Abstract
Background:
Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population.
Methods:
We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011–2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT).
Results:
24 pts were included. Grade 3 or 4 HT occurred in 11 pts. 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Median PFS was 3.7 months (95% CI: 3.0 – 5.7) with a median OS of 11.6 months (95% CI: 6.14 – 15.7). For first line pts, median PFS and OS were 5.1 (95% CI: 2.0 – 12.8) and 12.2 months (95% CI: 4.8 – 30.8), respectively.
Conclusions:
In this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts.
Keywords: FOLFIRINOX, Elderly, Safety, Chemotherapy, Retrospective studies, Geriatric oncology
Introduction:
In 2018, approximately 44,000 people in the United States died of pancreatic cancer, representing the fourth most common cause of cancer death.1 Increasing in incidence, pancreatic cancer has been projected to become the second most common cause of cancer death by 2030.2 The median age at diagnosis of pancreatic cancer is 71 years, indicating that older patients bear much of the disease burden.3 Elderly patients with pancreatic cancer have historically been treated less frequently and less aggressively than their younger counterparts.4 However, population-based studies have suggested that older patients are increasingly being treated with chemotherapy for this disease. There is some indication that elderly patients may have a worse survival than younger patients despite treatment.5,6
After Conroy et al published their landmark paper in 2011 describing the improvement in median overall survival (OS) in metastatic pancreatic cancer patients from 6.8 months with gemcitabine to 11.1 months with FOLFIRINOX (5-Fluorouracil [5-FU], leucovorin, irinotecan and oxaliplatin), the four-drug regimen became the standard of care in this patient population.7 Importantly, patients age 76 years or older were excluded from their pivotal study, and the median age of participants was 61 years.
The toxicities associated with FOLFIRINOX are well-established and include myelosuppression, fatigue, diarrhea and neurotoxicity, among others. In 2013, Von Hoff et al published the results of a phase 3 study demonstrating improved survival in patients treated with gemcitabine and nab-paclitaxel compared to gemcitabine alone, establishing this combination as another front-line treatment option.8 Many clinicians find the gemcitabine and nab-paclitaxel doublet to be better tolerated and forego FOLFIRINOX in the treatment of older patients, who often have more co-morbid conditions. Although never prospectively compared directly to one another, there is some retrospective data to support the conclusion that gemcitabine and nab-paclitaxel is less toxic than FOLFIRINOX.9 Some institutions, including MD Anderson, have adopted the use of modified FOLFIRINOX (mFOLFIRINOX) in this patient population with the intention of reducing toxicity while preserving efficacy.10,11
As a growing number of pancreatic cancer patients are elderly, the decision regarding chemotherapy tolerance will remain of paramount importance. The purpose of our study was to assess the safety and efficacy of mFOLFIRINOX in elderly patients with advanced pancreatic cancer.
Methods:
We retrospectively analyzed patients with unresectable pancreatic cancer who were age 75 or older and treated with FOLFIRINOX/mFOLFIRINOX at The University of Texas MD Anderson Cancer Center during the period of January 1, 2011 to July 1, 2017. Patients were included if they were 75 years or older at the time of their first cycle of FOLFIRINOX/mFOLFIRINOX and received at least their first cycle of chemotherapy at MD Anderson. Only patients with biopsy-proven pancreatic adenocarcinoma were included in the analysis; other histologies were excluded. The primary outcome of our study was the rate of grade 3 or 4 hematologic toxicity. Secondary outcomes included median OS, median progression-free survival (PFS) and chemotherapy doses. We also obtained data on patient demographics, line of treatment and reason for discontinuation of treatment.
Ethics
Our study was approved by the institutional review board and a waiver of consent was granted due to patients lost to follow-up, no longer at the institution, or expired.
Statistical Analysis
Statistical analysis was performed using descriptive statistics. Continuous variables were described using median and range while categorical data were summarized using frequencies and percentages. OS, one of the primary endpoints, was calculated from start of FOLFIRINOX/mFOLFIRINOX to death or last follow-up date. PFS was calculated from start of FOLFIRINOX/mFOLFIRINOX to progression or date of death/last follow-up. Common Terminology Criteria for Adverse Effects (CTCAE) version 4 was utilized to determine toxicity grade retrospectively when applicable.
Results:
A total of 24 patients were included in the analysis. Median age was 76 years (range: 75 to 84). Nineteen (79.2%) were male with only 5 females who met inclusion criteria. Eighteen (75%) patients had distant metastases at the time of treatment with FOLFIRINOX/mFOLFIRINOX compared with 6 (25%) who were considered to have locally advanced disease. The majority (75%) of patients received FOLFIRINOX/mFOLFIRINOX as their first line of systemic therapy, with the other quarter of patients receiving it in the second line. Table 1 contains further information on the patients’ baseline characteristics.
Table 1.
Baseline Characteristics of Patients
| Baseline Characteristics | N (%) |
|---|---|
| Age | Median = 76 years |
| Range = 75–84 years | |
| Gender | |
| Female | 5 (21%) |
| Male | 19 (79%) |
| Stage at Treatment with FOLFIRINOX | |
| Locally advanced | 6 (25%) |
| Metastatic | 18 (75%) |
| Line of Therapy | |
| First | 18 (75%) |
| Second | 6 (25%) |
The most frequently prescribed starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400 mg/m2 (range 1500 to 2400 mg/m2), 150 mg/m2 (range 70 to 150 mg/m2) and 75 mg/m2 (range 60 to 85 mg/m2), respectively. Bolus 5-FU and leucovorin were omitted in all but 3 patients.
The median number of cycles received was 4, and 6 patients were treated with at least 8 cycles. Grade 3 or 4 hematologic toxicities occurred in 11 patients (46%, 95% CI: 26% to 67%), and 9 patients (38%) were supported with granulocyte colony-stimulating factor at some point during treatment. Grade 3 or 4 lymphopenia, neutropenia, anemia and thrombocytopenia occurred in 7 (29%), 6 (25%), 2 (8%) and 1 (4%) patients, respectively. Thirteen patients (54%) had at least one treatment delay. The most common grade 3 or 4 non-hematologic toxicities were fatigue (25%) and diarrhea (21%). Six patients (25%) required hospital admission for any toxicity during treatment with FOLFIRINOX/mFOLFIRINOX, the most common reason being infection (3 patients). Ten patients (42%) stopped FOLFIRINOX/mFOLFIRINOX due to toxicity, most commonly fatigue/declining performance status (6 patients). Six patients (25%) required dose reductions in at least one of the three chemotherapy agents. Table 2 summarizes tolerability and supportive care in these patients.
Table 2.
Summary of Patient Tolerability and Supportive Care
| Variable | N (%) |
|---|---|
| Grade 3 or 4 Hematologic Toxicity | 11 (46%) |
| Lymphopenia | 7 (29%) |
| Neutropenia | 6 (25%) |
| Anemia | 2 (8%) |
| Thrombocytopenia | 1 (4%) |
| Grade 3 or 4 Non-hematologic Toxicity | 10 (42%) |
| Fatigue | 6 (25%) |
| Diarrhea | 5 (21%) |
| Nausea and/or vomiting | 1 (4%) |
| Infection | 1 (4%) |
| Growth Factor Use | 9 (38%) |
| Treatment Delay Required | 13 (54%) |
| Number of delays: | |
| 1 | 11 (46%) |
| 2 | 2 (8%) |
| Admissions for Toxicity | 6 (25%) |
| Reason for admission: | |
| Infection | 3 (13%) |
| Diarrhea | 2 (8%) |
| Diabetic ketoacidosis | 1 (4%) |
| Reason For Discontinuing Treatment | |
| Toxicity | 10 (42%) |
| Disease progression | 8 (33%) |
| Patient/physician choice | 6 (25%) |
The median OS was 11.6 months (95% Confidence Interval [CI]: 6.1 to 15.7). For the 18 patient cohort that had metastatic disease at the time of treatment, the median OS was 6.5 months (95% CI: 4.2 to 8.8), while the median OS for the 6 patients with locally advanced disease was 16.0 months (95& CI: 7.3 to 24.8). The median PFS for the entire group was 3.7 months (95% CI: 3.0 to 5.7). For the metastatic and locally advanced patients, the median PFS was 3.1 months (95% CI: 2.1 to 4.0) and 7.0 months (95% CI: 4.8 to 9.1), respectively. As first line therapy, median PFS and OS were 5.1 months (95% CI: 2.0 to 12.8) and 12.2 months (95% CI: 4.8 to 30.8), respectively. As second line therapy, median PFS and OS were 2.3 months (95% CI: 0.9 to 5.9) and 2.6 months (95% CI: 1.1 to 6.7), respectively. Kaplan-Meier curves for PFS and OS are depicted in Figures 1–4.
Figure 1.
Kaplan Meier curve – PFS for locally advanced vs metastatic
Figure 4.
Kaplan Meier curve – OS for first line vs second line
Discussion:
In this single-institution retrospective analysis, we identified 24 patients with unresectable pancreatic cancer who were treated with FOLFIRINOX or modified dosing FOLFIRINOX at the age of 75 years or older.
The doses of the individual chemotherapy agents utilized by providers in our study were generally lower than the doses given in the original 2011 trial. Additionally, only 3 patients in our analysis received bolus 5-FU and leucovorin, whereas it was a required component of FOLFRINOX in the original study. Rates of grade 3 or 4 hematologic toxicities appeared to be similar in our study and the original 2011 trial. While we described 11 of 24 patients (45.8%) experiencing grade 3 or 4 hematologic toxicities which were most commonly lymphopenia (29%) and neutropenia (25%), Conroy et al reported rates of grade 3 or 4 neutropenia, thrombocytopenia and anemia in the FOLFIRINOX arm to be 45.7%, 9.1% and 7.8%, respectively. Importantly, the toxicity rates we found were similar despite the chemotherapy dose reductions used in the population we evaluated. The rates of grade 3 or 4 non-hematologic toxicities were also similar with fatigue (25%) and diarrhea (21%) being the most common in our study.
The median OS in this population was 11.6 months with a median PFS of 3.7 months. When considering only patients receiving first line FOLFIRINOX/mFOLFIRINOX, the median OS and PFS were 12.2 and 5.1 months, respectively. Though our sample size is small, these first line survival results do appear comparable to the median OS of 11.1 months and median PFS of 6.4 months that were reported in the original 2011 study of first line FOLFIRINOX by Conroy et al. The median OS and PFS that we describe when including patients treated in the second line are lower than those in the initial trial.
Given the similar survival results, it does not appear that the lower doses used in treating this elderly patient population significantly impacted treatment efficacy. Conroy et al did report that age greater than 65 years was an independent risk factor for worsened overall survival in their study, though improved OS was still seen with FOLFIRINOX compared with gemcitabine when adjusting for age along with other prognostic variables.
In another practice-changing study published in December 2018, Conroy et al found mFOLFIRINOX to be superior to gemcitabine in the adjuvant setting for pancreatic cancer.12 In this study, patients up to the age of 79 were included. Interestingly, patients age 70 years or older did not have a statistically significant benefit, though this represented only about 20% of the study population.
Pancreatic cancer already heavily afflicts elderly patients. As life expectance increases across the globe, age will continue to be the non-modifiable risk factor with the greatest impact on the development of this dismal disease. An evidence-based treatment strategy for elderly patients represents a growing need in the field, and clinical trials should be designed with more liberal age cutoffs. Further prospective trials are needed to better determine what chemotherapy regimens are most efficacious and safest in this patient population.
In conclusion, in this single-center retrospective analysis of 24 patients with unresectable pancreatic cancer age 75 and older treated with modified dosing FOLFIRINOX, the safety of this regimen appeared to be similar to what was reported by Conroy et al in the original 2011 study describing the efficacy of FOLFIRINOX, with comparable rates of hematologic toxicity. In elderly patients who received FOLFIRINOX/mFOLFIRINOX in the first line, survival also appeared to be comparable to what was reported in the initial study.
Figure 2.
Kaplan Meier curve – PFS for first line vs second line
Figure 3.
Kaplan Meier curve – OS for locally advanced vs metastatic
Acknowledgements:
The authors would like to acknowledge the patients who were treated at MD Anderson for pancreatic cancer and their families as well as the nursing, administrative, research and other clinical staff who helped in providing them care.
Funding/Support: This research was supported by the National Institutes of Health T32 Ruth L. Kirschstein Institutional National Research Service Award.
Footnotes
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Conflicts of Interest: The authors report no conflicts of interest relevant to this research.
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