Abstract
Background:
Pancreatic ductal adenocarcinoma (PC) is an aggressive form of cancer treated with chemotherapy regimens such as leucovorin, 5-fluorouracil (5-FU), irinotecan, oxaliplatin (FOLFIRINOX), and gemcitabine plus albumin-bound paclitaxel (nab-Paclitaxel). Maintenance chemotherapy is increasingly being studied as an option for patients with a prior response to chemotherapy, prolonged stable disease, and those unable to tolerate the toxicities of traditional chemotherapy.
Objective:
Our retrospective analysis aims to evaluate the effectiveness and tolerability of capecitabine as maintenance therapy in patients with PC.
Design:
Thirty-three patients treated for PC with capecitabine (an oral formulation of 5-FU) maintenance therapy at our single institution between 8/01/2013 and 9/02/2021 were identified on chart review via the electronic medical record (EMR).
Methods:
Kaplan–Meier curves were fit to evaluate patient progression-free survival (PFS) and overall survival (OS).
Results:
Thirty-three individuals were identified: 21 males and 12 females, with a median age of 69 years. Fifteen of 33 had stage IV PC. Nineteen had progression of disease; 8 completed therapy and transitioned to observation or other treatments; 2 did not tolerate treatment; and 4 were still undergoing treatment. The median PFS was 13.01 months (396.0 days), and the median OS was 28.42 months (865.0 days).
Conclusion:
Maintenance with capecitabine seems safe and may represent a valuable option in patients with advanced PC controlled using FOLFIRINOX or gemcitabine/nab-Paclitaxel induction treatment.
Introduction
Pancreatic ductal adenocarcinoma (PC) is an aggressive cancer that generally carries a poor prognosis and is diagnosed late in the disease process due to the lack of screening tests. Despite advances in surgical and medical therapies, PC is expected to become the second leading cause of cancer deaths in the United States in the next decade. 1 Five-year survival was estimated to be 11% for all stages and 3% for those with metastatic disease.2,3 The evolution of therapies has modestly improved survival but does not usually result in complete remission, so pancreatic cancer remains a treatment challenge. Much effort is needed to find new targets for novel therapies. 1
Gemcitabine is one chemotherapy agent that became accepted as the standard of care due to its effectiveness for advanced-stage pancreatic cancer. 4 Many combination chemotherapy regimens have been tested in comparison to gemcitabine and several have shown improvement in efficacy and tumor response. 5 In recent years, leucovorin (LV), 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX) combination chemotherapy regimen and gemcitabine plus albumin-bound paclitaxel (nab-Paclitaxel) have emerged as common first-line chemotherapy options for PC. 6
Although effective, tolerability remains a concern with these combination regimens as harmful side effects often result in dose reductions and premature termination of treatment.5,7 As outcomes have improved for patients with advanced PC, long-term maintenance therapies following initial chemotherapy have emerged with the hopes of enhancing patient survival while limiting toxicity.
Capecitabine, an oral chemotherapy agent, could be a good option for maintenance therapy. Capecitabine generates 5-FU when metabolized and works by inhibiting DNA and RNA synthesis. 8 However, data investigating capecitabine for long-term maintenance therapy in patients with metastatic PC remain limited. We conducted a retrospective analysis of PC patients treated with capecitabine maintenance therapy at HonorHealth from 8/01/2013 to 9/02/2021.
Materials and methods
We conducted a retrospective chart review for patients with a diagnosis of PC who were treated at HonorHealth in Scottsdale, AZ between 08/01/2013 and 09/02/2021 with oral daily capecitabine maintenance chemotherapy at 1000 mg twice daily. The inclusion criteria included any adult with a diagnosis of pancreatic cancer who received capecitabine maintenance therapy at HonorHealth and all other subjects were excluded. A thorough electronic medical record (EMR) review was completed to retrieve demographic information, clinical stage of disease, date of capecitabine initiation, date of capecitabine termination, reason for termination of therapy, date of progression of disease (POD), date of death, and the presence of any pathogenic germline mutations. The project received approval from the local institutional review board (IRB), and all patients found were included in the study.
The primary outcome examined progression-free survival (PFS) in patients with PC who received capecitabine as maintenance therapy. There were four reasons for termination of therapy in this cohort: POD, did not tolerate (DNT), ongoing, and therapy complete. POD was determined by clinical notes in the EMR by the oncologist describing new findings that met the criteria for termination of therapy. Patients were tracked from the date of capecitabine initiation to the date of POD or the date of data collection (9/02/2021) in which case they were right-censored. The secondary outcome assessed the overall survival (OS) in PC patients who received capecitabine as maintenance therapy. Patients were tracked from the date of capecitabine initiation to the date of death or the date of data collection (9/02/2021) in which case they were right-censored.
Patient age, sex, stage at the start of capecitabine as maintenance therapy, and outcome of treatments were calculated as medians and interquartile ranges or frequencies and proportions (Table 1). PFS and OS of patients receiving oral daily capecitabine maintenance chemotherapy were evaluated with Kaplan–Meier curves (Figures 1 and 2). We also reported the median survival time and its corresponding 95% confidence interval (CI) for both outcomes. All analyses were performed in SAS version 9.4 (SAS Institute, Cary, NC, USA). The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement 9 (Supplemental Table 1).
Demographics of pancreatic cancer patients.
DNT, did not tolerate; IQR, interquartile range; POD, progression of disease.
PFS of patients with pancreatic cancer receiving capecitabine.
OS of patients with pancreatic cancer receiving capecitabine.
Results
In all, 33 patients were included in the analysis. The population had a median age of 69 years and the majority were men (63.6%), shown in Table 1. At the date of assessment (9/02/2021), nine patients (27.3%) had passed away (Table 1). There were four reasons for the termination of capecitabine. The primary reason for the termination of capecitabine was due to POD (n = 19; 57.6%; Table 1). Two (6.1%) stopped because they DNT therapy, citing abdominal cramps, and fatigue. Eight (24.2%) patients completed therapy as it was part of their post-adjuvant treatment plan and transitioned to observation due to a lack of visible disease (Table 1). Four (12.1%) patients were still undergoing treatment with capecitabine at the date of data collection (Table 1). There were no patients with clinical stage IA disease, and 15 (45.5%) had stage IV disease at the time of capecitabine initiation (Table 1). Of those patients who did not have metastatic disease, they had locally advanced PC or were ineligible for surgery. These individuals had maximized or had difficulty tolerating prior systemic chemotherapy with or without radiation as listed in Table 2. Patient 30 trialed capecitabine due to concerns for recurrence following surgery.
Prior treatments before capecitabine.
5-FU, 5-fluoruracil; AA, ascorbic acid; FOLFIRINOX, 5-fluoruracil/leucovorin/irinotecan/oxaliplatin; GAP, gemcitabine/nab-paclitaxel/cisplatin; IMRT, intensity modulated radiation therapy; LV, leucovorin; nab-paclitaxel, albumin-bound paclitaxel; SBRT, stereotactic body radiation therapy.
Kaplan–Meier curves were constructed to visually represent both progression-free and OS. Figure 1 shows the PFS. Censored events are indicated in the curve. Based on the censored survival analysis, the estimated median PFS in this population was 396.0 (95% CI: 206.0–553) days or 13.01 months (Figure 1). Figure 2 represents OS in the study. The median estimated OS for all patients who received capecitabine for PC was 865.0 (95% CI: 808.0–infinity) days or 28.42 months (Figure 2).
Five patients had a pathogenic germline mutation among which only one was targetable (BReast CAncer 2—BRCA2). This patient did not benefit from capecitabine administration after the failure of olaparib as maintenance therapy, but it is possible that the reintroduction of platinum could have been more efficacious. Table 3 summarizes the demographics of these patients, the clinical stage of the disease, specific mutation information, individual OS, and individual PFS.
OS and PFS in patients with germline mutations.
Reported in days.
Indicates censored data.
Ala, alanine; APC, adenomatous polyposis coli; BRCA2, BReast CAncer 2; CFTR, cystic fibrosis transmembrane conductance regulator; del, deletion; Gln, glutamine; Glu, glutamic acid; Gly, Glycine; MSS, microsatellite stable; OS, overall survival; PFS, progression-free survival; PTEN, phosphatase tensin homolog; Val, valine.
Discussion
Treatment for pancreatic cancer is challenging due to diagnosis in more advanced stages and the need to balance the therapeutic benefit and toxicity of the many agents. As chemotherapy combinations have improved survival, maintenance therapy has found its way to the forefront as a strategy to maximize time on therapy and minimize disease progression.
The PANOPTIMOX prospective randomized trial was essential in studying maintenance therapy in PC. 10 The traditional standard of care group or arm A received 6 months (12 cycles or less) of FOLFIRINOX; the maintenance group or arm B received 4 months (8 cycles) of induction FOLFIRINOX followed by leucovorin plus fluorouracil until disease progression; and arm C received sequential treatment alternating irinotecan, leucovorin, and fluorouracil for 2 months (FOLFIRI.3) with 2 cycles of gemcitabine (FIRGEM). 10 The median OS in the maintenance treatment arm B was superior to the median OS in arm A and arm C. However, patients on maintenance therapy over time received a higher total cumulative dose of oxaliplatin resulting in grade 3 and 4 neurotoxicity, but this side effect was reached later than before. 10 Ultimately, maintenance therapy with leucovorin and fluorouracil after induction chemotherapy with FOLFIRINOX was shown to offer an effective treatment option aimed at preserving functional status for patients with metastatic PC. 10 The study suggested other maintenance agents like capecitabine may be even more beneficial with better ease of administration and fewer medical visits. 10
Another randomized trial evaluating maintenance therapy for metastatic PC investigated sunitinib versus best supportive care following first-line chemotherapy treatment. 11 It illustrated improvement both in PFS and OS in patients. 11 A phase Ib randomized trial of metformin with and without rapamycin for maintenance therapy in patients with stable metastatic PC following initial treatment also demonstrated encouraging activity. 12 Metformin/rapamycin was well tolerated and demonstrated a 24-month survival rate of 37% in the 22 patients. 12
Capecitabine has been investigated as a maintenance regimen for other gastrointestinal malignancies. One specific study investigated the use of FOLFIRINOX induction and 5-FU/leucovorin maintenance with reinduction when necessary. 13 Their results suggested that alternating with maintenance therapy may increase PFS and combat cumulative toxicity. 13 Capecitabine was also evaluated as maintenance therapy in patients with metastatic PC following initial treatment with FOLFIRINOX chemotherapy. 14 The study observed that patients were able to extend the amount of time receiving chemotherapy by implementing maintenance therapy until disease progression was observed, and then FOLFIRINOX was reintroduced for further treatment. 14 Median OS from the time of capecitabine initiation was 17 months. 14
In this study, capecitabine 1000 mg twice daily, Monday through Friday, appears to be a promising maintenance strategy for advanced PC based on the survival analysis. Greater than 80% of patients were alive at 1 year, and greater than 65% were alive at 2 years, with a median estimated OS of greater than 2 years. Comparatively, a prior study of capecitabine in the post-adjuvant setting estimated a median OS as high as 48 months, but it included only patients with stage I or II localized disease and those without disease recurrence on adjuvant chemotherapy. 15 Conversely, approximately 46% of our patients had stage IV disease and 24% had locally advanced/stage III PC at the time of capecitabine initiation. The OS and PFS seen in our study are promising given that individuals diagnosed with stage IV pancreatic cancer usually have a relative survival rate of 22% at 1 year. 16 Very little data have been reported on the effectiveness of capecitabine maintenance therapy in a population with advanced pancreatic disease. Further research is needed to examine the benefits of capecitabine as maintenance therapy versus other agents.
In general, capecitabine was well tolerated, even in some who received therapy for several years. However, some patients required dose reductions or interruptions due to an expected adverse event of palmar-plantar erythrodysesthesia (PPE or hand–foot syndrome). Patients with PPE were able to continue capecitabine with dose modifications and aggressive topical lubrication. Two of the 33 patients had to end treatment with capecitabine, one due to persistent abdominal cramps and the other due to fatigue and diffuse shoulder pain.
As survival has slowly improved in patients with PC, research has been aiming to find biological targets for potential therapies. It is estimated that approximately 5%–7% of patients with pancreatic cancer have a DNA repair mutation in a BRCA gene. 17 Approximately 17% of individuals have a pathogenic mutation in a DNA double-stranded break repair gene. 17 In our study, five patients were found to have pathogenic germline mutations, represented in Table 3. Due to the limited sample size, it is difficult to ascertain any statistical comparison to patients without these mutations. The BRCA2 patient had the poorest OS in days when compared to other mutations. It is also important to note that the use of the poly ADP ribose polymerase inhibitor olaparib for individuals with metastatic PC with a germline BRCA mutation was approved in 2019 based upon improved PFS of olaparib of 7.4 months compared to 3.8 months with placebo. 18
There were several limitations to our study. Foremost, this was a retrospective analysis rather than a prospective analysis. Clinical trials with control groups will be necessary to determine the true efficacy and dosing of capecitabine as monotherapy. Another limitation was the small sample size of 33 patients. Enrolling more subjects in the future would be more reflective and applicable to the larger population. Currently, there is an ongoing phase II maintenance study of the histone deacetylase inhibitor ivaltinostat with capecitabine compared to capecitabine alone in metastatic PC in those who have not progressed on front-line fluoropyrimidine-based chemotherapy (NCT05249101).
Our findings lend evidence that capecitabine is generally well tolerated as maintenance chemotherapy, even in a population with mostly advanced disease. As a monotherapy, it offers an appropriate palliative approach aimed at prolonging life and helping to minimize recurrence. In addition, it may be more cost-effective and helps to promote compliance. Future larger prospective studies are needed to evaluate capecitabine as maintenance therapy.
Conclusion
Pancreatic cancer remains difficult to treat due to its aggressive nature. Chemotherapy with FOLFIRINOX and gemcitabine/nab-Paclitaxel has prolonged survival in this patient population but is associated with many side effects such as fatigue, neuropathy, and pancytopenia that cause dose reduction or early termination of therapy. In our retrospective cohort, capecitabine represents a convenient maintenance option with the suspension of systemic chemotherapy in a subset of patients who have prolonged tumor control after administering FOLFIRINOX or gemcitabine/nab-Paclitaxel induction chemotherapy.
Supplemental Material
sj-docx-1-tam-10.1177_17588359251321894 – Supplemental material for Retrospective analysis of capecitabine maintenance therapy in pancreatic ductal adenocarcinoma
Supplemental material, sj-docx-1-tam-10.1177_17588359251321894 for Retrospective analysis of capecitabine maintenance therapy in pancreatic ductal adenocarcinoma by Jordan Powell, Alexa F. Viniotis, Chase Irwin, Gayle S. Jameson, Lana Caldwell and Erkut H. Borazanci in Therapeutic Advances in Medical Oncology
Footnotes
References
Supplementary Material
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