Medical Oncology

, 30:747

S-1 plus CIK as second-line treatment for advanced pancreatic cancer

Authors

  • Meng Wang
    • Department of Internal MedicineShan Dong Ji Ning First People’s Hospital
  • Sheng-bin Shi
    • Department of Internal MedicineShan Dong Tumor Hospital
    • Department of Internal MedicineShan Dong Tumor Hospital
  • Xiao-yong Tang
    • Department of Internal MedicineShan Dong Tumor Hospital
  • Jing Tian
    • Department of Internal MedicineShan Dong Tumor Hospital
Original Paper

DOI: 10.1007/s12032-013-0747-9

Cite this article as:
Wang, M., Shi, S., Qi, J. et al. Med Oncol (2013) 30: 747. doi:10.1007/s12032-013-0747-9

Abstract

This study aimed to evaluate the efficacy and tolerability of S-1 (Tegafur, Gimeracil, and Oteracil Potassium Capsules) plus CIK (Cytokine-induced killer cells) in patients with advanced pancreatic cancer who had previously received gemcitabine-based therapy. In this prospective study, fifty-eight patients were randomly divided into two groups. One group (CT group) was given S-1 alone, and the other group (immuno-CT group) was given S-1 plus CIK. S-1 was administered orally twice a day at 80 mg/m2/day on days 1–21 of a 28-day cycle till disease progression or unacceptable toxicity occurred. CIK was given for one cycle of 28 days. The disease control rate for S-1 and CIK was 40.0 and 53.6 %, respectively (p = 0.621). The serum CA19-9 level decreased for more than 25 % was significantly different (33.3 and 60.7 % in CT group and immuno-CT group, respectively, p = 0.037). The median time to progression was 2.5 (95 % CI 2.3–2.8) and 2.9 (95 % CI 2.6–3.2) months (p = 0.037) for CT group and immuno-CT group, respectively. The median overall survival was 6.1 (95 % CI 5.7–6.5) and 6.6 (95 % CI 6.1–7.1) months (p = 0.09) for CT group and immuno-CT group, respectively. The difference in hematological toxicity, including leukocytopenia, anemia, and neutropenia, was insignificant between the two groups. In contrast, the differences in non-hematological toxicity, fatigue, and non-infective fever were significantly different between the two groups (p < 0.05). The S-1 plus CIK regimen was well tolerated in a second-line setting in patients with gemcitabine-refractory and advanced pancreatic cancer.

Keywords

Pancreatic cancerSecond-line treatmentS-1CIK

Introduction

Pancreatic cancer has the poorest 5-year survival rate, especially in the late stages, with a short median survival time [1]. Because of the difficulty in the detection of the disease at an early stage, the majority of the tumors are either locally advanced or metastatic upon diagnosis. Therefore, chemotherapy plays an important role in the treatment of pancreatic cancer. Although gemcitabine remains as a backbone of any new first-line chemotherapy regimen for advanced or metastatic pancreatic cancer, the period of relief is short in first-line treatment [2]. An increasing number of patients maintain good clinical conditions after optimized first-line chemotherapy. All patients with good functional performance status should be considered for participating clinical trial, because the currently available therapeutic options only provide the modest benefit. Thus, the development of new approaches for treatment of this disease remains a pressing task in clinical oncology. Recent evidence suggests that the combination of chemotherapy and immunotherapy can mediate synergistic effects [3] and achieve better results [4, 5].

S-1 is an orally administered drug that is a combination of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and oteracil potassium (Oxo) in 1:0.4:1 molar concentration ratio [6]. The antitumor effect of S-1 in advanced pancreatic cancer as a first- or second-line therapy has been reported in Japan [7, 8]. It has also been reported to be active against gemcitabine-refractory pancreatic cancer with tolerable toxicity [9, 10]. In two phase II studies, S-1 monotherapy has been used as a second-line chemotherapy for advanced pancreatic cancer after gemcitabine failure. A partial response has been obtained in 9.5–15 % of the cases, and stable disease has been seen in 43 % of the cases. The median progression-free survival (PFS) is 2.0–4.1 months, and the median survival time (MST) is 4.5–6.3 months. The toxicity is acceptable [11, 12].

Cytokine-induced killer (CIK) cells proliferate rapidly. They have high- and broad-spectrum tumor-killing activities, as well as low toxicity to normal hematopoietic precursor cells in bone marrow. They are also effective in removing multi-drug-resistant tumor cells [13]. Ying et al. have confirmed the safety and feasibility of treatment with dendritic cell (DC)-based and cytokine-induced killer cell (CIK)-based therapies for patients with advanced pancreatic adenocarcinoma [14]. Immunotherapy has the potential to provide a non-cross-resistant mechanism of antitumor activity that can be integrated with surgery, radiation, and chemotherapy. A major advantage of immune-based therapies is their abilities to target a tumor cell specifically relative to the corresponding cell origin, thereby minimizing non-specific toxicities. Some studies have reported that 5-FU induces cytokine production and natural killer (NK) cell activity in vivo and in vitro [15, 16].

Materials and methods

Patient

Patients with histologically or cytologically proven locally advanced or metastatic pancreatic cancer received capecitabine plus CIK as the second-line treatment in Shandong Tumor Hospital and Jining First Peoples Hospital from April 2009 to March 2012. The patient selection criteria for this prospective study were 18–74 years of age, ECOG performance status (PS) ≤2, adequate hematological manifestation (white blood cell count ≥4.0 × 109/l, neutrophil count ≥1.5 × 109/l, platelet count ≥100 × 109/l and hemoglobin ≥10 g/dl), hepatic (AST/ALT ≤ 2.5 × normal upper limits; bilirubin ≤1.5 mg/dl) and renal (creatinine clearance ≥60 ml/min or creatinine ≤ normal upper limits) functions, life expectancy of at least 12 weeks, and with at least 1 measurable lesion according to modified response evaluation criteria in solid tumors (RECIST). All patients underwent clinical examination. Abdominal CT, chest X-ray, and plasma CA19.9 measurements were performed before S-1 plus CIK was administered. Patients who had not received S-1 as part of their previous regimen, patients who had massive pleural effusion, ascites, active concomitant malignancy or brain metastasis, and women who were pregnant or lactating were excluded from the study.

Treatment

S-1 was administered orally twice daily at a dose of 80 mg/m2 for 21 consecutive days, followed by 7 days of rest. The initial doses were determined according to the body surface area (BSA). Patients with BSA of 1.25 m2 received S-1 at 80 mg/day. Patients with BSA of more than 1.25, but less than 1.50 m2 received S-1 at 100 mg/day, and patients with BSA of more than 1.50 m2 BSA received S-1 at 120 mg/day. Blood samples were collected from the patients at the first day of the chemotherapy. Lymphocytes were separated from blood samples, cultured in vitro, and then applied to the patients by CIK cell intravenous reinjection. Treatment cycles were repeated every 28 days. This treatment course was repeated till disease progression, unacceptable toxicity occurred, and when the patient no longer wished to continue the treatment. CIK treatment schedule is shown in Table 1.
Table 1

CIK treatment schedule

Day

Project

Approach

Injection site

1

Blood acquisition

Cubital vein

N/A

12

CIK

Vein reinjection

Cubital vein

14

CIK

Vein reinjection

Cubital vein

16

CIK

Vein reinjection

Cubital vein

18

CIK

Vein reinjection

Cubital vein

20

CIK

Vein reinjection

Cubital vein

Preparation of CIK

For CIK cell preparation, cell density was adjusted to 3 × 106 cells/ml with RPMI1640 containing 1,000 U/ml human IFN-γ (Jiang Lai Bio-Technology, Shanghai, China) and cultured in 75-cm3 culture flasks at 37 °C under 5 % CO2. After 24 h, anti-CD3 monoclonal antibody, human IL2 (Jinan, China), and human rIL-1α (Suo Lai Bao Bio-Technology, Shanghai, China) were added into the culture at a final concentration of 50 ng/ml, 300, and 100 U/ml, respectively. During 2–12 days post-cell inoculation, the cell density was determined every 3 days and readjusted to 3 × 106/ml using fresh RPMI1641 containing 300 U/ml human IL-2. Twelve days after initial cell inoculation, CIK cells were collected by centrifugation and washed with normal saline for two times. Intravenous injection was performed within 4 h after cell collection.

Evaluation and statistical methods

Tumor response was assessed by CT according to the Response Evaluation Criteria in Solid Tumors (RECIST, ver. 1.0) after the second treatment cycle. According to the RECIST guideline, complete response (CR), PR, SD, and PD were determined. The level of tumor marker carbohydrate antigen (CA19-9) was measured every month till treatment failed. Adverse events were assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. PFS was counted from the date of treatment initiation to the date of documentation of disease progression or death, and OS was measured from treatment of S-1 plus CIK till death or the last follow-up. PFS and overall survival curves were constructed using the Kaplan–Meier method.

Results

Patient characteristics

A total of 58 patients were enrolled in this study between April 2009 and March 2012. Seventeen (49 %) male and 18 (51 %) female patients with a median age of 62 years and a range of 40–76 years were treated with chemotherapy combined with CIK cells (immuno-CT). Seven male and 7 female patients with a median age of 48 years and a range of 40–65 years were treated with chemotherapy (CT). All patients had received previous chemotherapy with a gemcitabine-based regimen. Most of the patients in each group were metastatic (92.9 vs. 96.7). The demographic and clinical characteristics of the patients are summarized in Table 2. Treatment-unrelated early death occurred in one patient, who was considered as progressive at the time of death for all subsequent analyses.
Table 2

Characteristics of patients (n = 58)

Factor

Immuno-CT group

CT group

p

Median age

   

Sex

15 (53.6)

16 (53.3)

0.98

Male

13 (46.4)

14 (46.7)

 

Female

   

Performance status

  

0.99

0

7 (25.0)

8 (26.7)

 

1

10 (35.7)

9 (30.0)

 

2

11 (39.3)

13 (43.3)

 

Disease status

  

0.513

Locally advanced

2 (7.1)

1 (3.4)

 

Metastatic

26 (92.9)

29 (96.7)

 

Primary tumor site

  

0.862

Head

22 (78.6)

23 (76.7)

 

Body and tail

6 (21.4)

7 (23.3)

 

Prior chemotherapy

  

0.63

GEM alone

16 (57.1)

19 (63.3)

 

GEM plus other drugs

12 (42.9)

11 (36.7)

 

Histology

  

0.513

Adenocarcinoma

26 (92.9)

29 (96.7)

 

Acinar cell carcinoma

2 (7.1)

1 (3.4)

 

Response

All patients received at least one treatment cycle (median 3 cycles; range 2–5 cycles) and were included in the ITT analysis. All 58 patients were evaluable for response. In the immuno-CT group, two patients (7.1 %) experienced PR and 11 patients (39.3 %) experienced SD; while in the CT group, two patients (6.7 %) experienced PR and 10 (33.3 %) patients experienced SD. Unfortunately, there was no complete response. The DCR was 53.6 and 40.0 % in the immuno-CT group and the CT group, respectively (p = 0.62). The median PFS was 2.5 months (95 % CI 2.3–2.8) and 2.9 months (95 % CI 2.6–3.2) in the CT group and the immuno-CT group, respectively (p = 0.037) (Fig. 1). The median OS was 6.1 months (95 % CI 5.7–6.5) and 6.6 months (95 % CI 6.1–7.1) in the CT group and the immuno-CT group, respectively (p = 0.09) (Fig. 2; Table 3). Fifty-six and thirty-five percent of the patients in the immuno-CT group and chemotherapy group had more than 25 % decrease in the levels of serum CA19-9 from their baseline values, respectively (p = 0.92).
https://static-content.springer.com/image/art%3A10.1007%2Fs12032-013-0747-9/MediaObjects/12032_2013_747_Fig1_HTML.gif
Fig. 1

Progression-free survival in the study population

https://static-content.springer.com/image/art%3A10.1007%2Fs12032-013-0747-9/MediaObjects/12032_2013_747_Fig2_HTML.gif
Fig. 2

Overall survival calculated from the date of treatment with S-1 plus CIK

Table 3

Response

Response

Immuno-CT group

CT group

P

Complete response

0

0

 

Partial response

2 (7.1 %)

2 (6.7 %)

 

Stable disease

11 (39.3 %)

10 (33.3 %)

 

Progressive disease

15 (53.6 %)

18 (60.0 %)

 

Disease control rate

13 (53.6 %)

12 (40.0 %)

0.621

CA19-9 level decreasing more than 25 %

17 (60.7 %)

10 (33.3 %)

0.037

Time to progression, median (95 % CI)

2.9 (2.6–3.2) months

2.5 (2.3–2.8) months

0.037

Overall survival, median (95 % CI)

6.6 (6.1–7.1) months

6.1 (5.7–6.5) months

0.09

Toxicity

A total of 168 cycles of treatment were administered in this study. At the time of the final analysis, all patients had discontinued study treatment. The most common reason for discontinuation was disease progression, and only one patient in the immuno-CT group refused the treatment during the third cycle. Hematological toxicity was mild, including leukocytopenia, neutropenia, and thrombocytopenia. The incidence of hematological toxicity was not significant between the two groups. Non-hematological toxicities included diarrhea, skin rash, nausea and vomiting, non-infective fever, fatigue, stomatitis, chest distress, and total bilirubin. There were significant differences between the two groups in the incidence of fatigue and non-infective. No grade 4 toxicity or treatment-related death was observed (Table 4).
Table 4

Hematological and non-hematological toxicity

Toxicity

Grade 1–2

Grade 3–4

Immuno-CT group

CT group

Immuno-CT group

CT group

Leukocytopenia

6 (21.4)

7 (23.3)

1 (3.6)

2 (6.7)

Neutropenia

4 (14.3)

4 (13.3)

1 (3.6)

1 (3.3)

Thrombocytopenia

5 (17.8)

7 (23.3)

0

0

Nausea/vomiting

8 (28.6)

10 (33.3)

0

1 (3.3)

Diarrhea

9 (32.1)

8 (26.7)

2 (7.1)

2 (6.7)

Stomatitis

6 (21.4)

6 (20.0)

2 (7.1)

1 (3.3)

Skin rash

3 (10.7)

2 (6.7)

1 (3.6)

0

Fatigue*

7 (25.0)

16 (53.3)

0

1 (3.3)

AST

3 (10.7)

5 (16.7)

0

0

ALT

4 (14.3)

3 (10.0)

0

0

Total bilirubin

3 (10.7)

4 (13.3)

0

0

Creatinine

3 (10.7)

2 (6.7)

0

0

Chest distress

3 (10.7)

0

0

0

Non-infective fever*

9 (32.1)

1 (3.3)

0

0

* Fatigue p = 0.045, * Non-infective fever p = 0.004 (Grade 1–2)

Discussion

Pancreatic cancer is a malignant disease with poor prognosis. Approximately half of the patients with gemcitabine-pretreated disease may be candidates for further treatment [17]. A number of second-line treatment regimens have been evaluated in small phase II studies in mPC, and the median survival is typically long in patients with the best supportive care [18]. However, no standard regimen has been established so far.

S-1 is a fourth-generation oral fluoropyrimidine. The efficacy and toxicity of S-1 plus cisplatin as a second-line palliative chemotherapy for gemcitabine-refractory pancreatic cancer patients have been examined. The median time to progression was 44 days (95 % CI 25.4–62.6), and the median overall survival was 81 days (95 % CI 9.3–152.7) [19]. While in a phase II study of S-1 in gemcitabine-refractory metastatic pancreatic cancer, the most common adverse reactions were fatigue and anorexia, although most of those adverse reactions were tolerable and reversible. The median PFS was 2.0 months, and the median survival time was 4.5 months with a 1-year survival rate of 14.1 % [20]. The overall response rate to S-1 plus gemcitabine as an outpatient-based regimen in patients with advanced or metastatic pancreatic cancer was 27.3 % (95 % CI 8.7–45.9), and the progressive disease rate was 31.8 %. The median time to progression and overall survival were 4.6 (95 % CI 2–7.2 months) and 8.5 months (95 % CI 6.8–10.1 months), respectively. Grade 3/4 hematological adverse events were neutropenia (9.1 %) and anemia (4.5 %). Non-hematological adverse events were mainly gastrointestinal events [21]. One out of twelve patients with advanced pancreatic carcinoma who received DC vaccination and concomitant chemotherapy developed partial remission, and two patients had stable disease. The median survival was 10.5 months, and no severe side effects were observed [22].

In this study, no statistically significant difference in DCR was observed between the two groups, perhaps because of the case selection bias. Similar results have been obtained in other studies with chemotherapy combined with CIK cell (immuno-CT) treatment. We observed statistically significant differences in PFS, but not OS between the two groups. This was likely because the two groups received different follow-up treatment regimes after the second-line treatment. Most of the patients in the immuno-CT group with a PS score of 2 chose best supportive care; while some patients in the CT group chose oral administration of erlotinib or chemotherapy.

The difference in the number of patients with greater than 25 % increase in CA19-9 serum level was significant between the two groups. Some studies have shown that the CA19-9 serum level is a prognostic factor for inoperable pancreatic cancer [23, 24].A phase II trial of capecitabine combined with thalidomide as second-line treatment of advanced pancreatic cancer has indicated that there is significant difference in PFS between patients with more than 25 % decrease in the CA19-9 serum level and patients with less than 25 % decrease in the CA19-9 serum level [25].

The hematological toxicity was not significantly different, while there were differences in the incidence of fatigue and non-infective fever between the two groups. A retrospective study of S-1 monotherapy as the second-line treatment for advanced pancreatic cancer after gemcitabine failure has shown that the common grade 3/4 toxicities are diarrhea (8 %), anorexia (6 %), fatigue (6 %), anemia (6 %), and leucopenia (4 %) [26]. In studies involving DC-CIK combined with NP treatment, differences are mainly observed in the adverse incidence of fatigue and non-infective fever between the monotherapy group and the combination group [27].While in a study of patients with solid carcinomas with cytokine-induced killer cells treatment, the incidence of fever in the CIK therapy group was significantly higher than that in the non-CIK group (p = 0.02) [28].

In conclusion, S-1 plus CIK was well tolerated in the second-line treatment of GEM-refractory pancreatic cancer patients. Based on its safety profile and clinical activity, S-1 plus CIK merits further investigation in this setting. Limitation of this study includes small sample size, and more evidence-based medicines are needed.

Conflict of interest

No conflicts of interest exist for any author of this paper.

Copyright information

© Springer Science+Business Media New York 2013