reactions. This coincides with our study. According to their severities, the serious (≥ grade 3) hematologic toxicities were neutropenia, thrombocytopenia, and anemia.[6] In our study, the percentages of neutropenia and thrombocytopenia were both similar to the pivotal trial. However, the absence of febrile neutropenia and anemia of grade ≥3 stands out.

Regarding nonhematological adverse events, some studies[6],[18] include fatigue, nausea/vomiting, diarrhea, and peripheral neuropathy. We also reported these adverse events in our work. In the pivotal trial, these adverse reactions are mainly grade 3. However, in our study, only fatigue reached this grade. We also detected liver toxicity following treatment, suggested by raised transaminases. We do know the reason for excluding or not reporting this toxicity in other studies.

The limitations of our study are its retrospective nature and the sample size. However, excluding Congress communications and clinical trials, we only found one series of four cases[19] and one study with a similar sample size[18] in the literature. Despite this, in our study, we reproduce the efficacy demonstrated in the clinical trials (with even better results) and demonstrate toxicities that are in line with these studies. Another limitation of the study is the “nondetermination” of biomarkers for monitoring response to treatment. Some studies point out that a decrease of at least 90% in the CA19-9 marker has been associated with improved survival.[12] However, in our study, this was not a routinely determined marker, at least as a marker for monitoring treatment. Despite having data from few patients, the average marker level declined on starting treatment with respect to the baseline level. This was also the case in other studies.[6],[8],[20]


 > Conclusion Top


Nab-paclitaxel and gemcitabine therapy has proven to be safe and effective in our population. The effectiveness of the combination was better than expected according to the results of the pivotal trial that led to marketing the drug for patients with metastatic or locally advanced pancreatic cancer.

Acknowledgment

The authors wish to thank anonymous reviewers for providing valuable comments on this manuscript. Thanks to Blanca Camacho for her help in the review.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D, et al. Cancer survival in Europe 1999-2007 by country and age: Results of EUROCARE--5-a population-based study. Lancet Oncol 2014;15:23-34.  Back to cited text no. 1
    
2.
Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med 2014;371:1039-49.  Back to cited text no. 2
    
3.
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;15:2403-13.  Back to cited text no. 3
    
4.
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;25:1960-6.  Back to cited text no. 4
    
5.
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25.  Back to cited text no. 5
    
6.
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;369:1691-703.  Back to cited text no. 6
    
7.
National Comprehensive Cancer Network (NCCN). Practise Guidelines in Oncology for Pancreatic Adenocarcinoma- v. 1; 2015. Avaliable from: http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. [Last accessed on 2015 Dec].  Back to cited text no. 7
    
8.
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;29:4548-54.  Back to cited text no. 8
    
9.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55.  Back to cited text no. 9
    
10.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New Response Evaluation Criteria in Solid Tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.  Back to cited text no. 10
    
11.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Am Stat Assoc 1958;53:457-81.  Back to cited text no. 11
    
12.
Reni M, Wan Y, Solem C, Whiting S, Ji X, Botteman M. Quality-adjusted survival with combination nab-paclitaxel+gemcitabine vs gemcitabine alone in metastatic pancreatic cancer: A Q-TWiST analysis. J Med Econ 2014;17:338-46.  Back to cited text no. 12
    
13.
Benavides M, Abad A, Ales I, Carrato A, Díaz Rubio E, Gallego J, et al. TTD consensus document on the diagnosis and management of exocrine pancreatic cancer. Clin Transl Oncol 2014;16:865-78.  Back to cited text no. 13
    
14.
Goldstein D, El-Maraghi RH, Hammel P, Heinemann V, Kunzmann V, Sastre J, et al. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: Long-term survival from a phase III trial. J Natl Cancer Inst 2015;107. pii: Dju413.  Back to cited text no. 14
    
15.
Peixoto RD, Renouf DJ, Lim HJ, Cheung WY. Eligibility of metastatic pancreatic adenocarcinoma (MPA) patients for first-line palliative intent nab-paclitaxel plus gemcitabine (NG) versus FOLFIRINOX (FIO). J Clin Oncol 2014;32 Suppl 3. [abstr 259].  Back to cited text no. 15
    
16.
Fernandez-Montes A, Gonzalez Villarroel P, Valladares-Ayerbes M, De la Cámara Gómez JC, Quintero G, Vazquez Tuñas L, et al. Retrospective analysis of prognostic and predictive markers in patients with locally advanced unresectable and metastatic pancreatic adenocarcinoma treated with gemcitabine/nabpaclitaxel: Influence of the presence of stent. J Clin Oncol 2015;33 Suppl 3. [abstr 483].  Back to cited text no. 16
    
17.
Giordano G, Vaccaro V, Lucchini E, Bertocchi P, Bergamo F, Musettiniet G, et al. Analysis of prognostic factors in advanced pancreatic cancer (APDAC) patients (pts) undergoing to first-line nab-paclitaxel (Nab-P) and gemcitabine (G) treatment. J Clin Oncol 2015;33 Suppl 3. [abstr 412].  Back to cited text no. 17
    
18.
Ferris Villanueva E, Martínez Penella M, Cerezuela Fuentes P, Guerrero Bautista R, García Márquez A, Mira Sirvent Mdel C. Nab-Paclitaxel plus gemcitabine in patients with metastatic pancreatic adenocarcinoma: Experience of use. Farm Hosp 2015;39:181-5.  Back to cited text no. 18
    
19.
Vogel A, Pelzer U, Salah-Eddin AB, Köster W. First-line nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer from routine clinical practice. In Vivo 2014;28:1135-40.  Back to cited text no. 19
    
20.
Chiorean EG, Von Hoff D, Ervin T, Arena PF, Infante JR, Bathini VG. CA19-9 decrease at 8 weeks as a predictor of overall survival (OS) in a randomized phase III trial (MPACT) of weekly nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone in patients with metastatic pancreatic cancer (MPC). J Clin Oncol 2013;31 (Suppl 15). [abstr 4058].  Back to cited text no. 20
    


    Figures

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