Safety and efficacy of combination chemotherapy regimens in older adults with pancreatic ductal adenocarcinoma: a systematic review

Introduction

Pancreatic ductal adenocarcinoma (PDA) is often diagnosed in older adults. The median age at diagnosis is 70 years, and the highest incidence is found among people aged 65–74 years (28.4%) followed by 75–84 years (24.7%) (1). However, most published studies investigating chemotherapy for PDA include a predominantly younger population, and some studies exclude older adults altogether. Single agent gemcitabine has been studied in patients ≥70 years with unresectable PDA, and demonstrated safety and efficacy (mOS 10.3 months, P<0.05) (2). Over the last decade, several phase III trials have shown that combination chemotherapy regimens are associated with improved survival compared to single agent regimens in patients with advanced PDA, although often at the expense of increased toxicity (3-5). How to apply these findings to older adults with PDA, however, is not well established in the scientific literature. In the MPACT study, older adults comprised 42% of the study population (4), while in the PRODIGE trial patients over age 76 were excluded (3). Our objective in this systematic review is to assess the safety and efficacy of combination chemotherapy regimens for locally advanced or metastatic PDA in older adults greater than 65 years of age.

We present the following article in accordance with the PRISMA reporting checklist (available at https://dx.doi.org/10.21037/jgo-21-87).

Methods

The PICOS (Population, Intervention, Comparison, Outcomes, and Study Design) inclusion and exclusion criteria used to perform the literature review are listed in Table 1.

A literature search of randomized controlled trials, retrospective cohort studies, prospective cohort studies and abstracts from national and international oncology meetings was conducted using the PubMed, EMBASE and MEDLINE databases, as well as ClinicalTrials.gov and ASCO.org. The search was performed using the following terms: Pancreatic Neoplasms [Mesh], Antineoplastic Combined Chemotherapy Protocols [Mesh], Antineoplastic Agents [Mesh], Aged [Mesh], Elderly [tiab] Others: non-resectable pancreatic adenocarcinoma, locally advanced pancreatic ductal adenocarcinoma, geriatric, age*65, fluorouracil, leucovorin, folinic acid, oxaliplatin, gemcitabine, paclitaxel, capecitabine, folfox, folfirinox, capox.

The search was restricted to human studies published up to October 2018 in English. The study selection process was performed in the COVIDENCE software and is detailed in Figure 1.

Figure 1 PRISMA flow chart. A total of 1,939 references were imported for screening, of which 460 duplicates were removed. 1,479 references were imported for screening, of which 1,455 were deemed irrelevant (these referenced include other types of GI tumors, other therapeutic regimens or study objective that were not related to this search). 24 full text studies were assessed for eligibility. Of these studies, 15 abstracts that did not result in a publication and 4 additional studies were excluded. This last 4 studies were defined as wrong study, by which we are referring to meta-analysis, insufficient results reported, or study population with age groups that did not meet inclusion criteria. Five studies were included in the final analysis.

Two investigators (P Saade-Lemus and L Biller) independently performed the literature search and selected eligible articles on the basis of prespecified inclusion criteria. For eligible studies, both authors extracted data and assessed study quality using the Newcastle-Ottawa Scale (6). Discrepancies were resolved by the senior author (A Bullock).

The following study characteristics were extracted: name of first author, title, journal, study design, date of publication, study duration (years), total number of participants, age range, sex, setting (country and number of institutions included), eligibility criteria, interventions (chemotherapy regimen, need for dose attenuation and prophylaxis, median follow-up), overall survival (OS), median overall survival (mOS), median progression-free survival (mPFS), response rate (RR) and grade 3/4 toxicities.

Results

Study Selection

The initial search identified 1,939 references imported for screening; 460 duplicates were removed, leaving 1,479 studies to screen of which 1,455 were not relevant to this review. Twenty-four full-text studies were assessed for eligibility. Nineteen were excluded due to wrong study design (n=4) or abstract only with no further publication (n=15). Studies categorized as wrong study design included: meta-analysis, insufficient results reported, or study population with age groups that did not meet inclusion criteria. A total of 5 full text studies met eligibility and were included in the present review.

Study characteristics and results

The compilation of results for the papers included in this article can be found in Table 2. Baldini et al. (7) describes a cohort of 42 subjects between the ages of 70–79 diagnosed with locally advanced or metastatic PDA at five institutions in France treated with FOLFIRINOX and followed for up to 86 months. Study population had the following characteristics: performance status (0=15%, 1=24%, 2=3%), BMI (median 24 kg/m²; range, 18–32 kg/m²), concurrent medications (≤3, 24 and ≥3, 16). Also, Charlson comorbidity index at the time of diagnosis: median 10; range, 9–12. Diabetes and hypertension were also included in the univariate analyses. Dose attenuation was necessary in 57% of cases, and primary prophylaxis with granulocyte-colony stimulating factor (GCSF) was administered in 33%. Median overall survival from time of diagnosis was 12.6 months (95% CI: 1.7–150 months) and from diagnosis of metastases 11.6 months (95% CI: 1–74 months). Median OS for patients with locally advanced PDA was 49.5 months (95% CI: 13.5–85.5 months). Primary dose reduction did not impact OS [11.7 months (6.9–16.4 months) compared to 16.6 months (0.37–32.8 months) without dose reduction, P=0.69]. Twenty-nine percent experienced a grade 3/4 toxicity with thrombocytopenia (81%), neutropenia (71%), asthenia (55%) and sensory neuropathy (23%) most often reported. One death was reported due to therapy-related sepsis. Baldini and colleagues concluded that FOLFIRINOX is feasible and effective in selected, fit older adult patients.

There are two retrospective cohort studies conducted at a single institution in Germany reported by Berger et al. The first in 2014 (8) included 53 patients with histologically proven PDA, all >70 years and with median age 73 years (range, 70–89 years), treated with multiple regimens per attending oncologist. These included: gemcitabine-based regimens (81.1%) and fluorouracil combinations¹: FOLFIRINOX (7.5%), OFF (5.7%), FOLFOX (3.8%), and capecitabine (1.9%); 30.2% required a dose reduction; no primary prophylaxis was reported. Median OS was 201 days (range, 17–1,480). Median OS for patients ≥75 years was 145.5 days, and did not differ from those <75 years 218 days (95% CI: 0.46–1.53 days, P=0.57). Median OS for patients with ECOG PS 0 or 1 was 234.5 vs. 118 days for patients with ECOG ≥2 (95% CI: 1.38–S4.52 days, P=0.003). Median PFS was 118 days (range, 17–597 days), with a significant difference between patients with ECOG 0 or 1 vs. ECOG ≥2 of 234.5 days vs. 84 days, respectively (95% CI: 1.54–5.17 days, P=0.008). 30.2% of patients experienced grade 3/4 toxicities, most commonly hematotoxicity 20.7% and fatigue 5.7%. Patients with an ECOG PS ≥2 had a statistically significant shorter median duration of therapy (59 days) compared to those with ECOG PS ≤1 (105 days; P<0.009). Berger and colleagues concluded that older patients did not have inferior outcomes compared to the reported trial populations that included predominantly younger patients.

In 2017, Berger et al. (9) reported on a retrospective cohort of 88 subjects with PDA treated with FOLFIRINOX. Two subgroups were identified: <65 years (82%) and ≥65 years (17%). Dose attenuation was required in 56.8% of the total population and in 46.7% of the ≥65 years subgroup. There was no difference in OS between the two subgroups. Among those <65 years, median OS was 11.2 months (95% CI: 8.9–13.6 months), and among those ≥65, median OS was 7.9 months (95% CI: 5.8–10.0 months, P=0.83). Median PFS for the entire cohort was 6.4 months (95% CI: 5.7–7.2 months). Among those with ECOG PS 0, mPFS was 6.9 months (95% CI: 6.2–7.6 months) compared to 5.4 months (95% CI: 3.8–6.9 months) among those with ECOG PS 1, and 2.3 months (95% CI: 1.0–3.6 months) among those with ECOG PS 2 (P=0.019). Toxicities in the ≥65 years group included: fatigue (13.3%), nausea/vomiting (13.3%), diarrhea (6.7%), cholangitis (6.7%), and thrombosis/PE (6.7%). No therapy-related deaths were reported. The study concluded that age ≥65 years was not associated with significantly different PFS or OS, nor were there significant differences in therapy interruptions, dosage modifications or grade 3/4 toxicity.

Guion-Dusserre et al. (10) reported on a retrospective study of 34 subjects treated with FOLFIRINOX for locally advanced or metastatic PDA or colorectal cancer (mean age 74 years; range, 70–87 years) at a single institution in France. 83.0% of the patients were ≥80 years. Median OS among patients treated for PDA was 12.51 months (range, 8.85–17.2 months). The need for dose reduction occurred in 75% during cycle 1. Toxicity data was presented for the combined colorectal and PDA populations and included: neutropenia (32.7%), diarrhea (5%), nausea (9.6%), vomiting (9.6%), asthenia (9.6%), and anemia (9.6%).

Bruera et al. (11) performed a Phase II prospective single arm trial of 29 patients at two institutions in Italy diagnosed with metastatic PDA that included a subgroup of 13 patients (45%) ≥65 years. Patients received a modified regimen: FIr/Fox. Median received dose intensities of the projected dose intensities, per patient, were: 70.4% 5-fluorouracil (5-FU), 70% irinotecan (CPT-11) and 72.5% oxaliplatin (OXP). Median OS for the entire cohort was 11 months (range, 0–33 months). Median PFS was 4 months (range, 0–21 months) for the entire cohort, and 4 months (range, 1–21 months) in the older adult subgroup. Median OS was significantly worse in patients with ECOG PS 2 when compared to ECOG PS 0–1 [1 month (range, 1–3 months) vs. 12 months (range, 0–33 months), P=0.022]; PFS was not significantly different [1 month (range, 1–3 months) vs. 4 months (range, 0–21 months), P=0.078]. Limiting toxicities, defined as grade 3–4 non-hematological toxicity, grade 4 hematologic toxicity, febrile neutropenia, or any toxicity determining >2 weeks treatment delay, were evaluated (12,13). These were reported in 38.4% of the >65 years subgroup. Toxicities reported in the entire cohort included: diarrhea (17%), neutropenia (17%), and stomatitis/mucositis (6%). The study concluded that intensive first-line triplet FIr/FOx is tolerable at modulated doses, and that PFS and mOS were not significantly worse in elderly compared to non-elderly patients (P=0.360 and P=0.235, respectively).

Additionally, fourteen abstracts were identified (Table 3) during the initial review. These were excluded from the main analysis because they did not result in a peer reviewed publication; most were presented in conferences with no further manuscripts. The efficacy and safety profile of combination regimens was comparable to that seen in the younger adult population. Dose attenuations were common, but AEs were manageable. One treatment-related death was reported on one of the abstracts (septic shock). Otherwise, no deaths were reported in the remaining abstracts.

Discussion

Older adults comprise a large proportion of patients with advanced PDA but are disproportionately excluded from clinical trials establishing safety and efficacy of combination chemotherapy. The PRODIGE trial establishing FOLFIRINOX as a standard of care regimen in advanced PDA included patients with median age 61 years and excluded patients ≥76 years. The PRODIGE trial stated that age >65 years old was identified as an independent adverse prognostic factor for overall survival (HR 1.47, 95% CI: 1.07–2.02, P=0.019). In contrast, the PRODIGE group published another study by Conroy et al. (14) evaluating adjuvant FOLFIRINOX in patients with localized pancreatic adenocarcinoma, and showed that there was no statistically significant difference in overall survival between the <70 year group and those ≥70 years (HE 1.16, 95% CI: 0.89–1.52, P=0.28). The MPACT trial included patients regardless of age, and those ≥65 years were represented in proportion to that seen in the general population. Multivariable analysis showed that age was one of the statistically significant independent predictors of survival when comparing age <65 vs. ≥65 (HR 0.81, 95% CI: 0.69–0.96, P=0.16). How to optimally treat older adult patients greater than 65 years, however, is not well defined.

Combination chemotherapy in older adults has been studied in other gastrointestinal malignancies such as colorectal and gastric cancer. Goldberg et al. 2006 (15) performed a retrospective analysis of 3,742 patients diagnosed with colorectal cancer, including a subgroup of 614 patients ≥70 years. Grade 3/4 toxicities were significantly higher in the older patients (49%, P=0.04) but the relative benefit as assessed by RR, PFS (P=0.42), and OS (P=0.79) did not differ for FOLFOX4 (16) versus control in the older versus younger populations. Other studies using the FOLFOX regimen found similar results for older patients with colorectal cancer (17) and advanced gastric cancer (18). Sastre et al. (19) compared RR, TTP and OS outcomes of first-line oxaliplatin plus capecitabine in older patients with colorectal cancer vs. younger patients and concluded that older patients benefit from these combinations to the same degree as younger patients (mOS 16.8 months >70 years and 20.5 months <70 years, P=0.74) without increased toxicity.

Papers examined in this systematic review concluded that the use of combination chemotherapy regimens is safe among older adults with few comorbidities and adequate performance status; and is associated with similar survival to what has been reported in younger populations with advanced PDA. The need for dose reductions was common throughout the studies evaluated in this review but was not associated with reduced survival. Dose reductions occurred more frequently in patients with longer treatment periods, suggesting cumulative toxicity with prolonged courses of chemotherapy. It is important to highlight that the lack of statistical significance in outcomes such as decrease in overall survival as reported by Baldini et al. (7) when a dose attenuation was required, might reflect a small sample size and warrants larger population studies.

Rather than age, performance status and comorbidities may be better predictors of treatment tolerance and benefit. Toward this end, Berger et al. recommend assessment of functional age by the Comprehensive Geriatric Assessment (CGA) (20) tool to assess eligibility for combination therapy (8).

The most common reported grade 3/4 toxicities across studies included: sensory neuropathy and neutropenia. Neutropenia was addressed by primary prophylaxis with GCSF in one study. Two studies each reported one death related to treatment-associated sepsis (7,8).

Guion-Dussere 2016 and Baldini 2016 evaluated the FOLFIRINOX regimen in older adults and concluded that its use is feasible in older adults, and primary dose reduction does not significantly impact OS. Berger et al. 2014 concluded that palliative chemotherapy should be considered independent from chronological age but adjusted for PS. While the sample sizes were small and results inconclusive, Berger and colleagues (9) concluded that FOLFIRINOX is safe in fit older adults and should not be withheld from patients based solely on chronologic age.

Limitations

The majority of studies included in this review were retrospective. In addition, the small sample sizes and limited number of institutions at which they were performed limit power and generalizability. Importantly, the definition for older adult age varied across studies, from 65 to 80 years. It is not possible to draw firm conclusions about any one regimen from these results, which focus on combination chemotherapy altogether.

Conclusions

In conclusion, the available literature presented in this systematic review suggests that the use of combination chemotherapy regimens is safe and effective for older adults with minimal comorbidities and adequate performance status. The validity of these results is limited by their small sample-size populations but should prompt physicians to consider these factors, rather than age alone, in their decision making when treating older adults with PCA. Prospective data is needed to confirm these findings and determine the optimal regimen in this population.

Acknowledgments

We appreciate the support provided by Paul Bain, Librarian, Countway Library, Harvard Medical School, in preparation of this manuscript.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://dx.doi.org/10.21037/jgo-21-87

Peer Review File: Available at https://dx.doi.org/10.21037/jgo-21-87

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jgo-21-87). AB participated on academic advisory boards for Geistlich Pharma and Exelixis. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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