Kim B, Kim J, Yang S, Ahn J, Jung K, Lee JC, Hwang JH. Identification of patients with advanced pancreatic cancer who might benefit from third-line chemotherapy. World J Gastrointest Oncol 2025; 17(2): 100167 [DOI: 10.4251/wjgo.v17.i2.100167]
Corresponding Author of This Article
Jaihwan Kim, PhD, Professor, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82, Gumi-ro 173 Beon-gil, Seongnam 13620, South Korea. drjaihwan@snu.ac.kr
Research Domain of This Article
Medicine, General & Internal
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Bomi Kim, Jaihwan Kim, Soomin Yang, Jinwoo Ahn, Kwangrok Jung, Jong-Chan Lee, Jin-Hyeok Hwang, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, South Korea
Author contributions: Kim B and Kim J contributed to conceptualization; Ahn J and Yang S curated the data; Lee JC conducted formal analysis; Jung K performed investigation and methodology; Hwang JH provided supervision; Kim B wrote the original draft; Kim J reviewed and edited the manuscript.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of the Seoul National University Bundang Hospital (No. B-2207-768-103).
Informed consent statement: Informed consent was waived by the Seoul National University Bundang Hospital Institutional Review Board.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: The data used to support the findings are available from the corresponding author upon request.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jaihwan Kim, PhD, Professor, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82, Gumi-ro 173 Beon-gil, Seongnam 13620, South Korea. drjaihwan@snu.ac.kr
Received: August 13, 2024 Revised: November 27, 2024 Accepted: December 10, 2024 Published online: February 15, 2025 Processing time: 157 Days and 17.6 Hours
Abstract
BACKGROUND
Survival rates of patients with advanced pancreatic cancer (APC) have been improved with palliative chemotherapy series. The current preferred first-line regimen consists of combination therapy of 5-fluorouracil (5-FU)/leucovorin (LV), irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine plus albumin-bound paclitaxel (GNP). After failure of first-line chemotherapy, there are a few options for subsequent therapy including switch to the unused first-line regimen or nano-liposomal irinotecan and 5-FU/LV. However, there are limited studies on the efficacy of third-line chemotherapy after failure of second-line chemotherapy.
AIM
To identify patients with APC who might benefit from third-line chemotherapy.
METHODS
Medical records from a single tertiary hospital were retrospectively reviewed between 2012 and 2021. The study included patients with histologically or cytologically confirmed metastatic or locally APC who underwent first-line FOLFIRINOX or GNP and subsequently received third-line chemotherapy. Overall survival (OS) after diagnosis and OS after third-line chemotherapy (OS3) were defined as the interval from the diagnosis to all-cause death and the time between the initiation of the third-line chemotherapy to all-cause death, respectively.
RESULTS
A total of 141 patients were enrolled. The median patient age at diagnosis was 61.8 years (36.0-86.0), and 54.9% were male. The first-line regimen was FOLFIRINOX (67.4%) or GNP (32.6%). The second-line regimen was FOLFIRINOX (27.0%), GNP (52.5%), or other (20.6%). The median OS was 19.0 months, and the median OS3 and progression-free survival after third-line treatment were 15.3 and 7.3 weeks, respectively. With regard to the best tumor response during third-line chemotherapy, 1.4% had partial response, 24.8% had stable disease, and 59.6% had progressive disease. The following clinical factors before third-line chemotherapy affected OS3: Good performance status (PS), serum carbohydrate antigen 19-9 (CA19-9) level < 1000 U/mL, duration of second-line chemotherapy ≥ 19 weeks, and no peritoneal seeding.
CONCLUSION
This study identified that patients with good PS, CA19-9 < 1000 U/mL, second-line chemotherapy ≥ 19 weeks, and no peritoneal seeding before starting third-line treatment may benefit more from third-line chemotherapy.
Core Tip: This study retrospectively analyzed 141 patients with advanced pancreatic cancer treated between 2012 and 2021, who underwent first-line oxaliplatin or gemcitabine plus nab-paclitaxel, followed by third-line chemotherapy. The median overall survival was 19 months, with 15.3 weeks after third-line treatment. The study identified that patients with good performance status, carbohydrate antigen 19-9 < 1000 U/mL, second-line chemotherapy ≥ 19 weeks, and no peritoneal seeding before starting third-line treatment had better outcomes regardless of the third-line regimen. These findings suggest that such patients may benefit more from third-line chemotherapy in spite of unsatisfactory treatment results from all patients.
Citation: Kim B, Kim J, Yang S, Ahn J, Jung K, Lee JC, Hwang JH. Identification of patients with advanced pancreatic cancer who might benefit from third-line chemotherapy. World J Gastrointest Oncol 2025; 17(2): 100167
Pancreatic cancer is expected to increase in incidence: 64050 new cases are estimated in the United States in 2023, and it is expected to be the second-leading cause of cancer deaths worldwide by 2030[1,2]. The 5-year survival rate of pancreatic cancer is approximately 12%, whereas this rate is only 3% for metastatic pancreatic cancer[2]. Slow but steady improvement in outcomes has been reported, but they remain unsatisfactory[3,4]. In recent times, new therapeutic targets such as the tumor microenvironment and epithelial-mesenchymal transition have been proposed in addition to the tumor itself[5-7].
For the systemic treatment of patients with advanced pancreatic cancer (APC), the current preferred first-line regimen consists of combination therapy of 5-fluorouracil (5-FU)/leucovorin (LV), irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine plus albumin-bound paclitaxel (GNP). In a randomized phase 3 study, FOLFIRINOX showed a significant improved survival duration of 11.1 months compared with 6.8 months for gemcitabine monotherapy[8]. GNP also showed a significant increase in survival time of 8.5 months compared with 6.7 months with gemcitabine monotherapy[9].
After failure of first-line chemotherapy, there are a few options for subsequent therapy[10]. If the patient has a good performance status (PS) [Eastern Cooperative Oncology Group (ECOG) 0-1] or intermediate PS (ECOG 2), the second-line regimen is often switched to the unused regimen, choosing between FOLFIRINOX and GNP, both of which are recommended as first-line options. In cases with poor PS (ECOG 3-4), gemcitabine, capecitabine, or 5-FU monotherapy is recommended[11]. Recently, a randomized phase 3 study reported that nano-liposomal irinotecan (nal-IRI) and 5-FU/LV showed a significant prolonged survival time of 6.1 months compared with 4.2 months with 5-FU monotherapy after previous gemcitabine-based therapy[12]; thus, it is also recommended for the subsequent regimen. Genetic testing can also guide the use of immunotherapy or target therapy, including pembrolizumab, larotrectinib, or entrectinib. Although the number of patients eligible for subsequent treatment has increased[13], clinical evidence is scarce in the setting beyond the second-line treatment. As with other types of cancer, there is an urgent need for research on third-line and beyond treatments[14-18].
In this study, we aimed to identify patients with APC who might benefit from third-line chemotherapy after failure of second-line treatment.
MATERIALS AND METHODS
Patients
We reviewed a database of patients with APC who were treated at a single tertiary teaching hospital from December 2012 to December 2021. The inclusion criteria were as follows: (1) Patients with histologically or cytologically confirmed metastatic or locally APC; (2) Patients with the first-line chemotherapy with FOLFIRINOX or GNP; and (3) Patients who received second-line and third-line chemotherapy, except for those in clinical trials including immunotherapy or targeted therapy. The exclusion criteria were: (1) Progressive disease not confirmed after second-line chemotherapy; (2) Patients who underwent pancreatectomy; and (3) Patients with poor PS. The best tumor response was measured using radiological assessments, including computed tomography or magnetic resonance imaging scans, and graded according to the response evaluation criteria in solid tumors version 1.1. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the Seoul National University Bundang Hospital (No. B-2207-768-103).
Statistical analysis
Progression-free survival (PFS) was defined as the date from the start of third-line chemotherapy of any regimen to the date of disease progression or death, whichever occurred first. Overall survival (OS) after diagnosis and OS after third-line chemotherapy (OS3) were defined as the interval from the diagnosis and the time between the initiation of the third-line chemotherapy to all-cause death, respectively. We conducted propensity score matching (PSM) between the third-line chemotherapy and best supportive care groups. For the matching process, we considered variables that influenced OS3, specifically PS after second-line chemotherapy and the duration of second-line chemotherapy. These covariates were selected to ensure comparability between the matched groups and to minimize selection bias. We estimated survival outcomes using Kaplan-Meier analysis and compared using the log-rank test. The Cox proportional hazards model was used for multivariate analysis to identify clinical factors associated with OS and OS3, adjusting for relevant covariates such as age, gender, PS, and treatment regimen. Hazard ratios (HRs) were reported with 95% confidence intervals (CIs) to indicate the strength and direction of associations. All statistical analyses were performed using the Statistical Package for the Social Sciences (version 29.0; IBM statistical product and service solutions, Armonk, NY, United States). P values < 0.05 were considered significant at analysis.
RESULTS
Baseline characteristics
We included a total of 1152 patients with histologically or cytologically confirmed APC. Among them, 1102 patients did not undergo pancreatectomy, and 1031 patients received FOLFIRINOX or GNP as first-line chemotherapy. Among the patients who received best supportive care after second-line chemotherapy, death information is available for 167 patients, while the remaining patients either died or were lost to follow-up. 197 received second-line and third-line chemotherapy outside a clinical trial. Eventually, 141 patients received second-line chemotherapy; when disease progression was confirmed, they received third-line chemotherapy (Figure 1 and Supplementary Figure 1).
Figure 1 Study flowchart.
Of 1152 patients with advanced pancreatic cancer, 1031 received first-line 5-fluorouracil/leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine plus albumin-bound paclitaxel, and 559 and 199 received second-line and third-line chemotherapy, respectively. 167 patients received best supportive care and their survival outcomes are known. In total, 141 patients were enrolled in this study. FOLFIRINOX: 5-fluorouracil/leucovorin, irinotecan, and oxaliplatin; GNP: Gemcitabine plus nab-paclitaxel; PD: Progressive disease.
The baseline characteristics of the third-line chemotherapy group and the best supportive care group were not significantly different in many aspects. The mean age was slightly higher in the third-line chemotherapy (61.8 years vs 59.52 years, P = 0.200). Males comprised more in best supportive care (54.9% vs 61.1%, P = 0.277). In both groups, a higher proportion had initial stage metastatic disease (76.8% vs 63.9%, P = 0.010). The prevalence of initial metastatic lesions significantly differed, with liver metastases being more common in both groups (67.9% vs 41.9%, P < 0.001). There was a significant difference in the duration of second-line chemotherapy, with 63.1% of third-line chemotherapy patients receiving less than 19 weeks of treatment compared to 80.9% in the best supportive care group (P < 0.001). Regarding PS after second-line chemotherapy, 83.7% of patients in the third-line chemotherapy group had good PS, whereas only 1.8% in the best supportive care group did, with 56.9% having poor PS (P < 0.001) (Table 1).
FOLFIRINOX/GNP/TS-1/nal-IRI plus 5FU and leucovorin/other
38/74/3/8/18 (27.0/52.5/2.1/5.7/12.8)
36/110/9/5/7 (21.6/65.9/5.4/3.0/4.2)
< 0.001
Third-line regimen
TS-1/nal-IRI plus 5FU and leucovorin/other
68/53/20 (48.2/37.6/14.2)
Median duration (week)
First/second-line CTx
27.2/16.0 (29.0/15.9)
27.4/11.9(46.3/19.7)
0.797/0.800
Duration of second-line CTx
< 19 weeks/≥ 19 weeks
89/52 (63.1/36.9)
127/30 (80.9/19.1)
< 0.001
Median relative dose
First-/second-/third-line CTx
74/78/100 (0.18/0.17/0.19)
PS after second-line CTx
Good/intermediate/poor
118/23/0 (83.7/16.3/0.0)
3/69/95 (1.8/41.3/56.9)
< 0.001
Treatment outcomes
The best tumor response during the third-line chemotherapy, there was no complete response, 2 (1.4%) patients had a partial response, 35 (24.8%) had stable disease, and 84 (59.6%) had progressive disease (Table 2 and Figure 2A). Consequently, the disease control rate was 26.2%. The median OS was 19.0 months (95%CI: 16.6-21.4). The median OS3 and PFS after third-line treatment was 15.3 weeks (95%CI: 12.9-17.7) and 7.3 weeks (95%CI: 6.3-8.3), respectively (Figure 2B and C). Forty-four patients (31.2%) survived more than 5 months after third-line therapy (Supplementary Figure 2).
Figure 2 Treatment outcomes of third-line chemotherapy.
A: Waterfall plot illustrating the best tumor response during third-line chemotherapy. The evaluation was based on the response evaluation criteria in solid tumors system, with a disease control rate of 26.2%; B: Kaplan-Meier curve showing a median overall survival of 15.3 weeks during third-line chemotherapy; C: Kaplan-Meier curve showing a median progression-free survival of 7.3 weeks during third-line chemotherapy. OS: Overall survival; CI: Confidence interval; PFS: Progression-free survival.
Table 2 Overall summary of efficacy in third-line chemotherapy.
(n = 141)
Best response, n (%)
PR
2 (1.4)
SD
35 (24.8)
PD
84 (59.6)
NA
20 (14.2)
Disease control rate (CR + PR + SD)
37 (26.2)
Median survival from third-line chemotherapy, weeks (95%CI)
OS3
15.3 (12.9-17.7)
PFS (n = 110)
7.3 (6.3-8.3)
Median survival from diagnosis, months (95%CI)
OS
19.0 (16.6-21.4)
For those who received best supportive care after second-line chemotherapy (n = 167), the median survival was only 9.0 weeks (95%CI: 8.5-9.5). We found a significant difference in survival between the group that underwent third-line chemotherapy and the group that received best supportive care [15.3 (95%CI: 12.9-17.7) weeks vs 9.0 (95%CI: 8.5-9.5) weeks, P < 0.001] (Supplementary Figure 3). We conducted PSM considering factors that could influence OS, such as PS after second-line chemotherapy and duration of second-line chemotherapy (reference 19 weeks) between the best supportive care and third-line chemotherapy groups. Each group was matched with 26 patients based on baseline characteristics (Supplementary Table 1). The group that underwent third-line chemotherapy showed a median OS of 10.4 weeks (95%CI: 5.5-15.3), while the best supportive care showed a median OS of 9.3 weeks (95%CI: 7.1-11.4). No significant difference was observed in OS between the groups, but it showed that even patients with similar conditions undergoing chemotherapy can have a longer OS (P = 0.731, Supplementary Table 2).
Prognostic factors for survival outcomes
We performed Cox proportional hazards regression analysis to identify the factors affecting survival outcomes (Table 3). Intermediate PS at third-line chemotherapy (HR = 2.46, 95%CI: 1.5-4.1, P = 0.001), serum carbohydrate antigen 19-9 (CA19-9) level ≥ 1000 U/mL before third-line chemotherapy (HR = 1.58, 95%CI: 1.1-2.4, P = 0.028), duration of second-line chemotherapy < 19 weeks (HR = 1.50, 95%CI: 1.0-2.2, P = 0.037), and peritoneal seeding before third-line chemotherapy (HR = 1.48, 95%CI: 1.0-2.2, P = 0.046) were significantly associated with OS3 (Table 3 and Figure 3).
Figure 3 Prognostic factors influencing overall survival in third-line chemotherapy.
A: Performance status; B: Serum carbohydrate antigen 19-9 levels; C: Duration of second-line chemotherapy; D: Presence of peritoneal seeding were significantly associated with overall survival. PS: Performance status; CA19-9: Carbohydrate antigen 19-9; 2L: Second-line chemotherapy.
Table 3 Univariable and multivariable analyses of survival outcomes after third-line chemotherapy.
Univariable
Multivariable
HR
95%CI
P value
HR
95%CI
P value
Sex (female)
1.39
1.0-2.0
0.062
Age
1.00
1.0-1.0
0.621
Initial stage (locally advanced)
1.15
0.8-1.8
0.511
Intermediate PS at third-line CTx (good PS)
2.22
1.4-3.6
0.001
2.46
1.5-4.1
0.001
CA19-9 (U/mL)
Initial
1.00
1.0-1.0
0.596
≥ 1000 U/mL before third-line CTx (< 1000 U/mL)
1.53
1.0-2.2
0.030
1.58
1.1-2.4
0.028
CTx regimen
Third-line CTx (TS-1)
1.07
1.0-1.2
0.253
Duration of the second-line CTx
< 19 weeks (≥ 19 weeks)
1.75
1.2-2.5
0.003
1.50
1.0-2.2
0.037
Metastases
Liver metastases before third-line CTx (no liver metastases)
1.26
0.8-1.9
0.267
Peritoneal seeding before third-line CTx (no peritoneal seeding)
1.42
1.0-2.0
0.047
1.48
1.0-2.2
0.046
Adverse events
Table 4 lists adverse events that occurred during third-line chemotherapy. Among all patients, 85 (60.3%) experienced significant treatment-related adverse events. The most common adverse events were fatigue (36.2%) and vomiting (27.0%). The most common grade 3 or 4 adverse events were also fatigue (11.3%) and vomiting (9.9%). Adverse events for each chemotherapy regimen were presented in a supplementary table. Fatigue and vomiting were the most common adverse events associated with titanium silicate-1 (TS-1), while fatigue and bone marrow suppression were common in nal-IRI plus 5FU and LV.
Table 4 Adverse events of patients at third-line chemotherapy, n (%).
Any grade
Grade 3 or more
Fatigue
51 (36.2)
16 (11.3)
Vomiting
38 (27.0)
14 (9.9)
Bone marrow suppression
26 (18.4)
2 (1.4)
Anorexia
20 (14.2)
2 (1.4)
Peripheral neuropathy
18 (12.8)
10 (7.1)
Diarrhea
16 (11.3)
5 (3.5)
Constipation
13 (9.2)
4 (2.9)
Skin rash
1 (0.7)
0 (0)
DISCUSSION
There have been limited studies on third-line chemotherapy in patients with APC pancreatic cancer, mainly because of the characteristics of this lethal disease. However, patients with tolerable PS after second-line chemotherapy are not uncommon, especially in the era of the first-line FOLFIRINOX or GNP. For these patients, third-line chemotherapy or individualized treatment strategies based on bioinformatic knowledge, similar to those used in other cancers, are crucial for improving outcomes[14,16-19]. In the current study, we focused on the therapeutic efficacy of third-line chemotherapy.
For the patients undergoing third-line chemotherapy in this study, the median OS3 was 15.3 weeks, and the disease control rate was 26.2%. A previous study reported a median OS3 of 3.9 months for third-line chemotherapy with FOLFIRINOX in combination with 5FU/LV (FOLFOX), showing results similar to ours[20]. Consequently, the current study showed a median OS of 19.0 months, which was much longer than reported in previous phase 3 studies[8,9].
Favorable conditions in this study, including good PS at third-line chemotherapy, serum CA19-9 level < 1000 U/mL, and no peritoneal seeding before third-line chemotherapy, were identified with a longer OS3, which aligned with the findings of previous studies[21-23]. Of these conditions, it should be noted that the longer duration of second-line chemotherapy (≥ 19 weeks) was associated with better survival. Although further studies are necessary, there is a possibility that longer second-line chemotherapy might reflect better PS, as we found a borderline significant (P = 0.077, data not shown) association between good PS and second-line chemotherapy of ≥ 19 weeks. Similar to our research, a previous study also reported that the efficacy of previous treatment had a significant effect on the outcomes of subsequent treatment[24]. The current guidelines recommend considering subsequent therapy but do not specify the appropriate candidates for such treatment. Our study is significant in that it suggests which patients could benefit from third-line therapy.
There were studies have studied whether specific chemotherapy regimens in third-line chemotherapy affect OS[25-27]. A recent retrospective study reported that erlotinib-based chemotherapy and gemcitabine monotherapy showed a tendency towards negative outcomes[25]. Another study reported that treatment sequence affected OS[26]. However, this study found no difference in OS based on the type of third-line chemotherapy regimen.
With regard to grade 3 adverse events, the most common adverse events were fatigue and vomiting. We observed grade 3 bone marrow suppression in only 1.4% of patients. It is regarded that most regimens in the third-line include less bone marrow–suppressive agents such TS-1 or nal-IRI plus 5-FU/LV (n = 121, 85.8%) along with a dose reduction in case of FOLFIRINOX or GNP (mean reduction rate 53.0%).
This study has several limitations. First, it had a retrospective design, which contributed to the potential biases including selection bias, recall bias, and the confounding bias. Second, this research relied on data from a single center, limiting the generalizability of the findings. Third, due to the use of various agents, there were limitations in the search of the effects of the chemotherapy regimen, although the first-line regimen was confined to FOLFIRINOX or GNP. Fourth, the duration of the second-line chemotherapy and good PS each significantly influenced OS3 in the multivariable analysis, indicating a potential correlation between the two factors, which remains a limitation. Following second-line chemotherapy, patients with poor PS received best supportive care. Consequently, there are differences in baseline characteristics between patients receiving best supportive care and those undergoing third-line chemotherapy, making comparisons challenging and it is hard to clarify the real efficacy of third-line treatment without control group with best supportive care.
Recent data from the NAPOLI-3 trial support the consideration of NALIRIFOX as a potential new first-line standard of care in cytotoxic regimens[28]. Additionally, multiple ongoing clinical trials are investigating various molecular targets, including KRAS mutations, DNA damage repair deficiencies, mismatch repair pathway alterations, and rare genetic fusions[29,30]. These intensive research efforts are expected to lead to improved outcomes for patients with APC in the near future.
In conclusion, the results of the current study suggest that third-line chemotherapy could be recommended for some patients with specific conditions such as good PS, low CA19-9 level, no peritoneal seeding, and longer duration of response to second-line chemotherapy.
CONCLUSION
The results of the current study suggest that third-line chemotherapy could be recommended for some patients with specific conditions such as good PS, low CA19-9 level, no peritoneal seeding, and longer duration of response to second-line chemotherapy before starting third-line treatment in spite of unsatisfactory results from all patients.
ACKNOWLEDGEMENTS
We would like to thank all the patients who generously participated in this study.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: South Korea
Peer-review report’s classification
Scientific Quality: Grade B, Grade B
Novelty: Grade A, Grade B
Creativity or Innovation: Grade A, Grade B
Scientific Significance: Grade A, Grade B
P-Reviewer: Lv JY; Zheng HJ S-Editor: Fan M L-Editor: A P-Editor: Zhang L
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