Real‑world treatment outcomes among patients with metastatic pancreatic cancer in Japan: The Tokushukai real‑world data project
- Authors:
- Published online on: October 25, 2023 https://doi.org/10.3892/mco.2023.2694
- Article Number: 98
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Copyright: © Shimoyama et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Pancreatic cancer is one of the most aggressive cancers, with an extremely low five-year survival rate of 10% in the US and Japan, and its incidence continues to increase (1,2). Diabetes (3), obesity (4,5), smoking (6), heavy drinking (7) and chronic pancreatitis (8) are listed as risk factors for the development of pancreatic cancer. Although increase in the incidence of these lifestyle-related factors and aging have been cited as causes of the increased incidence of pancreatic cancer, not all the mechanisms of onset have been elucidated. In most cases, pancreatic cancer is detected at an advanced stage, representing the fourth leading cause of cancer-related mortality in both the U.S. and Japan (1,2). Surgical resection is the only potentially curative treatment, but only 20% of cases are resectable at diagnosis, and most patients have unresectable disease (1,2). Furthermore, the recurrence rate is very high even in patients who have undergone radical resection, and the 5-year survival rate does not reach 30% (2).
Before 2010, only 5-fluorouracil (5-FU), gemcitabine, and tegafur/gimeracil/oteracil (S-1) regimens had been approved for use in cases of advanced/recurrent pancreatic cancer in Japan. Gemcitabine has been used worldwide for many years because of its demonstrated improvement in quality of life and prolongation of overall survival (OS) in a gold-standard phase III trial (vs. 5-FU) (9) and was approved for use in Japan in 2001. S-1 is an oral 5-FU derivative developed in Japan and was approved for use in 2006 based on the results of phase II studies in patients with advanced pancreatic cancer (10,11). In 2007, the results of a phase III trial examining the efficacy of gemcitabine in combination with erlotinib were reported and showed a statistically significant improvement in survival, but the difference was small and did not have enough impact to change actual clinical practice (12).
Recently, some additional regimens for chemotherapy-naïve pancreatic cancer, proven to be effective in gold-standard clinical trials have been approved and are now in widespread use, including fluorouracil, folinic acid, oxaliplatin, and irinotecan (FOLFIRINOX) (approved in Japan since 2013) (13-15) and gemcitabine plus nab-paclitaxel (approved in Japan since 2014) (16). In addition, a Japanese phase III study in 2013 demonstrated the non-inferiority of S-1, but not the superiority of gemcitabine plus S-1 therapy compared to gemcitabine (17). Notably, previous clinical trials have shown that each combination therapy prolongs OS when compared with gemcitabine alone; NCCN guidelines recommend FOLFIRINOX and gemcitabine plus nab-paclitaxel for metastatic pancreatic cancer with good performance status (PS) (18). Japanese guidelines for pancreatic cancer also recommend the same two regimens (19), and they are widely used as standard treatments for metastatic pancreatic cancer. Other approved regimens include liposomal irinotecan plus 5-FU and leucovorin for patients who have failed gemcitabine-based therapy (20) and olaparib as maintenance therapy after platinum-based chemotherapy for BRCA mutation-positive patients (21) (approved in Japan since 2020). The history of approved agents in Japan is shown in Fig. 1.
On the other hand, patients enrolled in clinical trials are highly selected patients with good general condition and organ functions. Therefore, there is often a discrepancy between the treatment results shown in clinical trials and actual clinical practice due to this selection bias (22). In recent years, cohort studies based on large-scale databases have been conducted to fill these gaps (23-26). Fortunately, real-world data (RWD) regarding the health and treatment status of patients receiving daily medical care are collected within standard organizational processes (e.g., electronic medical records and hospitalization data) (27). To evaluate whether the results of clinical trials are carried over to the real-world, we conducted an exploratory cohort study using RWD to investigate temporal trends in treatment patterns for metastatic pancreatic cancer as well as treatment outcomes and prognostic factors that influence OS.
Materials and methods
Study overview
This nationwide retrospective cohort study was conducted as part of the TREAD project, the outline of which has been described elsewhere (28). This project was approved by the Ethics Committee of the Tokushukai Group in April 2020 (No. TGE01427-024) and was conducted following the principles of the Declaration of Helsinki, and patients were provided with information using opt-out methods. This study was registered in the UMIN Clinical Trial Registry (http://www.umin.ac.jp/ctr/index.htm) and clinical trial number was UMIN000050590.
Objective patients
We evaluated patients with pathologically or radiologically confirmed metastatic pancreatic cancer who were started on first-line chemotherapy at Tokushukai Medical Group hospitals, which included 46 hospitals with 14829 beds, using the same medical record system (e-Karte and Newtons2; Software Service Inc., Osaka, Japan) and chemotherapy protocol system (srvApmDrop; Software Service Inc., Osaka, Japan) between April 1, 2010, and March 31, 2020.
All patients were administered gemcitabine, S-1, gemcitabine plus S-1, gemcitabine plus nab-paclitaxel, or FOLFIRINOX as first-line treatment. Pathological diagnoses including adenocarcinoma, adenosquamous carcinoma, and carcinoma/malignant neoplasms were included in the current study, but patients with acinar and neuroendocrine carcinoma were excluded (see Fig. 2 for more information). Additional key exclusion criteria were the presence of active double cancer, inadequate treatment history, and missing fundamental patient data, such as body weight and height.
Data collection
In the current study, we evaluated eligible patients identified from electronic medical records. Patient information such as age, sex, body mass index (BMI), the latest data on survival confirmation, survival outcomes, and diagnosis on medical receipt were extracted from the medical record system. Treatment information related to chemotherapy regimens, start and end dates of chemotherapy, and PS was extracted from the chemotherapy protocol system. The linked cancer registry information including diagnostic information (site, pathology, stage), treatment details (surgery, endoscopic procedure, radiotherapy, chemotherapy), and prognosis (final date of survival confirmation, date of death, cause of death) was extracted from the National Cancer Registry Data in Japan (29). Hospital volume and hospital type (government designated cancer hospital, prefectural designated cooperative cancer hospital, or non-designated general hospital) were also noted.
The treatment history was organized based on the extracted chemotherapy information, and when discrepancies or missing information were detected, the missing data were investigated by directly checking the medical records at Tokushukai Information Inc. (Osaka, Japan). Patients with inadequate treatment history (i.e., previous or subsequent cancer treatment outside of Tokushukai Medical Group hospitals or no detailed treatment information available) were excluded from the study. The study was divided into three periods for the elucidation of secular trends (A, 2010-2013; B, 2014-2016; C, 2017-2020).
Statistical analysis
The primary endpoint evaluated in the current study was OS, which is defined as the time from the start date of initial palliative chemotherapy to the date of death or final survival confirmation. The secondary endpoint was time to treatment failure (TTF), which is defined as the time from the start date of the first-line chemotherapy treatment to discontinuation of the treatment for any reason.
Basic statistics (absolute and relative frequencies for categorical variables; quartiles, maximum values, minimum values, and means for continuous variables; and quartiles and relative frequencies for discrete variables) were obtained to summarize the distribution of variables related to patient background factors, complications, other prognostic factors, and primary and secondary endpoints. Survival analyses were performed using OS as the primary endpoint. The start date of the study was April 1, 2010, and the study end date was March 31, 2020. The time variable represents the number of days from the start date of the first-line chemotherapy treatment to the date of death. The censored cases included patients who were alive at the study end date or who dropped out of the study for any reason.
Kaplan-Meier curves (univariate analyses) and log-rank test were applied for each stratum, defined according to the patient background and prognostic factors (age at the start of first-line chemotherapy, sex, PS, BMI, smoking status, pathology, primary disease site, study period, hospital volume, hospital type, and first-line chemotherapy regimen) for the occurrence of events associated with study endpoints (OS, TTF).
In addition, several hierarchical predictive models were constructed by combining explanatory variables that were expected to contribute to the evaluated endpoints, and single- and multi-tiered proportional hazard models were established by incorporating each predictive model. Stratified/conventional Cox multiple regression analyses were performed. Conventional Cox regression was applied when the proportional hazards hypothesis was valid; otherwise, a stratified Cox regression was applied.
The Akaike Information Criterion (AIC), based on partial likelihood, was used to explore the optimal model in the current study (i.e., when the number of eligible cases differed between models, the average AIC per case was substituted). Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained for each category of OS-related prognostic factors selected in the optimal model, and the impact of prognostic factors in the optimal model was examined using likelihood tests with associated p-values for each item. All analyses were performed using R, version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria). All statistical analyses were two-sided, and probability values of <0.05 were considered statistically significant.
Results
Patient flow
A total of 1,093 patients were detected using the procedures described above, and 846 patients were found to be eligible according to the study inclusion and exclusion criteria specified above, as shown in Fig. 2.
Patient characteristics
Patient medical and demographic characteristics were typical for metastatic pancreatic cancer (Table I). Approximately 30% of the patients were over 75 years of age. Over 90% of the included patients had an Eastern Cooperative Oncology Group PS of 0 or 1. Most patients had pathologically proven disease. Patient characteristics by treatment regimen are shown in Table II. There was a trend toward fewer patients over 75 years of age and PS 2 or higher for combination chemotherapy. Patient backgrounds were generally similar among the three time periods, but the proportion of patients receiving combination therapy increased over time to 11.2, 37.8, and 67.8% in study periods A, B, and C, respectively (Table III). The patient background between hospital volume and type is also presented in Table SI.
Trends in the implementation of chemotherapy regimens
Trends in the implementation of first-line chemotherapy are shown in Fig. 3. In 2010, when the study began, gemcitabine was the most commonly used drug, but its percentage gradually decreased, while that of nab-paclitaxel increased after 2014, when nab-paclitaxel was approved. However, the use of FOLFIRINOX remained consistently low during the study period, even after its approval in 2013.
Kaplan-Meier survival curves
The crude (before adjusting for background factors) survival curves evaluating OS and TTF using the Kaplan–Meier method are shown in Fig. 4. The median follow-up duration was 5.4 months (95% confidence interval [CI], 4.8-6.0). The median OS of all included patients was 6.8 months (95% CI, 6.3-7.4), and the median TTF was 2.5 months (95% CI, 2.3-2.7). In addition, crude Kaplan-Meier OS curves according to the first-line chemotherapy regimen and study period are shown in Fig. 5. The median OS for gemcitabine, S-1, gemcitabine plus S-1, gemcitabine plus nab-paclitaxel, and FOLFIRINOX was 5.9, 5.3, 7.7, 9.0, and 9.5 months, respectively, and the median OS according to study period (A, B, C) was 6.2, 7.1, and 7.8 months, respectively.
Cox regression analyses
Cox regression analyses evaluating prognostic factors for OS are presented in Table IV. In a univariate analysis, age, PS, BMI, study period, and first-line systemic therapy regimens were found to affect OS. However, a multivariate analysis showed that study period did not affect OS (P=0.989). Based on first-line systemic therapy, patients who received gemcitabine plus nab-paclitaxel or FOLFIRINOX demonstrated significantly longer survival times (with HRs of 0.622 and 0.608, respectively) than those who received gemcitabine monotherapy.
The details of treatment regimens with gemcitabine plus nab-paclitaxel and FOLFIRINOX, are shown in Table V. Both regimens are recommended as first-line therapy in the Japanese and NCCN guidelines (18,19). In total, 11% of patients treated with gemcitabine plus nab-paclitaxel crossed over to FOLFIRINOX, and 46% of patients treated with FOLFIRINOX crossed over to a gemcitabine plus nab-paclitaxel regimen. During the study period, erlotinib, nal-irinotecan, pembrolizumab, and olaparib were not used for subsequent systemic therapy in this population. The adjusted Kaplan-Meier OS curves for each prognostic factor are shown in Fig. 6, based on the results of the stratified Cox regression analyses provided in Table IV.
Discussion
In this large retrospective cohort study of patients with metastatic pancreatic cancer, we clarified the actual state of treatment in clinical practice in a large representative hospital system. Although there is concern that treatment outcomes for the portion of the patient population that fulfills the eligibility criteria for clinical trials do not apply to older adults or the clinical population of patients experiencing complications (22), this RWD study demonstrated that most patients could be administered standard treatment and obtained survival benefits.
As of 2010, only gemcitabine and S-1 had been approved for use in Japan, and consistent with previous Japanese RWD study (30), nearly 80% of our study population received gemcitabine. Although FOLFIRINOX became available in 2013, it was not frequently used in our study population; the use of this regimen remained at approximately 10% through 2020. One of the reasons why FOLFIRINOX therapy is not widely used is its serious adverse events, including myelosuppression. A phase II study of FOLFIRINOX in Japan showed that 77.8% of patients had Grade 3 or higher neutropenia and 22.2% of patients had febrile neutropenia, which was much higher than the 45.7 and 5.4% in the global Phase III study (13). Therefore, it is recommended only for selected patients in good general condition (19). On the contrary, since less toxic gemcitabine plus nab-paclitaxel regimen became available in 2014, the frequency of its use has increased rapidly, and the use of this regimen in our study population exceeded 60% as of 2020. According to a previous paper published by Terashima et al (31), as of 2015, the frequency of the use of gemcitabine plus nab-paclitaxel was approximately 25%. According to the latest clinical practice guidelines (18,19), both gemcitabine plus nab-paclitaxel and FOLFIRINOX regimens were recommended as first-line treatments for metastatic pancreatic cancer. However, gemcitabine and S-1 were given weak recommendations; these regimens were recommended only for patients who are unsuitable for the aforementioned treatment regimens. Moreover, gemcitabine plus S-1 was only recommended in the neoadjuvant setting (19). Our work provides a timely follow-up to previously reported data and suggests that the treatment strategies selected by physicians in actual clinical practice adhere closely to these guidelines.
Univariate and multivariate analyses in our study showed a greater survival benefit of gemcitabine plus nab-paclitaxel and FOLFIRINOX than that of gemcitabine alone. On the other hand, no survival benefits of S-1 monotherapy or S-1 + gemcitabine over gemcitabine monotherapy was demonstrated. These results are consistent with the results of previous clinical trials and RWD studies. The results of previous clinical trials and RWD studies are shown in Table V. In addition, our univariate analyses revealed a prolongation of OS in the late study period. However, this effect was not confirmed by multivariate analyses after adjusting for other prognostic factors, such as treatment regimen. Furthermore, our univariate analyses did not suggest a hospital volume-outcome relationship, unlike a previous report from the Netherlands accounting for patients diagnosed with metastatic pancreatic cancer between 2007 and 2011(30). Indeed, in our study, the variances in chemotherapy regimens administered categorized by hospital volume and type exhibited uniformity, with combination therapy consistently accounting for approximately 40% (Table SI). These results suggested that improvement in survival over time may be primarily due to the approval of new treatment regimens, even though other factors such as advances in diagnostic imaging and supportive care could also have improved survival, and the widespread use of more effective standard treatments may have reduced differences by hospital volume and type.
In two prior pivotal phase III studies, the median survival following the administration of FOLFIRINOX was 11.1 months (13), while the median survival following the administration of gemcitabine plus nab-paclitaxel was 8.5 months (16). A phase II study on modified FOLFIRINOX, in which irinotecan was reduced from 180 to 150 mg/m2 and bolus 5-FU was omitted, showed favorable results with a median survival of 11.2 months in 2018, and it is now widely used in Japan (15). In the present study, the median survival times following the administration of gemcitabine plus nab-paclitaxel and FOLFIRINOX were 9.0 and 9.5 months, respectively, which are comparable to the median survival associated with gemcitabine plus nab-paclitaxel reported in prior clinical trials but approximately 1.6 months shorter than that associated with FOLFIRINOX (13,16). No data were extracted on the dose of FOLFIRINOX in this study; hence, there are no data on whether FOLFIRINOX or modified FOLFIRINOX was administered or how withdrawal or dose reduction was performed. In several recent RWD studies on gemcitabine plus nab-paclitaxel and FOLFIRINOX in metastatic pancreatic cancer, OS varied; moreover, OS tended to be shorter with FOLFIRINOX treatment in RWD studies compared to that in clinical trials (31-37) (Table VI). As mentioned above, actual analysis of dose intensity is needed, but it is possible that FOLFIRINOX dose reduction may have led to the shorter OS. We await the results of the trials currently underway in Japan comparing gemcitabine plus nab-paclitaxel, modified FOLFIRINOX, and S-1 plus irinotecan and oxaliplatin for final conclusions (38).
 | Table VIOverall survival data from recent clinical trials and RWD investigations evaluating treatment regimens for advanced/metastatic pancreatic cancer. |
The present study had several limitations. First, this study had a retrospective design, and hence, the choice of the first-line treatment regimen administered to each patient was left to the attending physician, and no clear criteria have been established yet. As shown in Table II, the background of each regimen differs greatly. Therefore, it is possible that FOLFIRINOX was selected by the attending physician for patients with large tumors and extensive metastases, resulting in a shorter OS. Second, as discussed before, although dose intensity is a factor that may contribute significantly to OS, data on dose intensity were not extracted in this analysis. Third, several prognostic factors, such as metastatic sites, tumor markers, prognostic scores based on laboratory data, comorbidities, and complications, were not examined. Finally, in the current study, treatment data were extracted from the protocol system; hence, only data on treatment duration could be extracted, and it was not possible to distinguish between treatment discontinuation due to disease progression or adverse events (28). As this is an RWD study, periodic imaging assessment were not performed, and descriptions of disease progression were not mandatory. In addition, it is not possible to extract data on subjective adverse events, because physicians are not required to state their judgment of intolerance.
Allowing for these limitations, however, the strength of this study is that we included a large population and the evaluation of RWD for many treatment regimens that reflect current population trends.
In conclusion, our RWD analyses demonstrated that a standard care for metastatic pancreatic cancer was largely available in hospitals across Japan and verified the survival benefits of gemcitabine plus nab-paclitaxel and FOLFIRINOX regimens observed in previous clinical trials. As such, our findings provide important information for future research directions, policy initiatives, medical guidelines, and clinical decision-making.
Supplementary Material
First-line chemotherapy by hospital scale and type.
Acknowledgements
The authors acknowledge the dedication of Dr. Hisaaki Afuso (chair of Medical Corporation Tokushukai, Tokyo, Japan and General Incorporated Association Tokushukai, Tokyo, Japan) for their support in conducting clinical research within the Tokushukai Group, and Ms. Megumi Shiragami (software development department, Tokushukai Information System, Inc., Osaka, Japan) and Mr. Katsuhiko Ozaki (President of Tokushukai Information System, Inc., Osaka, Japan) for their assistance in using the medical database.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
RS, YI and MO made substantial contributions to the study design and conception. RS, YF and MH were responsible for data acquisition. RS and YI interpreted the data and drafted the manuscript. KU, TM, KO, NS and HM provided advice on research design and aided in the critical interpretation of this research for critical content. RS and YI confirm the authenticity of all the raw data. NS and HM comprehensively reviewed and approved the final version of this manuscript. All authors have read and approved the final version of the manuscript.
Ethics approval and consent to participate
This project was approved by the Ethics Committee of the Tokushukai Group (Tokyo, Japan) in April 2020 (no. TGE01427-024) and was conducted following the principles of the Declaration of Helsinki. Patients were provided with information using opt-out methods and no patient declared not to participate.
Patient consent for publication
Patient consent for publication was obtained through opt-out methods.
Competing interests
Some of the authors have received research funding, honoraria, or scholarship donations from various pharmaceutical companies and other organizations outside of the submitted work, none of which construe actual or potential conflicts of interest. RS received speakers' bureau fees/honoraria from Daiichi-Sankyo, Ono Pharm, Taiho Pharma and Chugai outside of the submitted work. YI received speakers' bureau fees/honoraria from Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer and Ono Pharm outside of the submitted work. HM has received speakers' bureau fees/honoraria from Daiichi-Sankyo and Ono Pharm, research funding from Astelas-Amgen Biopharma, Bayer, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Incite, Novartis, Ono Pharm, Pfizer and Rakuten-Medical, and scholarship donations from Bayer, Chugai, Daiichi-Sankyo, Eisai, Kyowa-Kirin, Lilly, Ono Pharmaceutical, Pfizer, Taiho Pharma and Takeda outside of the submitted work. These organizations had no role in the design, conduct, or reporting of this work. All other authors declare that they have no competing interests.
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