Abstract
Background:
Treatment with nab-paclitaxel with gemcitabine demonstrates a survival advantage when compared with single-agent gemcitabine. However, the combination is associated with significant toxicities, leading to a high rate of drug discontinuation. We implemented a modified regimen of gemcitabine and nab-paclitaxel (mGNabP) in an attempt to minimize toxicities while maintaining efficacy.
Methods:
A total of 79 evaluable patients with metastatic pancreatic adenocarcinoma (mPC) treated with a modified regimen of gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 15 of every 28-day cycle were identified from our prospective database. A total of 57 patients received this regimen as first-line treatment and were evaluated for toxicities, progression-free survival (PFS), and overall survival (OS). Overall, 22 patients with advanced or metastatic PC treated with the modified regimen outside the first-line setting were only evaluated for toxicities.
Results:
The median OS and PFS were 10 months [95% confidence interval (CI) 5.9–13 months] and 5.4 months (95% CI 4.1–7.4 months) for patients that received the modified regimen as first-line therapy. Neurotoxicity occurred in 27% with only 1.6% of patients experiencing grade ⩾3 toxicity. The incidence of grade ⩾3 neutropenia was 19%, resulting in growth factor support in 12% of patients. This rate was similar in patients who received the modified regimen for first-line treatment of mPC versus the overall group.
Conclusions:
A modified regimen of biweekly nab-paclitaxel with gemcitabine is associated with a lower cost, acceptable toxicity profile and appears to be relatively effective in pancreatic cancer. Prospective randomized studies confirming its potential benefits compared with standard weekly mGNabP are warranted.
Keywords: efficacious, gemcitabine-improved toxicity, modified regimen, nab-paclitaxel, pancreatic cancer
Introduction
Despite recent advances in treatment, pancreatic cancer remains a lethal disease and is the fourth leading cause of cancer related mortality in the United States and Europe [Malvezzi et al. 2013; Siegel et al. 2013]. The majority of patients present with advanced or metastatic disease where the overall 5-year survival rate is a dismal 5% [Siegel et al. 2013]. Gemcitabine-based regimens have represented the standard of care for greater than a decade [Burris et al. 1997; Cantore et al. 2004] where its combination with novel agents have resulted in disappointing findings [Oettle et al. 2005; Stathopoulos et al. 2006; Cunningham et al. 2009; Poplin et al. 2009; Colucci et al. 2010; Kindler et al. 2010; Philip et al. 2010; Goncalves et al. 2012], including its combination with erlotinib, which showed a modest improvement in overall survival (OS) compared with gemcitabine alone in patients with pancreatic cancer [Moore et al. 2007]. More recently, two chemotherapy regimens, both based on randomized phase III trials, have shown effectiveness and superiority over single-agent gemcitabine. A combination of 5-fluorouracil (5-FU) with oxaliplatin and irinotecan (FOLFIRINOX) was shown to provide a survival benefit of 4.5 months compared with gemcitabine alone at the expense of significant toxicities [Conroy et al. 2011]. MPACT, a large, randomized phase III trial showed the combination of weekly gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) given on 3 weeks of a 4-week cycle had a significant improvement in OS (8.5 months versus 6.7 months) when compared with single-agent gemcitabine [von Hoff et al. 2013].
Although effective, the combination of weekly gemcitabine and nab-paclitaxel (mGNabP) is associated with significant cumulative toxicities and cost. In the MPACT trial, a large proportion of patients who received the combination of gemcitabine with nab-paclitaxel required a dose-reduction (47% for gemcitabine dose and 41% for nab-paclitaxel dose) with reported rates of >3 grade neuropathy or neutropenia at 17% and 38%, respectively [von Hoff et al. 2013]. Prior studies suggest patients receiving biweekly gemcitabine as a single agent or in combination may not lose efficacy while lessening treatment adverse effects, especially with decreased rates of hematological toxicities [Heinemann et al. 2006; Poplin et al. 2009].
Based on the information above, we adopted a modified, biweekly regimen of mGNabP for all our patients treated with this regimen. Herein, we report our experience with mGNabP in patients with metastatic pancreatic cancer (mPC), including an analysis of efficacy in first-line use, toxicity and cost.
Materials and methods
Patients and study design
This study was approved by the Ohio State University Institutional Review Board. Data were obtained from a prospectively collected database for patients with advanced or mPC who received mGNabP at the Ohio State University between 1 February 2013 and 31 March 2015. All patients were evaluated for toxicity while efficacy measurements were limited to patients with untreated metastatic disease [IRB 2014C0069].
Eligibility criteria
Patients had to be older than 18 years of age with a diagnosis of biopsy-proven pancreatic adenocarcinoma. Patients with metastatic disease as well as locally advanced or borderline resectable disease were included. In addition, patients were required to have an Eastern Cooperative Group (ECOG) Performance Status (PS) of 0 or 1. Patients with prior gemcitabine administration in the adjuvant setting or in combination with a different chemotherapeutic agent other than nab-paclitaxel were included.
Treatment schedule
Chemotherapy was administered on days 1 and 15 of a 28-day cycle and included nab-paclitaxel at 125 mg/m2 and gemcitabine 1000 mg/m2, both administered over 30 min. Pre-medications were administered as per the institutional standard. Treatment was continued until evidence of disease progression or unacceptable toxicity.
Treatment evaluation
Computed tomography (CT) scans of the chest, abdomen and pelvis were obtained every 8 weeks as per our institutional standard and results were reported by specialty radiologists. Final disease assessments were performed independently by the treating physician. Laboratory values (complete blood cell count, comprehensive metabolic panel, albumin, and CA 19-9 levels) were recorded at baseline and prior to each treatment.
Patients were seen every 2 weeks prior to treatment, and toxicities were assessed utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4 (CTCAE v4) [Conroy et al. 2011]. Toxicities were evaluated, graded, and recorded in the patient’s medical record prospectively at each visit by registered nurses, and subsequently verified by a medical oncologist and clinical oncology pharmacist.
All assessments in addition to data regarding patient demographics, stage of disease, presence and site of metastases, ECOG PS, history of previous resection, prior therapy, biliary stent placement, further subsequent lines of therapy, and reasons for therapy discontinuation were prospectively maintained in our database.
Statistical analysis
Demographics, patient characteristics, and toxicities were summarized using descriptive statistics (median/range for continuous outcomes, and frequency for categorical outcomes). Progression-free survival (PFS) was calculated from the date of clinic visit prior to starting gemcitabine with nab-paclitaxel to disease progression or death, whichever occurred first. If the patient did not have an event of disease progression nor died, informative censoring occurred at the date of the last available disease progression assessment. OS was determined from the date of clinic visit prior to starting chemotherapy to death from any cause. Patients who were still alive were censored at the date of last known follow up. Survival curves were estimated using the method of Kaplan–Meier. Estimated median with 95% confidence intervals (CIs) were reported. We report toxicity incidence for informative purposes only. All statistical analyses were conducted using SAS version 9.3 (SAS Institute, Cary, NC, USA).
Results
Patient characteristics
A total of 79 evaluable patients that received treatment with the modified regimen during the time period were included. Patient characteristics are summarized in Table 1. Of the 79 patients who received mGNabP, 57 patients received the modified regimen as first-line therapy for metastatic disease, 11 patients in the second-line setting, and 11 patients for locally advanced or borderline resectable disease.
Table 1.
Patient baseline and disease characteristics.
| Characteristic | First-line treatment- metastatic disease n = 57 (%) | All patients with metastatic disease n = 68 (%) |
|---|---|---|
| Age | ||
| In years: | ||
| Median | 64 | 64 |
| Range | 41–84 | 41–84 |
| Sex: | ||
| Female | 22 (39) | 29 (43) |
| Male | 35 (61) | 39 (57) |
| Location of primary tumor: | ||
| Head | 27 (47) | 33 (49) |
| Body | 13 (23) | 15 (22) |
| Tail | 11 (19) | 13 (19) |
| Unknown/other | 6 (11) | 7 (10) |
| Number of metastatic sites: | ||
| 1 | 25 (44) | 26 (38) |
| 2 | 20 (35) | 24 (35) |
| 3 | 8 (14) | 10 (15) |
| >3 | 4 (7) | 8 (12) |
| Sites of metastatic disease: | ||
| Liver | 35 (61) | 43 (63) |
| Lung | 14 (25) | 19 (28) |
| Peritoneum | 15 (26) | 17 (25) |
| Regional nodes | 23 (40) | 28 (41) |
| Distant metastatic site | 24 (42) | 31 (46) |
| CA 19-9 level at start of therapy: | ||
| Normal (⩽37 U/ml) | 10 (18) | 13 (20) |
| Elevated (>37 U/ml) | 47 (82) | 55 (80) |
| Biliary stent placement: | ||
| Yes | 17 (30) | 21 (31) |
| No | 40 (70) | 47 (69) |
Efficacy analysis
In the 57 evaluable patients that received mGNabP in the first-line setting for mPC, the median OS was 10 months (95% CI: 5.9, 13), and the median PFS was 5.4 months (95% CI 4.1–7.4 months) (Figure 1). The response rate for these patients was 18.6%. The median number of cycles per patient was 3.5 (range of 0.5–15.5 cycles), with a median follow up of 6.5 months. The median duration of treatment with the modified regimen in the first-line setting was 4.2 months (95% CI 3.2–5.2 months). Among all included patients with metastatic disease (regardless of treatment line who received the modified regimen, a total of 68 patients), the median duration of treatment was 3.8 months (95% CI 2.8–4.9 months) with a median duration of follow up was 6.1 months. In patients who progressed while receiving mGNabP, 19 patients (33%) were able to receive second line treatment. Of the patients who received second-line therapy, 63% received either FOLFOX or XELOX, 16% received FOLFIRI, 10.5% received a gemcitabine-based regimen and 10.5% went on a clinical trial. A total of 26% of patients went on to receive third-line treatment.
Figure 1.
Kaplan–Meier estimates of PFS and OS.
Figure A shows the PFS in patients with mPC who received modified mGNabP in the first-line setting. Figure B shows OS for the same patient cohort.
mGNabP, modified regimen of gemcitabine and nab-paclitaxel; mPC, metastatic pancreatic cancer; OS, overall survival; PFS, progression-free survival.
Toxicity analysis
The majority of toxicities observed were grade <2, and included fatigue, neuropathy, nausea, and diarrhea. However, grade ⩾3 toxicities were rare and are outlined in Table 2. The most common grade 3 or 4 toxicities were hematologic and included neutropenia (16%), anemia (12%) and thrombocytopenia (1.6%). Among patients who experienced neutropenia, only 7 patients (10%) required growth factor support at any time and febrile neutropenia was seen in 1 patient (1.5%). The most common grade 3 or 4 nonhematologic side effects included fatigue (6%) and neuropathy in 1 patient (grade 3 neuropathy, 1.5% of patients). None of the patients experienced grade 4 neuropathy.
Table 2.
Toxicities grade 3 or 4 and growth factor support.
| Toxicity | Number of patients with grade 3 or higher toxicity (%) n = 68 |
|---|---|
| Neutropenia | 11 (16) |
| Febrile neutropenia | 1 (1.5) |
| Growth factor use | 7 (10) |
| Anemia | 8 (12) |
| Thrombocytopenia | 1 (1.5) |
| Neuropathy | 1 (1.5) |
| Fatigue | 4 (6) |
| Diarrhea | 0 |
| Nausea | 1 (1.5) |
A total of 40 patients were able to receive therapy without any treatment delays (51%). Only 12 patients (15%) required a dose reduction in gemcitabine and 15 patients (19%) in nab-paclitaxel due to toxicities. The majority of the patients were able to receive both drugs without requiring dose reduction, 64 (81%) and 61 (77%) respectively for mGNabP. Overall, 31 patients (39%) stopped treatment due to disease progression, 17 (21.5%) patients due to worsening disease-related symptoms and 2 (2.5%) patients due to treatment related toxicities. Of note, 28 of 79 (33%) patients experienced a venous thromboembolic event.
Discussion
Weekly gemcitabine with nab-paclitaxel (albumin-bound paclitaxel) has recently been shown to be superior to single-agent gemcitabine and is considered a standard regimen in the treatment of advanced pancreas cancer [von Hoff et al. 2013]. Although the combination provides a significant improvement in survival, its weekly administration is associated with significant toxicities, requiring dose delays or reductions in approximately 50% of patients. Moreover, the associated cumulative toxicities and the fact that pancreas cancer is hallmarked by an early development of treatment resistance to first-line chemotherapy may limit effective administration of subsequent lines of therapy.
Comparatively, nab-paclitaxel has a relatively different toxicity profile in comparison with solvent-based paclitaxel, such as an improved hematological toxicity profile while conferring a higher risk for neurotoxicity [Gradishar et al. 2005]. It is widely used in the treatment of various solid tumor malignancies including breast cancer, lung cancer and ovarian cancer. The dosing of nab-paclitaxel is variable and dependent on the type of malignancy and the chemotherapeutic agent that it is used in combination with. In metastatic breast cancer, nab-paclitaxel as a single agent is dosed at 100 or 150 mg/m2 on days 1, 8, 15 of a 28-day cycle [Gradishar et al. 2009], or alternatively at 260 mg/m2 every 21 days [Gradishar et al. 2005]. In non-small cell lung cancer where the combination of nab-paclitaxel and carboplatin is commonly used in standard practice, the dosing of nab-paclitaxel is administered at 100 mg/m2 on days 1, 8, 15 of a 21-day cycle along with carboplatin at an AUC of 6 on day 1.
In the MPACT trial where nab-paclitaxel was administered at 125 mg/m2 in combination with gemcitabine at 1000 mg/m2 on days 1, 8, 15 of a 28-day cycle, only 71% of patients received nab-paclitaxel at the planned full dose. Additionally, 41% and 47% of patients required dose reduction in nab-paclitaxel or gemcitabine respectively. A total of 22% of patients discontinued treatment due to toxicity, including 17% of who developed grade 3 or 4 neuropathy.
The above knowledge formed the rationale for selecting a modified (biweekly) schedule in which mGNabP was administered at an approved standard dose only on days 1 and 15 of a 28-day cycle, with the goals of improving toxicities while maintaining efficacy. Additional support for this dosing schedule regimen is based on the favorable results of multiple trials over the past decade assessing the biweekly administration of gemcitabine as a single agent or in combination while featuring similar efficacy and improving convenience and toxicities when compared with the historical weekly dosing schedule [Heinemann et al. 2006; Ko et al. 2006, 2007; Poplin et al. 2009].
The findings from our study suggest that the modified treatment regimen retains relative efficacy, with historically-comparable outcomes with the weekly regimen (Table 3). The rates of grade 3 and 4 toxicities were modest with the most common being neutropenia and only 9% patients requiring growth factor support. Interestingly, the rate of grade ⩾3 neuropathy remained low at 1%. In addition to a favorable toxicity profile, the majority (80%) of the patients were able to receive both chemotherapy agents without dose reductions. Recent results of a phase I study examined four different schedules of mGNabP in patients with advanced pancreatic cancer and poor PS, including dose intensification and biweekly scheduling [Guillen-Ponce et al. 2014]. The four arms examined in this study were: (arm B) nab-paclitaxel 150 mg/m2 and gemcitabine 1000 mg/m2 intravenously (i.v.) week 1, 3 every 4-week cycle; (arm C) nab-paclitaxel 100 mg/m2 gemcitabine 1000 mg/m2 i.v. week 1, 2, 3 every 4-week cycle; (arm D) nab-paclitaxel 125 mg/m2 gemcitabine 1000 mg/m2 i.v. week 1, 3 every 4-week cycle; and (arm E) nab-paclitaxel 125 mg/m2 gemcitabine 1000 mg/m2 i.v. week 1, 2, 3 every 4-week cycle. The investigators decided to move forward with arms C and E in their planned phase II study. When looking closely at each of the four arms, the number of grade 3 or higher toxicities were most common in arms B and E. Only one grade 3 adverse event was observed in arms C and D (which has a similar dose/schedule with the one described in this paper).
Table 3.
Comparison of survival, toxicity and cost between modified mGNabP with standardized dosing regimen of mGNabP.
| Variable | mGNabP: n (%) | MPACT trial n (%) |
|---|---|---|
| PFS, median | 5.4 months, n = 57 | 5.5 months, n = 431 |
| OS, median | 10 months, n = 57 | 8.5 months, n = 431 |
| Grade 3 or 4 toxicity, hematological | ||
| Anemia | 8/57 (14%) | 53/405 (13%) |
| Neutropenia | 11/57 (19%) | 153/405 (38%) |
| Thrombocytopenia | 1/57 (2%) | 52/405 (13%) |
| Growth factor support | 7/57 (12%) | 110/431 (26%) |
| Grade 3 or 4 neurotoxicity | 1/57 (2%) | 70/421 (17%) |
| Dose reduction in patients: | ||
| Nab-paclitaxel | 20% | 41% |
| Gemcitabine | 16% | 47% |
mGNabP, modified regimen of gemcitabine and nab-paclitaxel; OS, overall survival; PFS, progression-free survival.
In addition to the added convenience and the improved toxicity profile of the biweekly regimen, there are also potential cost considerations. With the rising cost of health care and the focus from the American Society of Clinical Oncology for increased awareness of the financial burden associated with treatment on patients [Meropol et al. 2009], it is important to consider the cost of each treatment regimen after it has been deemed to be safe and effective. While cost-effectiveness analysis is ideally done when comparing regimens in a single randomized study, our group recently presented the costs of different chemotherapy regimens commonly used in advanced pancreatic cancer. When taking into consideration the cost of drugs, administration and those secondary to toxicities, a difference of US$5505 per month of therapy (US$6716 compared with standard mGNabP regimen at US$12,221) is seen when comparing the modified biweekly gemcitabine/nab-paclitaxel approach with the standard regimen [Goldstein et al. 2016]. Moreover, using a modified biweekly gemcitabine/nab-paclitaxel regimen minimizes cumulative toxicities, allowing patients to tolerate and potentially receive further lines of therapy at the time of treatment failure. This rationale may account for the difference in median OS seen in our experience [von Hoff et al. 2013], similar to the findings seen with FOLFIRINOX by Conroy and colleagues [Conroy et al. 2011]. When considering a difference in costs, improvement in toxicities and convenience, patients are likely to have an improvement in quality of life measures, which we were unable to assess in this study.
Principle limitations of this study include its retrospective nature, in addition to its relatively small sample size. While toxicity assessment was based of CTCAE criteria from the treating physician, potential inaccuracies may be seen given the retrospective nature of the study. Additionally, several inherent biases include the potential for selection bias and the absence of a control arm. Nonetheless, virtually all patients with pancreatic cancer at our institution with a reasonable PS were treated with this modified combination. We believe this population likely provides a realistic representative group encountered in clinical practice enhancing the preliminary validity of our findings.
Conclusion
A modified regimen of biweekly nab-paclitaxel with gemcitabine in the treatment of mPC holds promise. The utilization of the modified regimen minimizes cumulative toxicities, which may allow patients to tolerate and receive further effective therapy in the refractory setting. In addition to an acceptable toxicity profile, this modified approach is associated with a lower cost, and appears to be relatively effective in advanced pancreatic cancer. Future prospective studies confirming the benefits of a modified biweekly combined mGNabP and its potential benefits in comparison with the standard weekly regimen are warranted.
Acknowledgments
Daniel H. Ahn and Kavya Krishna contributed to the manuscript equally.
Footnotes
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Contributor Information
Daniel H. Ahn, Department of Internal Medicine, Division of Hematology/Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
Kavya Krishna, Department of Medical Oncology, Ohio State University Wexner Medical Center, Richard Solove Research Institute and James Cancer Hospital, Columbus, OH, USA.
Marlo Blazer, Department of Pharmacy, Ohio State University Wexner Medical Center, Richard Solove Research Institute and James Cancer Hospital, Columbus, OH, USA.
Joshua Reardon, Department of Pharmacy, Ohio State University Wexner Medical Center, Richard Solove Research Institute and James Cancer Hospital, Columbus, OH, USA.
Lai Wei, Center for Biostatistics, Ohio State University, Columbus, OH, USA.
Christina Wu, Emory Winship Cancer Institute, Department of Hematology and Medical Oncology, Atlanta, GA, USA.
Kristen K. Ciombor, Department of Medical Oncology, Ohio State University Wexner Medical Center, Richard Solove Research Institute and James Cancer Hospital, Columbus, OH, USA
Anne M. Noonan, Department of Medical Oncology, Ohio State University Wexner Medical Center, Richard Solove Research Institute and James Cancer Hospital, Columbus, OH, USA
Sameh Mikhail, Department of Medical Oncology, Ohio State University Wexner Medical Center, Richard Solove Research Institute and James Cancer Hospital, Columbus, OH, USA.
Tanios Bekaii-Saab, Department of Internal Medicine, Division of Hematology/Medical Oncology, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA.
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