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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 2  |  Page : 240-245

Prognostic and predictive markers of response to treatment in patients with locally advanced unresectable and metastatic pancreatic adenocarcinoma treated with gemcitabine/nab-paclitaxel: Results of a retrospective analysis


1 Departament of Medical Oncology, Complexo Hospitalario Universitario de Ourense, Ourense, Spain
2 Departament of Medical Oncology, Complexo Hospitalario Universitario de Vigo, Pontevedra, Spain
3 Departament of Medical Oncology, Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain
4 Departament of Medical Oncology, Complexo Hospitalario Universitario de Ferrol, Ferrol, A Coruña, Spain
5 Departament of Medical Oncology, Hospital Lucus Augusti, Lugo, Spain
6 Departament of Medical Oncology, Hospital de Pontevedra, Pontevedra, Spain

Date of Web Publication23-Jun-2017

Correspondence Address:
Ana Fernández Montes
Departament of Medical Oncology, Complexo Hospitalario Universitario de Ourense, Servicio de Oncología Médica, E-32005 Ourense
Spain
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.181181

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 > Abstract 

Background: Recent studies support the use of gemcitabine and nab-paclitaxel in adults with locally advanced unresectable or metastatic pancreatic adenocarcinoma although insufficient data are available on prognostic and predictive markers of response to treatment.
Objective: The objective of this study is to identify treatment response markers in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma.
Materials and Methods: This is an observational, retrospective, and multicenter study. Sociodemographic, clinical, and therapeutic data were collected. Cox regression models were applied to determine associations.
Results: In total, 39 patients were included; 23.1% presented locally advanced pancreatic cancer and 76.9% metastatic disease. They received a mean of 6 ± 3 treatment cycles; 59% required dose reduction, 59% treatment delay, and 20.5% switched to a biweekly regimen. The overall response rate was 23% and the disease control rate was 81%. Median progression-free survival was 9 months and median overall survival (OS) was 15 months. A higher neutrophil/lymphocyte ratio (NLR) was significantly associated with lower OS. We reported Grades 1–4 nonhematological and hematological toxicities.
Conclusion: NLR is a useful prognostic factor for OS in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma treated with gemcitabine and nab-paclitaxel. Moreover, we suggest that a biweekly regimen is an option for certain groups of patients.

Keywords: Gemcitabine, locally advanced unresectable pancreatic cancer, metastatic pancreatic adenocarcinoma, nab-paclitaxel, predictive markers


How to cite this article:
Montes AF, Villarroel PG, Ayerbes MV, Gómez JD, Aldana GQ, Tuñas LV, Fernández MS, Fernández MJ. Prognostic and predictive markers of response to treatment in patients with locally advanced unresectable and metastatic pancreatic adenocarcinoma treated with gemcitabine/nab-paclitaxel: Results of a retrospective analysis. J Can Res Ther 2017;13:240-5

How to cite this URL:
Montes AF, Villarroel PG, Ayerbes MV, Gómez JD, Aldana GQ, Tuñas LV, Fernández MS, Fernández MJ. Prognostic and predictive markers of response to treatment in patients with locally advanced unresectable and metastatic pancreatic adenocarcinoma treated with gemcitabine/nab-paclitaxel: Results of a retrospective analysis. J Can Res Ther [serial online] 2017 [cited 2019 Oct 15];13:240-5. Available from: http://www.cancerjournal.net/text.asp?2017/13/2/240/181181

On Behalf of the GITuD Group



 > Introduction Top


Pancreatic cancers are among the most important unsolved health problems worldwide,[1] representing the fourth cause of cancer-related death in both sexes [2],[3] and ranking 11th in incidence.[4],[5]

Most patients are diagnosed too late for curative resection and even after curative resection, the disease relapses within 2 years in >80% patients.[1],[3],[6]

Patients with pancreatic cancer generally undergo surgical resection, radiation therapy, chemotherapy, or combined approaches. The choice of treatment modality, whether single or in combination, depends on the stage and size of the tumor and patient factors such as performance status, comorbidity, toxicity, and convenience.[3],[4]

In 1997, gemcitabine demonstrated superior clinical benefit over 5-fluorouracil,[5],[7],[8] and since then, it has been the standard first-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer.[7]

Preclinical studies showed that albumin-bound paclitaxel particles (nab-paclitaxel [Abraxane], Celgene) had antitumor activity as a single agent and synergistic activity in combination with gemcitabine in murine models of pancreatic cancer,[9] and subsequently, the combination entered into clinical development.

In a phase I–II clinical trial in previously untreated patients with metastatic pancreatic adenocarcinoma, the maximum dose of nab-paclitaxel (125 mg/m 2) in combination with gemcitabine, at a dose of 1000 mg/m 2, on days 1, 8, and 15 every 4 weeks, was associated with an acceptable level of adverse events and a median survival of 12.2 months.[10]

The pivotal phase III trial MPACT assessed the efficacy and safety of the combination compared with gemcitabine monotherapy in patients with metastatic pancreatic cancer. Nab-paclitaxel plus gemcitabine significantly improved overall survival (OS) (8.7 months; 95% confidence interval [95% CI]: 7.89–9.69) compared with 6.6 months (95% CI: 6.01–7.20) with gemcitabine alone; progression-free survival (PFS) (5.5 vs. 3.7 months; hazard ratio [HR] 0.69; 95% CI: 0.58–0.82, P< 0.001); and response rates. On the other hand, peripheral neuropathy and myelosuppression increased.[7]

The positive findings from this trial led to the regulatory approval of the combination of nab-paclitaxel and gemcitabine as the first-line treatment for patients with metastatic pancreatic adenocarcinoma in January 2014[11] (Abraxane ® prescribing information, http://abraxane.com).

Further support for the longer-term benefits of nab-paclitaxel plus gemcitabine on OS recently came from the extended follow-up of phase III clinical trial. The results also supported the use of the combination therapy as a new standard option for patients with advanced pancreatic cancer including those with higher-risk baseline features, such as Karnofsky performance status of 70–80, who did not experience any increase in adverse events of Grade 3 or higher. Subgroup analyses also highlighted the relevance of baseline carbohydrate antigen 19.9 (CA 19.9) and neutrophil-to-lymphocyte ratio (NLR) as prognostic markers in metastatic pancreatic cancer.[5]

These results suggest that baseline prognostic markers may be useful for designing more effective treatment plans for pancreatic cancer patients who receive this combination [5],[12],[13] and for selecting individuals more likely to benefit from it.[14]

The aim of this retrospective study, then, was to assess in routine clinical practice the potential prognostic factors that could predict response to gemcitabine and nab-paclitaxel combination therapy in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma.


 > Materials and Methods Top


Study design

Between October 2011 and April 2014, an observational, retrospective, multicenter study was conducted in Spain during outpatient office visits in the routine clinical practice of six Spanish hospitals belonging to the GITuD Group (Galician Group of Research on Digestive Tumours).

Ethics

Before participation, written informed consent was obtained from the patients, or from the patient's authorized representative, for the retrospective collection of data from medical charts. The study protocol was approved by the Ethics Committee of Human Experimentation in Santiago de Compostela (A Coruña, Spain) and procedures complied with the ethical standards of the Declaration of Helsinki (Edinburgh, Scotland, 2000).

Selection and description of participants

We retrospectively evaluated all consecutive adult patients (aged ≥18 years) with unresectable or metastatic pancreatic adenocarcinoma confirmed histologically or cytologically, receiving the first-line gemcitabine and nab-paclitaxel. Patients were also required to have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria,[15] an Eastern Cooperative Oncological Group performance status (ECOG PS) of 0–2 and adequate renal, hepatic, and bone marrow function at the time of diagnosis. Granulocyte colony-stimulating factor prophylaxis was not used.

Objectives and variables

Our primary objective was to evaluate potential prognostic factors that could predict the benefit of gemcitabine and nab-paclitaxel combination therapy in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma. Secondary objectives were to describe the sociodemographic, clinical, and treatment characteristics of patients and analyze treatment response and toxicity.

Data were collected from patients' hospital records from the time of diagnosis of advanced disease until disease progression or death (or loss-to-follow-up). The following variables were recorded for evaluation of potential prognostic factors: age, gender, ECOG PS, tumor/node/metastasis (TNM) stage system, lactate dehydrogenase (LDH) levels (U/L), alkaline phosphatase (AP) (U/L), NLR, CA 19.9 levels (U/L), weight loss (>10% in 6 months or >10% of the normal weight), presence of stent, and use of analgesic drugs. The relationship between these variables and PFS and OS was analyzed.

Tumor response was assessed according to RECIST criteria, and best response rate during treatment was described as follows: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD), according to RECIST 1.1. criteria. The probability of PFS (time from diagnosis to RECIST PD/death) and OS (time from diagnosis to death) was estimated using the Kaplan–Meier method.

The overall response rate (ORR) was calculated as the percentage of patients with PR while the rate of disease control rate (DCR) was calculated as percentage of patients with CR, PR, or SD.

All variables were included in a multivariate Cox regression model. HR and 95% CI were calculated.

Treatment parameters included doses, prescription date, number of cycles of the gemcitabine/nab-paclitaxel combination, dose reductions, and concomitant treatments (including use of analgesic drugs and biliary stents).

Hematological and nonhematological toxicities were evaluated according to National Cancer Institute Common Toxicity Criteria,[16],[17] Grades 1–4.

Statistics

In all cases, statistical significance was defined as a P< 0.05. The statistical software package SAS ® (Statistical Analysis System, version 9.2; SAS Institute Inc., Cary, NC, USA) was used for analysis.


 > Results Top


Demographic and clinical characteristics

A total of 39 patients were included with a mean age of 62.6 ± 8.7 years; the population was predominantly male (61.5%). Approximately one-quarter of patients had locally advanced pancreatic cancer (n = 9; 23.1%) and three-quarters had metastatic disease (n = 30; 76.9%), with liver (46.2%), lung (41.0%), and peritoneum (28.2%) metastases [Table 1].
Table 1: Patient demographics and clinical characteristics (n=39)

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Most patients had ECOG PS 1 (66.7%) followed by level 0 (20.5%) and 2 (12.8%) and most patients were TNM stage IV (76.9%; stage III: 23.1%) at the time of diagnosis [Table 1]. The majority of patients reported weight loss (69.2%). Many patients used analgesic drugs (64.1%) while only 30.8% of patients had biliary stents [Table 1]. Analytical parameters at the moment of diagnosis showed median AP, LDH, CA 19.9, and NRL values of 258.0 U/L, 331.0 U/L, 231.0 U/ml, and 2.455, respectively [Table 1].

Treatment characteristics

Patients received a mean of 6 ± 3 cycles of treatment. Dose reduction was required in 23 patients (59%), of whom 14 needed only one dose reduction. Treatment delay was necessary in 23 patients (59%) and of these, 12 required a delay of more than one cycle (>3 delayed cycles in four patients). Eight patients (20.5%) switched from the standard treatment (days 1, 8, and 15 of a 28-day cycle) to a biweekly regimen (days 1 and 15 of a 28-day cycle) [Table 2].
Table 2: Treatment characteristics and modifications (n=39)

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Efficacy

Efficacy analysis in terms of response was conducted in all study patients. ORR was 23% (eight PRs; no CRs were reported), with a DCR of 81% (58% of patients with SD; 23% with PR) [Figure 1].
Figure 1: Best response rate to treatment (n = 39)

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Median follow-up was 11 months (range: 2–25). At the time of analysis, 37 patients (95%) had experienced disease progression and two patients were lost-to-follow-up. A total of 22 patients (56%) died at the time of analysis.

The median PFS was 9 months (95% CI: 6.99–11.01 months) with a median OS of 15 months (95% CI: 10.53–19.47 months)[Figure 2].
Figure 2: Kaplan–Meier curves for survival. (a) Kaplan–Meier curve for progression-free survival, (b) Kaplan–Meier curve for overall survival

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Prognostic factors

In the multivariate Cox regression model, we did not identify any factor as significantly associated with PFS although we observed a trend for an association between higher NLR and lower PFS (P = 0.06). The HR associated with higher NLR was 1.29 (95% CI: 0.99–1.69) [Table 3].
Table 3: Multivariate analysis of overall survival using Cox proportional hazards regression model

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The multivariate Cox regression model assessing factors associated with OS also found that higher NLR was associated with lower OS (P = 0.002, HR = 1.84; 95% CI: 1.26–2.69) [Table 3]. We also found some association between higher LDH levels and longer OS (P = 0.061, HR = 0.99; 95% CI: 0.98–1.00) [Table 3].

No statistically significant differences were found in PFS or OS between patients with a biliary stent and those without (P = 0.213 for PFS and P= 0.254 for OS).

Toxicity

All patients included in the study were evaluable for the safety analysis (n = 39). The main Grades 1–2 toxicities were anemia in 26 patients (66.0%), asthenia in 11 (28.0%), and neurotoxicity in nine (23.0%). Grade 3 nonhematological and hematological toxicities included asthenia (12.8%), neurotoxicity (5.1%), anemia (2.5%), thrombocytopenia (7.7%), and neutropenia (30.8%) while Grade 4 hematological toxicities were thrombocytopenia (2.5%), neutropenia (12.8%). No Grade 4 nonhematological toxicity was reported [Table 4].
Table 4: Treatment toxicity (n=39)

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 > Discussion Top


Pancreatic cancer carries a dismal prognosis, with over 95% of affected individuals dying of the disease;[8],[18] in most cases, the high mortality rate reflects late diagnosis, early metastasis, and poor response to therapy.[8],[18]

To date, unfortunately, recent advances in the treatment of locally advanced and metastatic pancreatic cancer have provided only modest improvements in outcomes.[14],[19] Prognostic factors associated with current regimens must be investigated to improve currently available treatments [13], 14, [19],[20],[21] and to tailor treatment based on tumor and patient characteristics.[19]

The combination of nab-paclitaxel and gemcitabine has shown superior efficacy versus gemcitabine alone, with manageable toxicity in patients with metastatic and locally advanced unresectable pancreatic adenocarcinoma.[5],[7],[11],[13] Until now, however, no data on predictive markers of response have been assessed in routine clinical practice.

To redress this situation, we performed this retrospective study in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma in the routine clinical practice of six Spanish hospitals, aimed at identifying prognostic and predictive markers of benefits of combined treatment with gemcitabine and nab-paclitaxel.

We studied several variables (gender, ECOG PS, TNM, weight loss and stent, age, AP, LDH, NLR, and CA 19.9) and found a relationship between higher NLR levels and lower survival and a trend between higher LDH levels and longer survival.

These results are in line with previous studies [1],[22],[23],[24],[25],[26] and also confirm the recent pooled analysis of the updated OS data [5] from the phase III pivotal trial with nab-paclitaxel and gemcitabine,[7] in which patients with an NLR ≤5 had a statistically significantly better OS than patients with NLR >5. Moreover, the combination resulted in a statistically significantly longer OS than gemcitabine alone in patients with an NLR <5 while a trend favoring the combination was observed in patients with NLR >5.[5]

NLR, a marker of systemic inflammatory response, is an important prognostic factor for a number of malignancies including colorectal cancer and nonsmall cell lung cancer.[5],[27],[28],[29] This inflammatory response appears to promote the microenvironment to facilitate tumor progression and metastasis.[5],[30],[31] Although the role of this marker has not been fully evaluated in pancreatic cancer and further research is needed, these results suggest that NLR levels should also be taken into account as a prognostic factor when selecting treatment more aggressive treatments as Folfirinox may be required in cases of NLR high levels. Our intention is to confirm these results, obtained in routine clinical practice, in future larger prospective observational studies in patients treated with the combination. We hope that larger samples of patients will yield associations with PFS and other factors.

In our study, we also found some relationship between LDH levels and longer survival. LDH, a parameter indicating a high cell turnover with subsequent release of the intracellular enzyme, has been shown to have prognostic value in advanced pancreatic cancer,[32],[33] although its role in patients treated with nab-paclitaxel plus gemcitabine requires further investigation with higher number of patients.

We found no association between survival and AP, in line with previous studies,[34] or between survival and the use of biliary stents, also in line with results of the phase III study.[5]

Stenting of the biliary tree is a common palliative procedure to relieve obstructive jaundice in advanced malignancy.[35] It may be effective in the relief of biliary obstruction and palliation of symptoms,[35] but its role as a predictive factor for survival in patients treated with chemotherapy has not been not established.

In terms of toxicity, adverse events occurred at similar rate as in the phase III study;[7] neutropenia and asthenia were the most common Grades 3 and 4 adverse events.

It is interesting to note that in our study, a large percentage of patients (20.5%) switched from the standard treatment (days 1, 8, and 15 of a 28-day cycle) to a biweekly regimen (days 1 and 15 of a 28-day cycle). Other authors have also recently suggested that a less intensive regimen of nab-paclitaxel plus gemcitabine is as efficacious as the standard regimen in the first-line treatment for metastatic pancreatic cancer, with the advantage of being less toxic and far less expensive.[36] For this reason, the efficacy and safety of biweekly regimens deserve further comparative studies.

The strengths of our study are that we have confirmed the relevance of NLR as a prognostic factor and the feasibility of a biweekly regimen in a real-life population although further observational studies with larger samples are required.


 > Conclusion Top


We were able to use retrospective data obtained in routine clinical practice to support the relevance of NLR as a prognostic factor for response in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma treated with gemcitabine and nab-paclitaxel. Moreover, we suggest that a biweekly regimen is a possibility for certain groups of patients.

Acknowledgments

The authors wish to thank Nuria Pique for her editorial assistance.

Financial support and sponsorship

This study was funded by GITuD Group (Galician Group of Research on Digestive Tumours), with the collaboration of Celgene España, SL, Madrid, Spain.

Conflicts of interest

There are no conflicts of interest.

 
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