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The efficacy and toxicity of chemotherapy in the elderly with advanced pancreatic cancer
Journal Pre-proof The efficacy and toxicity of chemotherapy in the elderly with advanced pancreatic cancer Xiang Li, Da-bing Huang, Qi Zhang, Cheng-xiang Guo, Qi-han Fu, Xiao-chen Zhang, Tian-Yu Tang, Wei Su, Yi-Wen Chen, Wei Chen, Tao Ma, Shun-Liang Gao, Ri-Sheng Que, Xue-Li Bai, Ting-Bo Liang PII:
S1424-3903(19)30793-8
DOI:
https://doi.org/10.1016/j.pan.2019.11.012
Reference:
PAN 1122
To appear in:
Pancreatology
Received Date: 8 September 2019 Revised Date:
21 November 2019
Accepted Date: 22 November 2019
Please cite this article as: Li X, Huang D-b, Zhang Q, Guo C-x, Fu Q-h, Zhang X-c, Tang T-Y, Su W, Chen Y-W, Chen W, Ma T, Gao S-L, Que R-S, Bai X-L, Liang T-B, The efficacy and toxicity of chemotherapy in the elderly with advanced pancreatic cancer, Pancreatology (2019), doi: https:// doi.org/10.1016/j.pan.2019.11.012. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V. on behalf of IAP and EPC.
The efficacy and toxicity of chemotherapy in the elderly with advanced pancreatic cancer Running title: Chemotherapy in elderly patients
Xiang Li#,1,2,3 MD, PhD, Da-bing Huang#,1,2,3 MM, Qi Zhang1,2,3 MD, PhD, Cheng-xiang Guo1,2,3 MD, Qi-han Fu4 MD, Xiao-chen Zhang4 MD, Tian-Yu Tang,1,2,3 MM, Wei Su1,2,3 MD, Yi-Wen Chen1,2,3 MD, Wei Chen1,2,3 MD, PhD, Tao Ma1,2,3 MD, PhD, Shun-Liang Gao1,2,3 MD, PhD Ri-Sheng Que1,2,3 MD, PhD, Xue-Li Bai*,1,2,3, MD, PhD, Ting-Bo Liang*,1,2,3, MD, PhD
1 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China 2 Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China 3 Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, China 4 Department of Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
#These authors contributed equally to this work. *Corresponding authors: Xue-Li Bai, Ting-Bo Liang Address: 79 Qingchun Road, Hangzhou 310009, China. Tel: +86 0571 87236688 Fax: +86 0571 87236688 mail: [email protected], [email protected]
This work was sponsored by The National High Technology Research and Development Program of China (SS2015AA020405), The National Natural Science Foundation of China (No.81672337, 81871925, 81702332), The Key Program of the National Natural Science Foundation of China (81530079), Key research and development Project of Zhejiang Province（2015C03044）and Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents.
Abstract
OBJECTIVES: FOLFIRINOX (FFX) or abraxane plus gemcitabine (AG)-based chemotherapy is used widely as firstline treatment for patients with pancreatic cancer. however, their use in the elderly is discouraged because of adverse events. More clinical data about the therapeutic response and tolerability to FFX or AG in elderly patents (over 70 years old) are required. METHODS: Patients with advanced pancreatic cancer (n = 203; 131 metastatic pancreatic cancer patients (MPC) and 72 locally advanced pancreatic cancer patients (LAPC)) were treated using modified-FFX (mFFX) or AG and mFFX sequentially. The patients were grouped according to their age, patients below 70 years old and patients above 70 years old. The objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and adverse events were compared between the groups. RESULTS: The ORRs in the elderly and in patients below 70 were similar (30.0% versus 32.3%). The median OS and PFS were also similar between the groups (mOS 13.3m vs 12.7m, p = 0.729, HR 0.874 (95% CI 0.5310 to 1.438); mPFS mPFS 10.6m vs 10.3m, p = 0.363, HR 0.800 (95% CI 0.4954 to 1.293)). However, the elderly patients suffered a higher incidence of severe adverse events (50% vs. 28.3%). CONCLUSIONS: These data could provide guidance for chemotherapy use in elderly patients with advanced pancreatic cancer. Age did not affect treatment outcome; however, supportive treatment is very important for elderly patients receiving chemotherapy.
Key words: modified-FOLFIRINOX, abraxane plus gemcitabine, chemotherapy, elderly, tolerability
Introduction
Pancreatic cancer is one of the most common malignant gastrointestinal malignancies. The incidence of pancreatic cancer is still increasing rapidly, and is the 4th leading cause of cancer-related death in both males and females [1], with a current 5-year survival of only about 7% [2]. Difficulty in diagnosis and early tumor metastasis [3-4] mean that more than 75% of patients are ineligible for potentially curative surgery, and chemotherapy is the first recommendation. Nowadays, besides R0 surgical resection, adjuvant and neoadjuvant chemotherapy are also strongly associated with improved survival [5-6]. Pancreatic cancer is largely a disease of the elderly, nearly 90 percent of pancreatic cancers are diagnosed after the age of 55 and the median age at diagnosis is approximately 70 years [7]. However, the elderly are largely underrepresented in clinical trials, and gains made from trials may not necessarily apply to this important subgroup of patients. Changes in bodily functions and physiology caused by age would have a considerable impact on pharmacokinetic processes. These could have dramatic consequence for chemotherapy regimens, such as excessive drug concentrations and unacceptable toxicity, or subtherapeutic drug concentrations and ineffective treatment. Monotherapy or combination therapy with gemcitabine have been set as the standard treatments for advanced pancreatic cancer during the last decade [8]. Accumulated data has demonstrated that gemcitabine-based chemotherapy is feasible in elderly as well as in younger patients with pancreatic cancer [9-11]. Nowadays, the efficacy of treatment has improved significantly as new regimens and combination treatments have emerged. However, the incidence of severe adverse events increased dramatically as a result. Currently, FOLFIRINOX (FFX) and the combination of abraxane and gemcitabine (AG) are considered as the most efficacious regimens and are set as the first-line treatments for patients with advanced pancreatic cancer with a good performance score. The median
overall survival (OS) was prolonged to 8.7 months (AG) and 11.1 months (FFX) in patients with metastatic pancreatic cancer (MPC) [12-13]. Accompanying these improvements in outcomes, the incidence of severe adverse events has increased dramatically from 5.3% to 42.5% [12]. Neutropenia, fatigue, vomiting, and diarrhea are the most common adverse events observed in patients receiving chemotherapy with FFX or AG [12-13]. Whether these novel intensified combination treatments are well tolerated in elderly patients, and present promising survival benefits, remains unclear. In this retrospective study, a total of 203 patients were enrolled and 157 of them finished at least 2 months chemotherapy, including 30 patients aged over 70 years. For people over 70 years old, intensified combination regimens induced manageable toxicities but with similar, or even longer, median PFS and OS compared to younger patients.
Materials and Methods
Study patients
This was a retrospective study involving patients with MPC and locally advanced pancreatic cancer (LAPC) receiving chemotherapy with modified-FOLFIRINOX (mFFX) or the sequential use of abraxane plus gemcitabine (AG) and mFFX from February 4th, 2014 to April 1st, 2019 at the first affiliated hospital and second affiliated hospital of Zhejiang University School of Medicine. All cases were diagnosed by a multidisciplinary team according to the National Comprehensive Cancer Network (NCCN) definitions and were histologically confirmed as pancreatic adenocarcinoma. Patients with a higher Eastern Cooperative Oncology Group (ECOG) performance score than 1 or inadequate bone marrow, liver, or renal functions, or additional malignancies were excluded. Our study followed the Declaration of Helsinki, and all included patients provided written informed consent.
Treatment MFFX (the combination of oxaliplatin (68 mg/m2), irinotecan (135 mg/m2), leucovorin (400 mg/m2), and fluorouracil (2400 mg/m2) was administered biweekly [14-15]. The sequential use of AG and mFFX was set as abraxane (125 mg/m2) and gemcitabine (1000 mg/m2) on days 1, 8, and 15 of each 28-day treatment cycle, followed by two cycles of mFFX. Physical examination and laboratory tests were performed before each chemotherapy administration. After 2 months of treatment (four cycles of mFFX or one treatment cycle of AG and two cycles of mFFX), chest high-resolution computed tomography (HRCT), abdominal contrast-enhanced computed tomography (CE-CT), and contrast-enhanced magnetic resonance imaging (CE-MRI) of the liver were performed and a multidisciplinary team evaluated the treatment response. Hypertension, diabetes mellitus or other co-morbidities were well controlled before the treatment followed the suggestion of specialist physicians. During the usage of oxaliplatin (dissolved in 5% glucose), we strictly monitor blood glucose level of patients with diabetes.
Assessments
A multidisciplinary team evaluated the radiological response of all patients every 2 months. According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), treatment response was qualitatively classified into four categories as follows: Complete Response (CR, disappearance of all target lesions); Partial Response (PR, more than 30% shrinkage of the diameter of the tumor);
Progressive Disease (PD, more than 20% increase of the diameter of the tumor); Stable Disease (SD, neither PR nor PD).
Adverse events were recorded every time after chemotherapy and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (CTCAE 4.03). The most common hematological (neutropenia, febrile neutropenia, thrombocytopenia, and anemia) and non-hemotological adverse events (infection, fatigue, vomiting, diarrhea, sensory neuropathy, elevated level of ALT, and thromboembolism) were included.
OS was defined as the time from the beginning of treatment to the date of death from any cause. Progression free survival (PFS) was defined as the time from the beginning of treatment to the date of disease progression or death. All patients were followed up every 3 months; patients without events were censored on April 1st 2019.
Statistical analysis
Continuous variables were expressed as medians and compared using the Mann–Whitney U test. Associations between different categorical variables were assessed using the χ2 test or Fisher’s exact test. A Cox proportional hazards model was used for the multivariate analysis of predictive variables that were found to be significant in univariate analysis. OS and PFS curves were plotted using the Kaplan–Meier method and analyzed using the log-rank test. All tests were two-sided, with a p value of less than 0.05 considered to indicate statistical significance. All statistical calculations were performed using SPSS 23.0 (IBM Corp., Armonk, NY, USA) and Prism 7.0 (Graphpad, La Jolla, CA, USA).
Results
Patient characteristics
A total of 203 patients were recruited to receive mFFX or the sequential use of AG and mFFX treatment, and 157 patients completed at least 2 months of chemotherapy and 46 patients did not, for a number of reasons (Fig. 1). The 157 patients were divided into two groups according to their age, patients below 70 years (n = 127) and patients above 70 years (n = 30). The age of the elderly ranges from 70 to 81 years with a median age of 74 years old. The proportion above 75 years old of this population is 33.3% (10/30). The baseline characteristics of the patients are listed in table 1. More elderly patients suffered hypertension (p = 0.020), jaundice (p = 0.053), and showed a higher total bilirubin level (p = 0.009) and lower albumin level (p = 0.001) than did the younger patients. Compared with the elderly patients, more patients below 70 presented a better ECOG score; however, there was no significant difference between them (p = 0.065). Moreover, a total of 19 LAPC patients underwent downstaging operation, including 3 elderly patients. The conversional rate was 34.5% and 25% in patients below 70 years and patients above 70 years respectively with a p value of 0.730.
Response
The treatment response data are listed in table 2. CR was observed in only one MPC patient. The ORR was 32.3% (41/127) in patients below 70 and 30.0% (9/30) in the elderly. The disease control rate (DCR) in the elderly patients group (80.0%, 24/30) was higher than that in the patients below 70 (70.1%, 89/127) with a p value of 0.277.
Adverse events
The toxicity of chemotherapy was also evaluated in the patients. The incidences of adverse events and severe adverse events (Grade 3/4) are listed in tables 3 and 4. No significant difference was observed for the most common hematological (neutropenia, febrile neutropenia, thrombocytopenia, and anemia) or non-hemotological adverse events (infection, fatigue, vomiting, diarrhea, sensory neuropathy, elevated level of ALT, and thromboembolism) between the patients below 70 and above 70 years old. Neutropenia, anemia, and elevated ALT were the most common adverse events, with corresponding incidences of 65.4%, 42.5%, and 55.1% in patients below 70, respectively. Similar results were observed for the elderly patients (63.3%, 53.3%, and 46.7%, respectively).
For severe adverse events, neutropenia was the most frequent, with an incidence of 28.3% (36/127) in patients below 70, compare with 50.0% (15/30) in the elderly (p = 0.001). Additionally, more elderly patients suffered thrombocytopenia (13.3% vs. 3.9%, p = 0.068) and elevated ALT (13.3% vs. 2.4%, p = 0.529), compare with those in patients below 70 years old. However, there was no significant difference between them due to sample limitation. As a result, granulocyte-colony stimulating factor (G-CSF) was applied in more patients above 70 than in the younger patients (76.7% vs. 56.7%, p = 0.044). However, the ratio of patients who used interleukin-11 (IL-11) during treatment was similar in the two groups (18.1% vs. 23.3%, p = 0.513).
Survival
The contribution of chemotherapy to patient survival was also evaluated. All patients who finished at least 2 months treatment were included in the survival the analysis. The median PFS and OS of all patients (n = 157) were 10.6 months and 12.9 months, respectively (SFig. 1). The median OS and PFS
of the 30 patients above 70 years old were 13.3 months and 10.6 months, respectively. The 127 patients who were below 70 years old had a median OS and PFS of 12.7 months and 10.3 months. Interestingly, the survival benefit of chemotherapy in the elderly was similar to that in patients below 70 years old (mOS p = 0.729, HR 0.874 (95% CI 0.5310 to 1.438); mPFS p = 0.363, HR 0.800 (95% CI 0.4954 to 1.293) ) (Fig. 2).
Discussion
Pancreatic cancer is mainly a disease of the elderly population, with a median age at diagnosis of 70 years, and 40.2 % of cases are diagnosed after the age of 75 years [7]. Only a minority of patients with resectable disease can be cured by surgical resection, and systemic chemotherapy or chemoradiation therapy are the optimal treatments for other patients [16]. Gemcitabine has been used widely to treat pancreatic cancer in the last decade as a standard treatment. Gemcitabine resulted in an ORR of 11% with an incidence of grade 3/4 adverse events of 23% in advanced pancreatic cancer patients over 75 years old [17]. The median OS was 6.9 months and 11.4 months for MPC and LAPC respectively [17]. Gemcitabine-based combined therapy is efficacious and feasible in elderly patients [11]. The median OS was extended from 8.5 to 10.2 months and the ORR was as high as 27.6% without enhanced toxicity [11]. More intensive combination treatments have emerged in recent years and the use of FFX or AG has achieved significantly longer median OS and PFS in patients with advanced pancreatic cancer compared with gemcitabine monotherapy, as well as an increased response rate of around 30% [18-19]. mFFX/FFX was found to be the best option for patients with pancreatic cancer in terms of better ORR, and longer OS and PFS [13]. However, the incidence of adverse events occurred in 75.9% of the patients under treatment with mFFX, which was
significantly higher than that of patients treated with gemcitabine [13]. AG is another intensified combination regimen. Compared with gemcitabine, AG presented a much higher incidence of grade 3 or higher adverse events, such as neutropenia (38% in the AG group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%) [12]. Whether these novel intensified combination regimens are well tolerated and present promising survival benefits in elderly patients remains a matter of debate. In 2018, research about sequential use of AG and FOLFIRINOX from France showed promising data in metastatic pancreatic cancer patients. Sequential therapy resulted in an ORR of 63.2%, meanwhile mPFS and mOS were prolonged to 9.6m and 17.8m [20]. These data was much better than that of use AG or FOLFIRINOX alone. Hence, a part of patients received sequential use of mFFX and AG in our research. In 30 elderly patients, the PR, SD, and PD rates were 30.0%, 50%, and 20.0% respectively. The ORR of the elderly patients was similar to that of patients below 70 (31.5%). The DCR in the elderly group was even higher than that of the younger patients (80.0% vs. 70.1%). Similar results were obtained for survival. The median PFS and OS were 10.6 months and 13.3 months, respectively, in the elderly patients. The median OS was even longer than that of younger patients (13.3 months vs. 12.7 months, p = 0.729). The data for treatment response and outcomes in the elderly were in agreement with published data [21-22]. Patients above 70 could benefit from intensified combination chemotherapy as well. Taken together, the data seem to support the administration of an intensified chemotherapy regimen for eligible patients with a good performance score, whatever their age. Research has demonstrated that elderly patients seem to receive chemotherapy less frequently than younger patients because of increased frailty [23]. In data from a multicenter review, including 895 unresectable pancreatic cancer patients, only 52% of elderly patients (above 65 years) received
chemotherapy; however, the proportion of the younger patients was 74% [10]. Moreover, the limited information about side effects of treatment in the population above 70 years old makes it more difficult to weigh the balance between potential survival benefits and treatment-related toxicities. In total, 7 elderly patients and 39 younger patients did not finish at least 2 months treatment in our study for a number of reasons. The major reason in the elderly group was poor tolerance to severe adverse effects (n = 4, 57.1%), whereas most younger patients failed to finish treatment because of lack of faith in chemotherapy (n = 17, 43.5%). Compared with the younger patients, elderly patients with cancer present a decline in physiological functions caused by their different physiological and pathological characteristics. Therefore, the elderly are more prone to a series of risks that increase the incidence of adverse effects of chemotherapy. For example, a decrease in bone marrow hematopoietic function leads to an increased risk of neutropenia, anemia, and thrombocytopenia after chemotherapy. Chronic liver and kidney damage leads to an increase in the cumulative toxicity of chemotherapy drugs [24-25]. In the present study, the most common severe adverse event was neutropenia, with an incidence of 28.3% (36/127) in patients below 70, compared with 50.0% (15/30) in the elderly. Furthermore, more elderly patients suffered from thrombocytopenia (13.3% vs. 3.9%, p = 0.068) and elevated ALT (13.3% vs. 2.4%, p = 0.529), compared with those in younger patients. However, there was no significant difference between them due to sample limitation. The rate of severe adverse events in our study was a little higher than that in previously published data. In a retrospective monocentric study from Guion-Dusserre et al., 18 patients with pancreatic cancer aged over 70 were treated with FFX. The major toxicity was neutropenia, which was observed in 33% of all cases [26]. As a result, treatment delay caused by severe adverse events was observed in 13.3% patients above 70 years old, which was markedly higher than that in younger
patients (8.6%). To ameliorate these adverse effects, the proportion of G-CSF application was significantly higher in elderly patients. All in all, although the severe adverse events were more frequently observed in the elderly, the toxicities are acceptable when considered together with the survival benefits. The study had several limitations. All MPC patients were enrolled regardless of the number and kind of treatments they had received previously. Tumor resection after neoadjuvant chemotherapy is the most important factor to prolong the survival of patients with LAPC; however, we did not further subgroup the patients according to surgery or not because of sample limitation. When we compared the PFS and OS between the two groups according to age, although all MPC and LAPC patients were included, the results remained comparable because the proportion of patients with different staging was similar in the two groups.
Conclusion In our study, novel intensified combination therapy as AG and mFFX presented promising efficacy and acceptable toxicity in the elderly. Compared to the younger patients, similar survival benefit was obtained, although the elderly suffered a higher incidence of severe adverse events. Age does not affect treatment outcome and ECOG performance score seems more important. Our data might provide guidance for combination chemotherapy use in elderly patients with advanced pancreatic cancer.
Acknowledgement
This work was sponsored by The National High Technology Research and Development Program of China (SS2015AA020405), The National Natural Science Foundation of China (No.81672337,
81871925, 81702332), The Key Program of the National Natural Science Foundation of China (81530079), Key research and development Project of Zhejiang Province（2015C03044）and Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents.
Conflict of interest The authors declare no potential conflict of interest.
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Figure Legends
Figure 1. The reasons for failure to complete at least 2 months of treatment. Forty-six out of 203 patients did not complete at least 2 months of chemotherapy for a number of reasons: Lack of faith in treatment, severe adverse events, lost of follow-up, and others. a) The proportion of different reasons in patients who were below 70 years old; b) the proportion of different reasons in patients who were above 70 years old.
Figure 2. Kaplan–Meier estimates of PFS and OS in the different age groups. a) The median PFS was 10.6 and 10.3 months in the elderly group (≥ 70) and the younger group (< 70), respectively with a p value of 0.363, HR 0.800 (95% CI 0.4954 to 1.293) . b) The median OS was 13.3 in patients who were older than 70 years old, as compared with 12.7 months in the younger group (p = 0.729, HR 0.874 (95% CI 0.5310 to 1.438)).
Supplementary Figure 1. Kaplan–Meier estimates of PFS and OS in patients at different stages. a) The median PFS and OS of all patients included in this study (n = 203) were 10.6 and 12.9 months,
respectively. b) For patients with metastatic disease (MPC, n = 99), the median PFS and OS were 8.1 and 10.9 months, respectively. c) For patients with locally advanced disease (LAPC, n = 58), the median PFS and OS were 12.5 and 14.0 months, respectively.
Table 2. Treatment response to chemotherapy. Response rate
All Patients（n=157） <70 (n=127) ≥70 (n=30)
p 0.659
Radiologic response-no.(%) Complete response 1(0.8) 0 Partial response 40(31.5) 9(30.0) Stable disease 48(37.8) 15(50.0) Progression disease 38(29.9) 6(20.0) Objective response rate (ORR)-no.(%) 41(32.3) 9(30.0) 0.809 0.277 Disease control rate (DRC)-no.(%) 89(70.1) 24(80.0) The response rate of patients with advanced pancreatic cancer to chemotherapy. CR, disappearance of all target lesions; PR, more than 30% shrinkage of the diameter of the tumor; PD, more than 20% increase of the diameter of the tumor; SD, neither PR nor PD; ORR, the rate of CR and PR; DCR, the rate of CR, PR and SD.
Table 3. The most common adverse effects in patients with chemotherapy. All Patients（n=157） Adverse events <70 (n=127) p ≥70 (n=30) Hematologic 83 (65.4) 19 (63.3%) 0.835 Neutropenia 1 (0.8) 2 (6.7) 0.094 Febrile neutropenia 35 (27.6) 6 (20.0) 0.397 Thrombocytopenia 54 (42.5) 16 (53.3) 0.284 Anemia Non-hemotologic 20 (15.7) 5 (16.7) 0.999 Infection 27 (21.3) 8 (26.7) 0.522 Fatigue 28 (22.0) 6 (20.0) 0.807 Vomiting 8 (6.3) 2 (6.7) 0.999 Diarrhea 8 (6.3) 4 (13.3) 0.245 Sensory neuropathy 70 (55.1) 14 (46.7) 0.404 Elevated level of ALT The incidence of hematologic and non-hematologic adverse effects in patients with chemotherapy. Abbreviations: ALT, alanine transaminase.
Table 4. The severe adverse effects (grade 3/4) in patients with chemotherapy. All Patients（n=157） Grade 3/4 adverse events <70 (n=127) p ≥70 (n=30) Hematologic 36 (28.3) 15 (50.0) 0.001* Neutropenia 0 0 / Febrile neutropenia 5 (3.9) Thrombocytopenia 4 (13.3) 0.068 0.241 Anemia 10 (7.9) 0 Non-hemotologic 2 (1.6) 0 / Infection 1 (0.8) 0 / Fatigue 2 (1.6) 0 / Vomiting 0 1 (6.7) / Diarrhea 1 (0.8) 0 / Sensory neuropathy 3 (2.4) 2 (13.3) 0.529 Elevated level of ALT The incidence of hematologic and non-hematologic severe adverse effects in patients with chemotherapy. Abbreviations: ALT, alanine transaminase.
Table 1. Patient characteristics at baseline. Patients Characteristics Resectability-no.(%) LAPC MPC Gender-no.(%) Male Female Smoke-no.(%) No Yes Alcohol-no.(%) No Yes Presenting symptoms-no.(%) Jaundice Pain Weight loss Co-morbidities-no.(%) Hypertension Diabetes mellitus Coronary heart disease ECOG performance score-no.(%) 0 1 Pancreatic tumor location-no.(%) Proximal Distal Metastatic sites-no.(%) Liver Lung Peritoneal Others Previous therapy Chemotherapy Radiation Curative intent procedures Open-close surgery Biliary stent/PTCD Regimens
All Patients（n=157） <70 (n=127) ≥70 (n=30) 46(36.2) 81(63.8)
p 0.700
12(40.0) 18(60.0) 0.341
77(60.6) 50(39.4)
21（ 70） 9（ 30） 0.649
79(62.2) 48(37.8)
20(66.7) 10（ 33.3） 0.425
79(62.2) 48(37.8)
21（ 70） 9（ 30）
13(10.2) 92(72.4) 48(37.8)
7（ 23.3） 25（ 83.3） 12（ 40）
0.053 0.218 0.823
32(25.2) 27(21.3) 1(0.8)
14（ 46.7） 10（ 33.3） 1（ 3.3）
0.020* 0.161 0.831 0.065
90(70.9) 37(29.1)
16（ 53.3） 14（ 46.7） 0.713
64(50.4) 63(49.6)
14（ 46.7） 16（ 53.3）
74（ 58.3） 1（ 0.8） 14（ 11） 10（ 7.9）
16（ 53.3） 2（ 6.7） 1（ 3.3） 1（ 3.3）
0.623 0.169 0.345 0.632
7（ 5.5） 7（ 5.5） 22（ 17.3） 1(3.3) 13（ 10.2）
4（ 13.3） 1(3.3) 5（ 16.4） 0 7(23.3)
0.266 0.979 0.932 / 0.103 0.357
mFFX 110(86.6) 24(80.0) Sequential use of AG and mFFX 17(13.4) 6(20.0) Downstaging 16 (34.5) 3 (25.0) 0.730 Lab tests CA19-9 (U/mL) 3563.2((2-12000) 2698((2-12000) 0.311 0.334 CEA (U/mL) 32.4(0-1044) 12.2(1.1-148.2) 0.001* ALB (g/L) 40.2(30.4-49) 36.9(30-44.1) 0.626 SCR (umol/L) 56.5(30-113) 57.9(36-88) 0.009* TB (umol/L) 24(3.6-326) 50(5.5-344.4) 0.965 PLT (10E9/L) 186.3(70-536) 187(93-340） 0.051 WBC (10E9/L) 6.2(1.9-9.6) 5.5(2.7-8.1) The initial lab test results of patients after admission. Abbreviations: LAPC, locally advanced pancreatic cancer; MPC, metastatic pancreatic cancer; ECOG, eastern cooperative oncology group; PTCD, percutaneous transhepatic cholangio-drainage; mFFX, modified-FOLFIRINOX; AG, abraxane plus gemcitabine; CA19-9, carbohydrate antigen 19-9; CEA, carcino-embryonic antigen; ALB, albumin; SCR, serum creatinine; TB, total bilirubin; PLT, platelet; WBC, white blood cells.
S1424-3903(19)30793-8
DOI:
https://doi.org/10.1016/j.pan.2019.11.012
Reference:
PAN 1122
To appear in:
Pancreatology
Received Date: 8 September 2019 Revised Date:
21 November 2019
Accepted Date: 22 November 2019
Please cite this article as: Li X, Huang D-b, Zhang Q, Guo C-x, Fu Q-h, Zhang X-c, Tang T-Y, Su W, Chen Y-W, Chen W, Ma T, Gao S-L, Que R-S, Bai X-L, Liang T-B, The efficacy and toxicity of chemotherapy in the elderly with advanced pancreatic cancer, Pancreatology (2019), doi: https:// doi.org/10.1016/j.pan.2019.11.012. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V. on behalf of IAP and EPC.
The efficacy and toxicity of chemotherapy in the elderly with advanced pancreatic cancer Running title: Chemotherapy in elderly patients
Xiang Li#,1,2,3 MD, PhD, Da-bing Huang#,1,2,3 MM, Qi Zhang1,2,3 MD, PhD, Cheng-xiang Guo1,2,3 MD, Qi-han Fu4 MD, Xiao-chen Zhang4 MD, Tian-Yu Tang,1,2,3 MM, Wei Su1,2,3 MD, Yi-Wen Chen1,2,3 MD, Wei Chen1,2,3 MD, PhD, Tao Ma1,2,3 MD, PhD, Shun-Liang Gao1,2,3 MD, PhD Ri-Sheng Que1,2,3 MD, PhD, Xue-Li Bai*,1,2,3, MD, PhD, Ting-Bo Liang*,1,2,3, MD, PhD
1 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China 2 Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China 3 Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, China 4 Department of Oncology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
#These authors contributed equally to this work. *Corresponding authors: Xue-Li Bai, Ting-Bo Liang Address: 79 Qingchun Road, Hangzhou 310009, China. Tel: +86 0571 87236688 Fax: +86 0571 87236688 mail: [email protected], [email protected]
This work was sponsored by The National High Technology Research and Development Program of China (SS2015AA020405), The National Natural Science Foundation of China (No.81672337, 81871925, 81702332), The Key Program of the National Natural Science Foundation of China (81530079), Key research and development Project of Zhejiang Province（2015C03044）and Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents.
Abstract
OBJECTIVES: FOLFIRINOX (FFX) or abraxane plus gemcitabine (AG)-based chemotherapy is used widely as firstline treatment for patients with pancreatic cancer. however, their use in the elderly is discouraged because of adverse events. More clinical data about the therapeutic response and tolerability to FFX or AG in elderly patents (over 70 years old) are required. METHODS: Patients with advanced pancreatic cancer (n = 203; 131 metastatic pancreatic cancer patients (MPC) and 72 locally advanced pancreatic cancer patients (LAPC)) were treated using modified-FFX (mFFX) or AG and mFFX sequentially. The patients were grouped according to their age, patients below 70 years old and patients above 70 years old. The objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and adverse events were compared between the groups. RESULTS: The ORRs in the elderly and in patients below 70 were similar (30.0% versus 32.3%). The median OS and PFS were also similar between the groups (mOS 13.3m vs 12.7m, p = 0.729, HR 0.874 (95% CI 0.5310 to 1.438); mPFS mPFS 10.6m vs 10.3m, p = 0.363, HR 0.800 (95% CI 0.4954 to 1.293)). However, the elderly patients suffered a higher incidence of severe adverse events (50% vs. 28.3%). CONCLUSIONS: These data could provide guidance for chemotherapy use in elderly patients with advanced pancreatic cancer. Age did not affect treatment outcome; however, supportive treatment is very important for elderly patients receiving chemotherapy.
Key words: modified-FOLFIRINOX, abraxane plus gemcitabine, chemotherapy, elderly, tolerability
Introduction
Pancreatic cancer is one of the most common malignant gastrointestinal malignancies. The incidence of pancreatic cancer is still increasing rapidly, and is the 4th leading cause of cancer-related death in both males and females [1], with a current 5-year survival of only about 7% [2]. Difficulty in diagnosis and early tumor metastasis [3-4] mean that more than 75% of patients are ineligible for potentially curative surgery, and chemotherapy is the first recommendation. Nowadays, besides R0 surgical resection, adjuvant and neoadjuvant chemotherapy are also strongly associated with improved survival [5-6]. Pancreatic cancer is largely a disease of the elderly, nearly 90 percent of pancreatic cancers are diagnosed after the age of 55 and the median age at diagnosis is approximately 70 years [7]. However, the elderly are largely underrepresented in clinical trials, and gains made from trials may not necessarily apply to this important subgroup of patients. Changes in bodily functions and physiology caused by age would have a considerable impact on pharmacokinetic processes. These could have dramatic consequence for chemotherapy regimens, such as excessive drug concentrations and unacceptable toxicity, or subtherapeutic drug concentrations and ineffective treatment. Monotherapy or combination therapy with gemcitabine have been set as the standard treatments for advanced pancreatic cancer during the last decade [8]. Accumulated data has demonstrated that gemcitabine-based chemotherapy is feasible in elderly as well as in younger patients with pancreatic cancer [9-11]. Nowadays, the efficacy of treatment has improved significantly as new regimens and combination treatments have emerged. However, the incidence of severe adverse events increased dramatically as a result. Currently, FOLFIRINOX (FFX) and the combination of abraxane and gemcitabine (AG) are considered as the most efficacious regimens and are set as the first-line treatments for patients with advanced pancreatic cancer with a good performance score. The median
overall survival (OS) was prolonged to 8.7 months (AG) and 11.1 months (FFX) in patients with metastatic pancreatic cancer (MPC) [12-13]. Accompanying these improvements in outcomes, the incidence of severe adverse events has increased dramatically from 5.3% to 42.5% [12]. Neutropenia, fatigue, vomiting, and diarrhea are the most common adverse events observed in patients receiving chemotherapy with FFX or AG [12-13]. Whether these novel intensified combination treatments are well tolerated in elderly patients, and present promising survival benefits, remains unclear. In this retrospective study, a total of 203 patients were enrolled and 157 of them finished at least 2 months chemotherapy, including 30 patients aged over 70 years. For people over 70 years old, intensified combination regimens induced manageable toxicities but with similar, or even longer, median PFS and OS compared to younger patients.
Materials and Methods
Study patients
This was a retrospective study involving patients with MPC and locally advanced pancreatic cancer (LAPC) receiving chemotherapy with modified-FOLFIRINOX (mFFX) or the sequential use of abraxane plus gemcitabine (AG) and mFFX from February 4th, 2014 to April 1st, 2019 at the first affiliated hospital and second affiliated hospital of Zhejiang University School of Medicine. All cases were diagnosed by a multidisciplinary team according to the National Comprehensive Cancer Network (NCCN) definitions and were histologically confirmed as pancreatic adenocarcinoma. Patients with a higher Eastern Cooperative Oncology Group (ECOG) performance score than 1 or inadequate bone marrow, liver, or renal functions, or additional malignancies were excluded. Our study followed the Declaration of Helsinki, and all included patients provided written informed consent.
Treatment MFFX (the combination of oxaliplatin (68 mg/m2), irinotecan (135 mg/m2), leucovorin (400 mg/m2), and fluorouracil (2400 mg/m2) was administered biweekly [14-15]. The sequential use of AG and mFFX was set as abraxane (125 mg/m2) and gemcitabine (1000 mg/m2) on days 1, 8, and 15 of each 28-day treatment cycle, followed by two cycles of mFFX. Physical examination and laboratory tests were performed before each chemotherapy administration. After 2 months of treatment (four cycles of mFFX or one treatment cycle of AG and two cycles of mFFX), chest high-resolution computed tomography (HRCT), abdominal contrast-enhanced computed tomography (CE-CT), and contrast-enhanced magnetic resonance imaging (CE-MRI) of the liver were performed and a multidisciplinary team evaluated the treatment response. Hypertension, diabetes mellitus or other co-morbidities were well controlled before the treatment followed the suggestion of specialist physicians. During the usage of oxaliplatin (dissolved in 5% glucose), we strictly monitor blood glucose level of patients with diabetes.
Assessments
A multidisciplinary team evaluated the radiological response of all patients every 2 months. According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), treatment response was qualitatively classified into four categories as follows: Complete Response (CR, disappearance of all target lesions); Partial Response (PR, more than 30% shrinkage of the diameter of the tumor);
Progressive Disease (PD, more than 20% increase of the diameter of the tumor); Stable Disease (SD, neither PR nor PD).
Adverse events were recorded every time after chemotherapy and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (CTCAE 4.03). The most common hematological (neutropenia, febrile neutropenia, thrombocytopenia, and anemia) and non-hemotological adverse events (infection, fatigue, vomiting, diarrhea, sensory neuropathy, elevated level of ALT, and thromboembolism) were included.
OS was defined as the time from the beginning of treatment to the date of death from any cause. Progression free survival (PFS) was defined as the time from the beginning of treatment to the date of disease progression or death. All patients were followed up every 3 months; patients without events were censored on April 1st 2019.
Statistical analysis
Continuous variables were expressed as medians and compared using the Mann–Whitney U test. Associations between different categorical variables were assessed using the χ2 test or Fisher’s exact test. A Cox proportional hazards model was used for the multivariate analysis of predictive variables that were found to be significant in univariate analysis. OS and PFS curves were plotted using the Kaplan–Meier method and analyzed using the log-rank test. All tests were two-sided, with a p value of less than 0.05 considered to indicate statistical significance. All statistical calculations were performed using SPSS 23.0 (IBM Corp., Armonk, NY, USA) and Prism 7.0 (Graphpad, La Jolla, CA, USA).
Results
Patient characteristics
A total of 203 patients were recruited to receive mFFX or the sequential use of AG and mFFX treatment, and 157 patients completed at least 2 months of chemotherapy and 46 patients did not, for a number of reasons (Fig. 1). The 157 patients were divided into two groups according to their age, patients below 70 years (n = 127) and patients above 70 years (n = 30). The age of the elderly ranges from 70 to 81 years with a median age of 74 years old. The proportion above 75 years old of this population is 33.3% (10/30). The baseline characteristics of the patients are listed in table 1. More elderly patients suffered hypertension (p = 0.020), jaundice (p = 0.053), and showed a higher total bilirubin level (p = 0.009) and lower albumin level (p = 0.001) than did the younger patients. Compared with the elderly patients, more patients below 70 presented a better ECOG score; however, there was no significant difference between them (p = 0.065). Moreover, a total of 19 LAPC patients underwent downstaging operation, including 3 elderly patients. The conversional rate was 34.5% and 25% in patients below 70 years and patients above 70 years respectively with a p value of 0.730.
Response
The treatment response data are listed in table 2. CR was observed in only one MPC patient. The ORR was 32.3% (41/127) in patients below 70 and 30.0% (9/30) in the elderly. The disease control rate (DCR) in the elderly patients group (80.0%, 24/30) was higher than that in the patients below 70 (70.1%, 89/127) with a p value of 0.277.
Adverse events
The toxicity of chemotherapy was also evaluated in the patients. The incidences of adverse events and severe adverse events (Grade 3/4) are listed in tables 3 and 4. No significant difference was observed for the most common hematological (neutropenia, febrile neutropenia, thrombocytopenia, and anemia) or non-hemotological adverse events (infection, fatigue, vomiting, diarrhea, sensory neuropathy, elevated level of ALT, and thromboembolism) between the patients below 70 and above 70 years old. Neutropenia, anemia, and elevated ALT were the most common adverse events, with corresponding incidences of 65.4%, 42.5%, and 55.1% in patients below 70, respectively. Similar results were observed for the elderly patients (63.3%, 53.3%, and 46.7%, respectively).
For severe adverse events, neutropenia was the most frequent, with an incidence of 28.3% (36/127) in patients below 70, compare with 50.0% (15/30) in the elderly (p = 0.001). Additionally, more elderly patients suffered thrombocytopenia (13.3% vs. 3.9%, p = 0.068) and elevated ALT (13.3% vs. 2.4%, p = 0.529), compare with those in patients below 70 years old. However, there was no significant difference between them due to sample limitation. As a result, granulocyte-colony stimulating factor (G-CSF) was applied in more patients above 70 than in the younger patients (76.7% vs. 56.7%, p = 0.044). However, the ratio of patients who used interleukin-11 (IL-11) during treatment was similar in the two groups (18.1% vs. 23.3%, p = 0.513).
Survival
The contribution of chemotherapy to patient survival was also evaluated. All patients who finished at least 2 months treatment were included in the survival the analysis. The median PFS and OS of all patients (n = 157) were 10.6 months and 12.9 months, respectively (SFig. 1). The median OS and PFS
of the 30 patients above 70 years old were 13.3 months and 10.6 months, respectively. The 127 patients who were below 70 years old had a median OS and PFS of 12.7 months and 10.3 months. Interestingly, the survival benefit of chemotherapy in the elderly was similar to that in patients below 70 years old (mOS p = 0.729, HR 0.874 (95% CI 0.5310 to 1.438); mPFS p = 0.363, HR 0.800 (95% CI 0.4954 to 1.293) ) (Fig. 2).
Discussion
Pancreatic cancer is mainly a disease of the elderly population, with a median age at diagnosis of 70 years, and 40.2 % of cases are diagnosed after the age of 75 years [7]. Only a minority of patients with resectable disease can be cured by surgical resection, and systemic chemotherapy or chemoradiation therapy are the optimal treatments for other patients [16]. Gemcitabine has been used widely to treat pancreatic cancer in the last decade as a standard treatment. Gemcitabine resulted in an ORR of 11% with an incidence of grade 3/4 adverse events of 23% in advanced pancreatic cancer patients over 75 years old [17]. The median OS was 6.9 months and 11.4 months for MPC and LAPC respectively [17]. Gemcitabine-based combined therapy is efficacious and feasible in elderly patients [11]. The median OS was extended from 8.5 to 10.2 months and the ORR was as high as 27.6% without enhanced toxicity [11]. More intensive combination treatments have emerged in recent years and the use of FFX or AG has achieved significantly longer median OS and PFS in patients with advanced pancreatic cancer compared with gemcitabine monotherapy, as well as an increased response rate of around 30% [18-19]. mFFX/FFX was found to be the best option for patients with pancreatic cancer in terms of better ORR, and longer OS and PFS [13]. However, the incidence of adverse events occurred in 75.9% of the patients under treatment with mFFX, which was
significantly higher than that of patients treated with gemcitabine [13]. AG is another intensified combination regimen. Compared with gemcitabine, AG presented a much higher incidence of grade 3 or higher adverse events, such as neutropenia (38% in the AG group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%) [12]. Whether these novel intensified combination regimens are well tolerated and present promising survival benefits in elderly patients remains a matter of debate. In 2018, research about sequential use of AG and FOLFIRINOX from France showed promising data in metastatic pancreatic cancer patients. Sequential therapy resulted in an ORR of 63.2%, meanwhile mPFS and mOS were prolonged to 9.6m and 17.8m [20]. These data was much better than that of use AG or FOLFIRINOX alone. Hence, a part of patients received sequential use of mFFX and AG in our research. In 30 elderly patients, the PR, SD, and PD rates were 30.0%, 50%, and 20.0% respectively. The ORR of the elderly patients was similar to that of patients below 70 (31.5%). The DCR in the elderly group was even higher than that of the younger patients (80.0% vs. 70.1%). Similar results were obtained for survival. The median PFS and OS were 10.6 months and 13.3 months, respectively, in the elderly patients. The median OS was even longer than that of younger patients (13.3 months vs. 12.7 months, p = 0.729). The data for treatment response and outcomes in the elderly were in agreement with published data [21-22]. Patients above 70 could benefit from intensified combination chemotherapy as well. Taken together, the data seem to support the administration of an intensified chemotherapy regimen for eligible patients with a good performance score, whatever their age. Research has demonstrated that elderly patients seem to receive chemotherapy less frequently than younger patients because of increased frailty [23]. In data from a multicenter review, including 895 unresectable pancreatic cancer patients, only 52% of elderly patients (above 65 years) received
chemotherapy; however, the proportion of the younger patients was 74% [10]. Moreover, the limited information about side effects of treatment in the population above 70 years old makes it more difficult to weigh the balance between potential survival benefits and treatment-related toxicities. In total, 7 elderly patients and 39 younger patients did not finish at least 2 months treatment in our study for a number of reasons. The major reason in the elderly group was poor tolerance to severe adverse effects (n = 4, 57.1%), whereas most younger patients failed to finish treatment because of lack of faith in chemotherapy (n = 17, 43.5%). Compared with the younger patients, elderly patients with cancer present a decline in physiological functions caused by their different physiological and pathological characteristics. Therefore, the elderly are more prone to a series of risks that increase the incidence of adverse effects of chemotherapy. For example, a decrease in bone marrow hematopoietic function leads to an increased risk of neutropenia, anemia, and thrombocytopenia after chemotherapy. Chronic liver and kidney damage leads to an increase in the cumulative toxicity of chemotherapy drugs [24-25]. In the present study, the most common severe adverse event was neutropenia, with an incidence of 28.3% (36/127) in patients below 70, compared with 50.0% (15/30) in the elderly. Furthermore, more elderly patients suffered from thrombocytopenia (13.3% vs. 3.9%, p = 0.068) and elevated ALT (13.3% vs. 2.4%, p = 0.529), compared with those in younger patients. However, there was no significant difference between them due to sample limitation. The rate of severe adverse events in our study was a little higher than that in previously published data. In a retrospective monocentric study from Guion-Dusserre et al., 18 patients with pancreatic cancer aged over 70 were treated with FFX. The major toxicity was neutropenia, which was observed in 33% of all cases [26]. As a result, treatment delay caused by severe adverse events was observed in 13.3% patients above 70 years old, which was markedly higher than that in younger
patients (8.6%). To ameliorate these adverse effects, the proportion of G-CSF application was significantly higher in elderly patients. All in all, although the severe adverse events were more frequently observed in the elderly, the toxicities are acceptable when considered together with the survival benefits. The study had several limitations. All MPC patients were enrolled regardless of the number and kind of treatments they had received previously. Tumor resection after neoadjuvant chemotherapy is the most important factor to prolong the survival of patients with LAPC; however, we did not further subgroup the patients according to surgery or not because of sample limitation. When we compared the PFS and OS between the two groups according to age, although all MPC and LAPC patients were included, the results remained comparable because the proportion of patients with different staging was similar in the two groups.
Conclusion In our study, novel intensified combination therapy as AG and mFFX presented promising efficacy and acceptable toxicity in the elderly. Compared to the younger patients, similar survival benefit was obtained, although the elderly suffered a higher incidence of severe adverse events. Age does not affect treatment outcome and ECOG performance score seems more important. Our data might provide guidance for combination chemotherapy use in elderly patients with advanced pancreatic cancer.
Acknowledgement
This work was sponsored by The National High Technology Research and Development Program of China (SS2015AA020405), The National Natural Science Foundation of China (No.81672337,
81871925, 81702332), The Key Program of the National Natural Science Foundation of China (81530079), Key research and development Project of Zhejiang Province（2015C03044）and Zhejiang Provincial Program for the Cultivation of High-level Innovative Health talents.
Conflict of interest The authors declare no potential conflict of interest.
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Figure Legends
Figure 1. The reasons for failure to complete at least 2 months of treatment. Forty-six out of 203 patients did not complete at least 2 months of chemotherapy for a number of reasons: Lack of faith in treatment, severe adverse events, lost of follow-up, and others. a) The proportion of different reasons in patients who were below 70 years old; b) the proportion of different reasons in patients who were above 70 years old.
Figure 2. Kaplan–Meier estimates of PFS and OS in the different age groups. a) The median PFS was 10.6 and 10.3 months in the elderly group (≥ 70) and the younger group (< 70), respectively with a p value of 0.363, HR 0.800 (95% CI 0.4954 to 1.293) . b) The median OS was 13.3 in patients who were older than 70 years old, as compared with 12.7 months in the younger group (p = 0.729, HR 0.874 (95% CI 0.5310 to 1.438)).
Supplementary Figure 1. Kaplan–Meier estimates of PFS and OS in patients at different stages. a) The median PFS and OS of all patients included in this study (n = 203) were 10.6 and 12.9 months,
respectively. b) For patients with metastatic disease (MPC, n = 99), the median PFS and OS were 8.1 and 10.9 months, respectively. c) For patients with locally advanced disease (LAPC, n = 58), the median PFS and OS were 12.5 and 14.0 months, respectively.
Table 2. Treatment response to chemotherapy. Response rate
All Patients（n=157） <70 (n=127) ≥70 (n=30)
p 0.659
Radiologic response-no.(%) Complete response 1(0.8) 0 Partial response 40(31.5) 9(30.0) Stable disease 48(37.8) 15(50.0) Progression disease 38(29.9) 6(20.0) Objective response rate (ORR)-no.(%) 41(32.3) 9(30.0) 0.809 0.277 Disease control rate (DRC)-no.(%) 89(70.1) 24(80.0) The response rate of patients with advanced pancreatic cancer to chemotherapy. CR, disappearance of all target lesions; PR, more than 30% shrinkage of the diameter of the tumor; PD, more than 20% increase of the diameter of the tumor; SD, neither PR nor PD; ORR, the rate of CR and PR; DCR, the rate of CR, PR and SD.
Table 3. The most common adverse effects in patients with chemotherapy. All Patients（n=157） Adverse events <70 (n=127) p ≥70 (n=30) Hematologic 83 (65.4) 19 (63.3%) 0.835 Neutropenia 1 (0.8) 2 (6.7) 0.094 Febrile neutropenia 35 (27.6) 6 (20.0) 0.397 Thrombocytopenia 54 (42.5) 16 (53.3) 0.284 Anemia Non-hemotologic 20 (15.7) 5 (16.7) 0.999 Infection 27 (21.3) 8 (26.7) 0.522 Fatigue 28 (22.0) 6 (20.0) 0.807 Vomiting 8 (6.3) 2 (6.7) 0.999 Diarrhea 8 (6.3) 4 (13.3) 0.245 Sensory neuropathy 70 (55.1) 14 (46.7) 0.404 Elevated level of ALT The incidence of hematologic and non-hematologic adverse effects in patients with chemotherapy. Abbreviations: ALT, alanine transaminase.
Table 4. The severe adverse effects (grade 3/4) in patients with chemotherapy. All Patients（n=157） Grade 3/4 adverse events <70 (n=127) p ≥70 (n=30) Hematologic 36 (28.3) 15 (50.0) 0.001* Neutropenia 0 0 / Febrile neutropenia 5 (3.9) Thrombocytopenia 4 (13.3) 0.068 0.241 Anemia 10 (7.9) 0 Non-hemotologic 2 (1.6) 0 / Infection 1 (0.8) 0 / Fatigue 2 (1.6) 0 / Vomiting 0 1 (6.7) / Diarrhea 1 (0.8) 0 / Sensory neuropathy 3 (2.4) 2 (13.3) 0.529 Elevated level of ALT The incidence of hematologic and non-hematologic severe adverse effects in patients with chemotherapy. Abbreviations: ALT, alanine transaminase.
Table 1. Patient characteristics at baseline. Patients Characteristics Resectability-no.(%) LAPC MPC Gender-no.(%) Male Female Smoke-no.(%) No Yes Alcohol-no.(%) No Yes Presenting symptoms-no.(%) Jaundice Pain Weight loss Co-morbidities-no.(%) Hypertension Diabetes mellitus Coronary heart disease ECOG performance score-no.(%) 0 1 Pancreatic tumor location-no.(%) Proximal Distal Metastatic sites-no.(%) Liver Lung Peritoneal Others Previous therapy Chemotherapy Radiation Curative intent procedures Open-close surgery Biliary stent/PTCD Regimens
All Patients（n=157） <70 (n=127) ≥70 (n=30) 46(36.2) 81(63.8)
p 0.700
12(40.0) 18(60.0) 0.341
77(60.6) 50(39.4)
21（ 70） 9（ 30） 0.649
79(62.2) 48(37.8)
20(66.7) 10（ 33.3） 0.425
79(62.2) 48(37.8)
21（ 70） 9（ 30）
13(10.2) 92(72.4) 48(37.8)
7（ 23.3） 25（ 83.3） 12（ 40）
0.053 0.218 0.823
32(25.2) 27(21.3) 1(0.8)
14（ 46.7） 10（ 33.3） 1（ 3.3）
0.020* 0.161 0.831 0.065
90(70.9) 37(29.1)
16（ 53.3） 14（ 46.7） 0.713
64(50.4) 63(49.6)
14（ 46.7） 16（ 53.3）
74（ 58.3） 1（ 0.8） 14（ 11） 10（ 7.9）
16（ 53.3） 2（ 6.7） 1（ 3.3） 1（ 3.3）
0.623 0.169 0.345 0.632
7（ 5.5） 7（ 5.5） 22（ 17.3） 1(3.3) 13（ 10.2）
4（ 13.3） 1(3.3) 5（ 16.4） 0 7(23.3)
0.266 0.979 0.932 / 0.103 0.357
mFFX 110(86.6) 24(80.0) Sequential use of AG and mFFX 17(13.4) 6(20.0) Downstaging 16 (34.5) 3 (25.0) 0.730 Lab tests CA19-9 (U/mL) 3563.2((2-12000) 2698((2-12000) 0.311 0.334 CEA (U/mL) 32.4(0-1044) 12.2(1.1-148.2) 0.001* ALB (g/L) 40.2(30.4-49) 36.9(30-44.1) 0.626 SCR (umol/L) 56.5(30-113) 57.9(36-88) 0.009* TB (umol/L) 24(3.6-326) 50(5.5-344.4) 0.965 PLT (10E9/L) 186.3(70-536) 187(93-340） 0.051 WBC (10E9/L) 6.2(1.9-9.6) 5.5(2.7-8.1) The initial lab test results of patients after admission. Abbreviations: LAPC, locally advanced pancreatic cancer; MPC, metastatic pancreatic cancer; ECOG, eastern cooperative oncology group; PTCD, percutaneous transhepatic cholangio-drainage; mFFX, modified-FOLFIRINOX; AG, abraxane plus gemcitabine; CA19-9, carbohydrate antigen 19-9; CEA, carcino-embryonic antigen; ALB, albumin; SCR, serum creatinine; TB, total bilirubin; PLT, platelet; WBC, white blood cells.