Outcomes of patients with metastatic pancreatic cancer who progress on first restaging imaging
Introduction
Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis representing the fourth most common cause of cancer-related deaths (1). By 2030, PDAC is estimated to be the second leading cause of cancer death (2). Five-year overall survival (OS) rate for those with distant disease spread is 3% (3). Current metastatic first-line therapy is composed of two standard regimens 5-Fluorouracil (5-FU) + irinotecan + oxaliplatin (FOLFIRINOX) or gemcitabine + nab-paclitaxel (1). Both regimens improved survival compared to the standard at the time gemcitabine monotherapy.
Conroy et al. established FOLFIRNOX as a front-line regimen in 2011 by conducting a phase II–III multicenter, randomized controlled trial in patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 comparing standard of care gemcitabine alone to a fluoropyrimidine combination regimen of 5-fluorouracil + leucovorin + oxaliplatin + irinotecan (FOLFIRINOX) (4). FOLFIRINOX showed both an OS and PFS advantage to gemcitabine alone (FOLFIRINOX median OS 11.1 months vs. gemcitabine median OS 6.8 months, P<0.001; FOLFIRINOX median PFS 6.4 months vs. gemcitabine median PFS 3.3 months, P< 0.001). Progressive disease on reimaging scans in this study showed that some patients will not respond to FOLFIRINOX or gemcitabine alone (15.2% progressive disease with FOLFIRINOX and 34.5% progressive disease with gemcitabine alone). Von Hoff et al. established gemcitabine + nab-paclitaxel as a front-line regimen in 2013 by conducting a multicenter phase III randomized trial in patients with Karnofsky performance status score of 70 or more comparing GEM + nab-paclitaxel to gemcitabine alone in metastatic PDAC (5). The combination improved both OS and PFS (Gemcitabine + nab-paclitaxel median OS 8.5 months vs. gemcitabine median OS 6.7 months, P<0.001; gemcitabine + nab-paclitaxel median PFS 5.5 months vs. GEM median PFS 3.7 months, P<0.001). This study additionally showed that some patients will have progressive disease on reimaging scans with gemcitabine + nab-paclitaxel or gemcitabine alone (20% progressive disease with gemcitabine + nab-paclitaxel and 26% progressive disease with gemcitabine alone).
While disease stabilization is achievable for a significant percentage seen with FOLFIRINOX or gemcitabine + nab-paclitaxel, some patients will have radiographic evidence of disease progression on their first restaging imaging (4,5). With patients’ short life expectancy in the metastatic setting, limited systemic treatment options, and significant toxicities associated with multi-drug chemotherapy, it is crucial for clinicians to be prudent when deciding whom and when to treat. The purpose of our study was to evaluate outcomes of patients who progressed on their first restaging imaging while on first-line therapy.
We present the study in accordance with the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/jgo-20-569.
Methods
Our study was a single institution, retrospective chart review of patients with metastatic PDAC who showed progression on their first restaging evaluation of first-line chemotherapy. Adult metastatic PDAC patients who were diagnosed between March 2010 to April 2017 were included. First radiographic imaging was 6–8 weeks after starting therapy. Only those patients with progressive disease on first line treatment first restaging imaging were included. Patients must have received this treatment at our center along with radiographic follow-up every 8–12 weeks at our center. Patients who received recommendations from our center but received therapy elsewhere were excluded. Patients with unresectable locally advanced disease were excluded along with those lost to follow-up. Patients who received second-line therapy were compared to those that did not receive second-line therapy. OS was the primary objective.
Data collection included patient demographics [age, gender, race, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index] and tumor characteristics (metastatic disease sites, primary tumor location). Treatment factors collected were what first-line regimen and second-line regimen received. Treatment regimens given were per individual physician discretion. Reasons patients did not receive second-line therapy were also collected. CA19-9 was collected at first-line therapy start and at first-line progression. Molecular germline testing was collected when available. Additionally, date of progression and date of death were collected. Molecular analysis was collected when available.
Ethical statement
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Our institutional review board approved our study (PA16-0738). A waiver of consent was granted given the minimal risk of a retrospective evaluation.
Statistical analysis
The objectives of this study were to describe the study population overall and by second-line chemotherapy, and overall survival (OS). The Kaplan-Meier product limit method (Kaplan & Meier, 1958) was used to estimate the median OS. Univariate Cox proportional hazards regression was used to identify any association with each of the variables and OS. Statistical analysis was performed using Stata/SE version 16.0 statistical software (Stata Corp. LP, College Station, TX, USA).
Results
Ninety-eight patients were included with a median age of 64 years old. Median follow-up for the entire group was 6.8 months. Patient characteristics are described in Table 1. Most patients did not have germline testing performed (93%). One patient had BRCA1 7990del3ins2. The remainder were negative for BRCA1 and 2. Sixty-five patients received second-line therapy while 33 patients did not receive second-line therapy. Median first-line PFS for those that did receive second-line therapy was 1.84 months (95% CI: 1.81–2.01 months), and median first-line PFS for those that did not receive second-line therapy was 1.48 months (95% CI: 1.12–1.71 months). Reasons for not pursuing second-line therapy were PS decline due to disease complications (48%, n=16), patient’s choice to stop or pursue alternative medicine (24%, n=8), 5 PS decline due to other comorbidities such as dementia, congestive heart failure, chronic kidney disease (15%, n=5), organ dysfunction not suitable for second-line therapy options (6%, n=2), or poor PS due to chemotherapy toxicity (6%, n=2).
Table 1
| Characteristic | Data |
|---|---|
| Age at diagnosis | Median 64 yo (25–84 yo) |
| Baseline BMI | Median 26.1 (18.1–46.1) |
| Age | |
| <50 yo | 7 (7.1%) |
| |
91 (92.9%) |
| Gender | |
| Male | 58 (59.2%) |
| Female | 40 (40.8%) |
| ECOG PS at diagnosis | |
| 0 | 13 (15.9%) |
| 1 | 56 (68.3%) |
| 2–3 | 13 (15.9%) |
| Race | |
| Caucasian | 73 (74.5%) |
| Non-Caucasian | 25 (25.5%) |
| Metastatic disease sites | |
| Diffuse | 55 (56.1%) |
| Single organ | 43 (43.9%) |
| 1st Line therapy | |
| FOLFIRINOX | 34 (34.7%) |
| Gemcitabine + nab-paclitaxel | 57 (58.2%) |
| Gemcitabine + cisplatin | 2 (2.0%) |
| 5-FU +/− oxaliplatin | 1 (1.0%) |
| Gemcitabine +/− erlotinib | 3 (3.1%) |
| Trial | 1 (1.0%) |
| CA19-9 at diagnosis | |
| <35 | 9 (10.3%) |
| <59× ULN | 38 (43.7%) |
| >59× ULN | 40 (46.0%) |
| Second-line therapy received | |
| Yes | 65 (66.3%) |
| No | 33 (33.7%) |
| CA19-9 at first-line progression | |
| <35 | 8 (8.9%) |
| <59× ULN | 34 (37.8%) |
| >59× ULN | 48 (53.3%) |
| Second-line therapy | |
| None | 33 (33.7%) |
| Gemcitabine + nab-paclitaxel | 31 (31.6%) |
| FOLFIRINOX | 8 (8.2%) |
| 5-FU +/− oxaliplatin | 8 (8.2%) |
| 5-FU + irinotecan or liposomal irinotecan | 3 (3.1%) |
| Gemcitabine based therapy | 12 (12.3%) |
| Other | 3 (3.1%) |
| Second-line therapy radiographic results | |
| Disease-control | 18 (27.7%) |
| Progression | 47 (72.3%) |
ECOG, Eastern Cooperative Oncology Group; PS, performance status.
Patient characteristics between the two groups are summarized in Table 2. Factors statistically different between groups were age, ECOG PS at diagnosis, and first-line regimen. Patients were younger in the population that received second-line therapy (median age 61 years old) compared to those that did not receive second-line therapy (median age 67 years old, P<0.001). More patients had an ECOG PS of 2-3 at baseline in the non-second-line therapy group (7.5% in second-line therapy group vs. 31% in non-second line therapy group, P=0.021). Forty-five percent received FOLFIRNOX front-line in the second-line therapy group compared to 15% in the non-second-line therapy group. Forty-five percent in the second-line therapy group received gemcitabine + nab-paclitaxel front-line. Most patients in the non-second-line therapy group received gemcitabine + nab-paclitaxel first-line. Those that had disease-control with second-line therapy received gemcitabine + nab-paclitaxel (n=8), FOLFIRINOX (n=3), FOLFOX/5-FU (n=1), or gemcitabine-based therapy (n=6). Median OS was 9 months in the second-line therapy group compared to 4 months in the non-second-line therapy group, P<0.001 (Figure 1).
Table 2
| Characteristic | Yes | No | P value | |||
|---|---|---|---|---|---|---|
| N | % | N | % | |||
| Age at met diagnosis | <0.001 | |||||
| N | 65 | 33 | ||||
| Mean (SD) | 61 (10.0) | 68 (10.0) | ||||
| Median [Min–Max] | 61 [25–78] | 67 [37–84] | ||||
| Baseline BMI or height and weight at baseline | 0.916 | |||||
| N | 65 | 33 | ||||
| Mean (SD) | 26.88 (4.57) | 27.36 (5.84) | ||||
| Median [Min–Max] | 26.10 [18.10–39.10] | 26.90 [20.40–46.10] | ||||
| Follow-up (months) | <0.001 | |||||
| N | 65 | 33 | ||||
| Mean (SD) | 10.11 (6.29) | 4.73 (3.33) | ||||
| Median (Min–Max) | 8.51 (3.16–38.05) | 3.88 (1.88–19.29) | ||||
| Age | 0.418 | |||||
| <50 | 6 | 9.23 | 1 | 3.03 | ||
| ≥50 | 59 | 90.77 | 32 | 96.97 | ||
| Gender | 0.125 | |||||
| Male | 42 | 64.62 | 16 | 48.48 | ||
| Female | 23 | 35.38 | 17 | 51.52 | ||
| ECOG PS at diagnosis | 0.021 | |||||
| 0 | 10 | 18.87 | 3 | 10.34 | ||
| 1 | 39 | 73.58 | 17 | 58.62 | ||
| 2–3 | 4 | 7.55 | 9 | 31.03 | ||
| Overweight/obese | 0.588 | |||||
| No | 22 | 33.85 | 13 | 39.39 | ||
| Yes | 43 | 66.15 | 20 | 60.61 | ||
| White | 0.837 | |||||
| No | 48 | 73.85 | 25 | 75.76 | ||
| Yes | 17 | 26.15 | 8 | 24.24 | ||
| Site of disease | 0.437 | |||||
| Head | 31 | 47.69 | 19 | 57.58 | ||
| Body | 19 | 29.23 | 10 | 30.30 | ||
| Tail | 15 | 23.08 | 4 | 12.12 | ||
| Metastatic disease sites | 0.524 | |||||
| Diffuse | 35 | 53.85 | 20 | 60.61 | ||
| Single organ | 30 | 46.15 | 13 | 39.39 | ||
| 1st line therapy | 0.002 | |||||
| FOLFIRINOX | 29 | 44.62 | 5 | 15.15 | ||
| GA | 29 | 44.62 | 28 | 84.85 | ||
| Gem/Cis | 2 | 3.08 | 0 | 0.00 | ||
| FOLFOX/5-FU alone | 1 | 1.54 | 0 | 0.00 | ||
| Gem alone or erlotinib combo | 3 | 4.62 | 0 | 0.00 | ||
| Trial | 1 | 1.54 | 0 | 0.00 | ||
| CA 19-9 at first line start | 0.276 | |||||
| <35 | 8 | 14.29 | 1 | 3.23 | ||
| <59× ULN | 24 | 42.86 | 14 | 45.16 | ||
| >59× ULN | 24 | 42.86 | 16 | 51.61 | ||
| CA 19-9 at first line progression | 0.999 | |||||
| <35 | 6 | 9.84 | 2 | 6.90 | ||
| <59× ULN | 23 | 37.70 | 11 | 37.93 | ||
| >59× ULN | 32 | 52.46 | 16 | 55.17 | ||
Discussion
PDAC remains a challenging cancer to treat with unfortunately limited progress in management. Less than a decade ago, front-line therapy with FOLFIRINOX and gemcitabine + nab-paclitaxel were determined to be preferred regimens (1,4,5). However, almost half of patients remain in good condition following front-line therapy, yet second-line therapy is less defined (6). Limited data shows a potential survival benefit with second-line therapy (6-8). Unfortunately, these regimens studied prospectively in the second-line setting were following therapy that is no longer the preferred front-line treatment. Therefore, challenges exist with determining who will likely benefit from second-line therapy and with what second-line therapy.
Vienot et al. performed a prospective population-based cohort study in hopes of developing a prognostic nomogram and score that would predict OS from the start of second-line therapy (6). Three hundred ninety-five patients who had received front-line advanced PDAC therapy were eligible for medical evaluation for second line therapy. Sixty-six percent of patients (n=261) were treated with second-line therapy while 33.9% (n=134) did not received treatment second-line. Our study showed similarities in that most patients (66%) pursued second-line therapy. Vienot et al. found older age, worse ECOG performance status, and shorter duration of front-line therapy were found in the untreated second-line therapy group. The authors reported age, smoking status, presence of liver metastases, performance status, pain, jaundice, ascites, duration of front-line treatment, and second-line regimen were identified as independent prognostic factors for OS with second-line therapy. Models like that established by Vienot et al. are the start of establishing a clinical guide to making decisions after front-line therapy progression.
We recognize the limitations of our retrospective review as there were significant differences between our comparator group including older age and poorer ECOG PS in the group that did not receive second-line chemotherapy. However, our results did suggest that if patients maintained a good ECOG PS after front-line fast progression, patients had improved OS if they received second-line therapy. A specific second-line therapy for this population was unable to be determined given the small numbers of our study and variety of regimens received. We believe these patients should be offered second-line therapy. Our data collection was prior to national recommendations for all patients to receive germline testing. Therefore, no conclusions could be made regarding outcomes based off genetics.
Acknowledgments
Funding: None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/jgo-20-569
Data Sharing Statement: Available at http://dx.doi.org/10.21037/jgo-20-569
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jgo-20-569). MMJ currently serves as unpaid editorial board member of the Journal of Gastrointestinal Oncology from Jan 2021–Dec 2022. 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Our institutional review board approved our study (PA16-0738). A waiver of consent was granted given the minimal risk of a retrospective evaluation.
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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