Modified DCF (mDCF) regimen seems to be as

Modified DCF (mDCF) regimen seems to be as effective as original DCF in advanced gastric cancer (AGC) S. Keskin, I. Yıldız, F. Sen, F. Aydogan, L. Kilic, M. Ekenel, S. Saglam, B. Sakar, R. Disci & F. Aykan Clinical and Translational Oncology ISSN 1699-048X Clin Transl Oncol DOI 10.1007/s12094-012-0942-8

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Author's personal copy Clin Transl Oncol DOI 10.1007/s12094-012-0942-8

RESEARCH ARTICLE

Modified DCF (mDCF) regimen seems to be as effective as original DCF in advanced gastric cancer (AGC) S. Keskin • I. Yıldız • F. Sen • F. Aydogan • L. Kilic • M. Ekenel S. Saglam • B. Sakar • R. Disci • F. Aykan

•

Received: 20 July 2012 / Accepted: 5 September 2012 Ó Federacioń de Sociedades Espanõlas de Oncologıá (FESEO) 2012

Abstract Purpose The aim of this retrospective study (from January 2007 to December 2011) was to investigate the efficacy and tolerability of mDCF schedule for chemotherapy-naı¨ve AGC patients. Patients Patients (n = 54) with locally inoperable or distant metastasis and performance status of 0–2 were eligible. The triplet combination chemotherapy consisting of docetaxel 60 mg/m2 on day 1, cisplatin 60 mg/m2 on day 1, and 5-fluorouracil 600 mg/m2 for 5 days of continuous infusion were administered every 21 days, up to nine cycles. Prophylactic G-CSF was not allowed. Results In all, 36 (67 %) patients were male and 18 (33 %) were female; median age was 59 years. The majority of patients (n = 46, 85 %) had metastatic disease and 8 (15 %) of them had locally advanced disease. Liver metastasis and peritonitis carcinomatosa were found in 20 (43 %) and 18 (39 %) of the 46 cases, respectively. The median cycle of chemotherapy was 6. In assessing

50 patients for response evaluation, one had complete response. Partial response was achieved in 27 (54 %) patients. Seventeen patients (34 %) had stable disease and 5 (10 %) had progressive disease, while 4 % (n = 2) and 11 % (n = 6) of the patients developed severe (grade 3–4) neutropenia and anemia, respectively. During the median follow-up time (6.9 months, range 0.4–24), 28 (52 %) patients died. The overall and progression-free survival were 10.7 [95 % CI 8.9–12.4] and 6.8 [95 % CI 5.8–7.8] months, respectively. Conclusions Although this was not a prospective comparative study, the mDCF regimen seems to be as effective as the original DCF in AGC with acceptable and manageable side effects.

S. Keskin (&) I. Yıldız F. Sen F. Aydogan L. Kilic M. Ekenel B. Sakar F. Aykan Department of Medical Oncology, Institute of Oncology, University of Istanbul, Capa, 34093 Istanbul, Turkey e-mail: [email protected]

B. Sakar e-mail: [email protected]

I. Yıldız e-mail: [email protected]

S. Saglam Department of Medical Oncology, Istanbul Bilim University, Istanbul, Turkey e-mail: [email protected]

F. Sen e-mail: [email protected] F. Aydogan e-mail: [email protected] L. Kilic e-mail: [email protected]

Keywords Modified DCF Advanced gastric cancer Efficacy Adverse effect Survival

F. Aykan e-mail: [email protected]

R. Disci Department of Public Health, Faculty of Medicine, University of Istanbul, Istanbul, Turkey e-mail: [email protected]

M. Ekenel e-mail: [email protected]

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Author's personal copy Clin Transl Oncol

Introduction Gastric carcinoma is the fourth most common malignancy worldwide and it is the second most common cause of death [1, 2]. Incidence rates (per 100,000) vary from 10.9 in men and 5.0 in women in the USA to 65.9 in men and 25.9 in women in Korea [3]. Most patients diagnosed with gastric cancer present with advanced stages of disease, because early symptoms are often nonspecific. Approximately, 50 % of the patients are diagnosed with unresectable disease [4–6]. Once metastatic, gastric or gastroesophageal carcinoma is incurable and the patient’s life span is short, usually less than 1 year [1, 3–5]. The benefits of palliative chemotherapy over best supportive care (BSC) in the treatment of advanced gastric cancer have been demonstrated in randomized controlled trials [7, 8]. For patients considered suitable for systemic treatment, palliative chemotherapy improves median survival from 3 to 4 months, and with BSC alone to 7–10 months. Many chemotherapy agents have efficacy in the treatment of advanced gastric cancer, and it is recognized that combination therapy is superior to singleagent therapy. However, optimal first-line combination chemotherapy is still controversial and, based on the results of randomized phase III trials, different options are possible. Among the new-generation agents, docetaxel has demonstrated promising activity in gastric cancer, both as monotherapy and in combination with other agents [1, 4, 6, 9]. To date, docetaxel combinations, especially the docetaxel/cisplatin/5-fluorouracil (DCF) regimen, seem to be pivotal and, further, a taxane has been suggested to be the best potential partner of 5-fluorouracil (5-FU) and cisplatin [1, 9]. However, the main limitations of docetaxel containing regimens were toxicity profiles. In some of the studies, incidence rate of grade 3–4 neutropenia and gastrointestinal toxicities reached up to 82 and 49 %, respectively [10]. The purpose of this study was to investigate the efficacy and tolerability of a modified DCF regimen in patients with chemotherapy-naive AGC.

Patients and methods We retrospectively examined the records of 54 gastric cancer patients diagnosed between January 2007 and December 2011. The study protocol was approved by the University of Istanbul, Institute of Oncology Ethics Committee. All of the patients had histologically confirmed gastric cancer. Clinical records were reviewed and the patients’ age, gender, histology, disease stage, survival, and

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treatment details for recurrences and adverse effects were recorded. Treatment The patients received docetaxel (60 mg/m2) diluted in 500 ml normal saline as a 60 min intravenous infusion. Cisplatin (60 mg/m2) diluted in 1,000 ml normal saline was then intravenously infused for a period of 60 min. Finally, 5-FU (600 mg/m2) was intravenously infused for 5 days. Immediately after the completion of infusions, flushing was performed with 500 ml of normal saline over 30 min to prevent phlebitis. These drugs were repeated every 3 weeks. The next course of chemotherapy was started if the following criteria were met: neutrophil [1,500 mm-3, platelets count [100,000 mm-3, levels of serum AST and ALT \3 times the upper limit of normal, ECOG PS 0–2, and being afebrile. In the event of grade 3–4 neutropenia or thrombocytopenia and non-hematologic grade 3–4 toxicities, the doses of all three drugs were reduced by 20 % in the next course of chemotherapy. None of the patients were treated with radiotherapy. Concomitant therapy Dexamethasone (16 mg, -1st, 1st, and 2nd day), a 5-HT3 receptor blocker (1st day) and aprepitant (120 mg 1st day, 80 mg 2nd and 3rd day) were given to all patients before the initiation of chemotherapy as an antiemetic prophylaxis. Patients received full supportive care as needed, transfusions of blood and blood products, and antibiotics. Hematopoietic growth factors were not administered prophylactically. Response and toxicity evaluation Tumor response was classified by the standard Response Evaluation Criteria in Solid Tumors version 1.1. A complete response (CR) was defined as the complete disappearance of all clinically detectable tumors for at least 4 weeks. A partial response (PR) was defined as an at least 30 % decrease in the sum of the longest diameters of the target lesions for more than 4 weeks with no new area of malignant disease. Progressive disease (PD) indicated at least a 20 % increase in the sum of the longest diameter of target lesions or a new malignant lesion. Stable disease (SD) was defined as insufficient shrinkage to qualify for PR and insufficient increase to qualify for PD. Toxicity evaluations were performed based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0.


Follow-up After the completion of therapy, the patients were followed-up every 3 months. Disease progression and occurrence of new disease were examined using physical examination, carbohydrate antigen 19-9, carcinoembryonic antigen, chest radiography, and abdominal ultrasonography. Computed tomography (CT) or magnetic resonance imagings (MRI) were performed if clinically indicated.

Table 1 Patient characteristics (n = 54) Characteristics

Number of patients

%

Male

36

67

Female

18

33

Sex

Age (years) Median

59

Range

23–80

PS status

Statistics Age and duration of follow-up time, etc. are expressed as median and range. The Chi-square test and Mann–Whitney U test were used to compare groups. Progression-free survival (PFS) was defined as the time from the start of chemotherapy to disease recurrence or the last follow-up. Patients who died before disease recurrence were excluded from the analysis of PFS. Overall survival (OS) was defined as the time from the start of chemotherapy to death from any cause or to the last follow-up. OS and PFS were calculated via the Kaplan–Meier method. All analyses were performed using SPSS version 15.0 (Chicago, IL, USA), and p \ 0.05 was considered statistically significant.

Results In total, 54 patients were diagnosed with AGC at Istanbul University, Institute of Oncology between January 2007 and December 2011. The median age of the 36 (67 %) male and 18 (33 %) female patients was 59 years (range 23–80 years) (Table 1). In all, 46 patients (85 %) had metastatic disease and 8 (15 %) locally advanced disease. Among the metastatic patients, 20 (43 %) had liver metastasis, 18 (39 %) had peritonitis carcinomatosa, 4 (9 %) had Krukenberg tumor, 2 (4 %) had lung and liver metastasis, 1 (2 %) had lung metastasis, and 1 (2 %) had bone metastasis. Treatment compliance and toxicity Hematological toxicity was found as the principal doselimiting toxicity. Grade 3–4 neutropenia occurred in 4 % (n = 2) of the patients. One (2 %) of the patients experienced febrile neutropenia (FN). Two patients required G-CSF usage due to grade 3–4 neutropenia. Six patients (11 %) had grade 3–4 anemia. However, due to symptomatic anemia, three patients received a total of 10 units of packed red blood cells. Grade 3–4 thrombocytopenia was not observed. Grade 3–4 nausea and vomiting occurred in eight (15 %) patients. Mild or moderate increase of the serum levels of creatinine was observed in two patients. One

0

38

70

1

12

22

2

4

8

46

85

8

15

Liver

20

43

Peritonitis carcinomatosa

18

39

Krukenberg tumor

4

9

Lung and liver

2

4

Lung

1

2

Bone

1

2

Stage Metastatic Locally advanced Site of distant metastasis (n = 46)

patient developed grade 3 diarrhea and one patient developed upper gastrointestinal bleeding during chemotherapy. A total of 303 courses of chemotherapy were administered. The median number of treatment courses was 6 (range 1–9). The dose of chemotherapy was reduced at least once in 5 of 54 patients (9 %). Treatment was discontinued in 4 (7 %) and 4 (7 %) patients due to intolerance and disease progression, respectively. Response Four patients (7 %) had unknown response due to discontinuation of treatment before the response evaluation; totally 50 patients were assessed for response. One (2 %) of the patients had complete response and 27 (54 %) patients had partial response. Seventeen patients (34 %) had stable disease, while 5 patients (10 %) had progressive disease during chemotherapy. Survival At a median follow-up of 6.9 months (range 0.4–24 months), 26 patients (48 %) were alive with disease, while 28 patients (52 %) died. Mortality was associated with disease progression. The overall and progression-free survival were 10.7 [95 % CI 8.9–2.4] and 6.8 [95 % CI 5.8–7.8] months, respectively. The 1-year OS was 41.2 % and the 1-year PFS was 16.2 %. The survival curves are shown in Fig. 1.

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Fig. 1 Survival analysis

Discussion Advanced gastric cancer is a frequent malignant tumor with poor prognosis. The mainstay of treatment for AGC is chemotherapy. There are many agents including fluoropyrimidines, platinum agents, anthracyclines, irinotecan, and taxanes for the treatment of AGC. However, at present, there is no ‘standard’ chemotherapy regimen generally

accepted. Regimens containing 5-FU and cisplatin have been the most commonly used chemotherapy choices with reported response rates of 25–32 % and a median overall survival of 8.6–9.3 months [10, 11]. Docetaxel is an active agent for AGC. Docetaxel can incorporate many chemotherapy agents including cisplatin, oxaliplatin, 5-FU, capecitabine and S-1. The pivotal phase III V325 multinational trial evaluated the role of DCF regimen in patients with AGC [10]. At a median follow-up, the median TTP and OS were 5.6 and 9.2 months, respectively. The overall confirmed response rate was 37 %. On the other hand, all patients on DCF experienced at least one treatment-emergent adverse event. Despite enrolling a young population (median age 55 years) with good functional status (ECOG PS of 0-1), treatment related grade 3 or 4 treatment-emergent adverse events occurred in 69 % of patients. Grade 3–4 neutropenia, FN and diarrhea were seen in 82, 29 and 19 % of the patients, respectively. In the V325 phase III study, granulocyte–macrophage colony-stimulating factor (G-CSF) was used only as secondary prophylaxis once evidence of complicated neutropenia had been established [10]. In the DCF arm, complicated neutropenia was 29 % without and 12 % with the use of secondary G-CSF prophylaxis. In three phase II

Table 2 Outcomes of studies of DCF combinations Docetaxelc

n

Cisplatinc

5-FUc

Interval

RR (%)

G-CSF

Grade 3–4 toxicities (%) Np

Anemia

Tp

FN (%)

OS

PFS

221

III

75, d1

75, d1

750, d1–5

q3w

37

No

82

18

8

29

9.2

5.6

Ajani et al. [20]

79

II

75, d1

75, d1

750, d1–5

q3w

43

No

86

29

12

27

9.6

5.9

Ben Aharon et al. [21]

23

R

75, d1

75, d1

750, d1–5

q3w

59

No

78

13

4

22

12.8

10

Roth et al. [12]

41

II

75, d1

75, d1

300, d1–14

q3w

37

Yes

80

NR

3

41

10.4

4.6

Park et al. [22]

47

II

50, d1

80, d1

1,200, d1–5

q3w

40

No

68

34

0

26

9.7

4.6

Tomasello et al. [13]b

32

II

85, d1

75, d1

600, d1–2

q2w

56

Yes

53

16

34

22

10.1

9.1

Oh et al. [23]

43

II

70, d1

40, d2,3

1,200, d1–3

q3w

43

No

NR

0.6

0

9

5.6

30

II

75, d1

75, d1

750, d1–5

q3w

34

Yes

40

NR

NR

17

12.6

NR

30

II

40, d1

40, d3

1,000, d1–2

q2w

52

No

39

NR

NR

6

15.1

NR

Inal et al. [19] Inal et al. [19]

85 22

R R

75, d1 60, d1

75, d1 60, d1

750, d1–5 600, d1–5

q3w q3w

46 47

No No

48 14

21 5

26 9

19 4.5

9.9 8.6

7.4 6.5

Tebbutt et al. [24]a

50

II

30, d1,8

60, d1

200, d1–21

q3w

47

No

10

NR

0

6

11.2

5.9

Piacentini et al. [16]

27

R

35, d1

25, d1

180, d1–7

q1w

33

No

15

7

0

7

10.7

6.4

Overman et al. [17]a

95

R

20, d1

20, d1

350, d1

q1w

34

No

4

9

0

0

8.9

4.1

Van Custem et al. [10]

Shah et al. [14]

a

Shah et al. [14]a,

b

4.7

Kos et al. [18]

40

R

60, d1

60, d1

600, d1–5

q3w

30

No

7.5

5

0

5

8.7

6.2

Current study

54

R

60, d1

60, d1

600, d1–5

q3w

56

No

4

11

0

2

10.7

6.8

RR response rate (complete ? partial), R retrospective, Np neutropenia, Tp thrombocytopenia, FN febrile neutropenia The study also included patients with esophageal cancer

a

b

Folinic acid and bolus 5-FU were added to this regimen

c

mg/m2

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trials in which prophylactic G-CSF was administered, grade 3–4 neutropenia was observed in 80, 53 and 40 % of the patients, and FN was observed in 41, 22 and 17 % of the patients [12–14]. Although DCF has become a new reference regimen for the treatment of AGC, research is already underway to further improve its efficacy and tolerability. Several variations of DCF have either been reported or are currently under investigation, with different administration schedules and alternative platinum and fluoropyrimidine components (Table 2). The weekly administration of DCF appears to be well tolerated, with limited hematologic toxicities. In a phase I trial in 21 patients with AGC, patients received a weekly regimen of docetaxel 33.3 mg/m2, cisplatin 30 mg/m2 and dose-escalating 5-FU starting at 1,000 mg/m2 for three consecutive weeks every 4 weeks. Grade 3–4 hematologic and non-hematologic toxicity occurred in less than 10 % of the patients [15]. Recently, weekly DCF was studied in patients with AGC by Piacentini et al. [16]. This study enrolled 27 patients and demonstrated an ORR of 33 %, median PFS of 6.4 months, and median OS of 10.7 months. Grade 3–4 FN, neutropenia, and anemia occurred in 7, 15, and 7 % of the patients, respectively. In another weekly DCF study, none of the patients experienced FN [17]. In two retrospective studies from Turkey other then this one, Kos et al. and Inal et al. [18, 19] evaluated the role of modified docetaxel, cisplatin, and 5-FU regimen at the doses of 60 mg/m2, 60 mg/m2, and 600 mg/m2, respectively. Kos et al. [18] compared the efficacy and toxicity of cisplatin/5-FU/folinic acid (CFF) and mDCF regimens in the first-line treatment of AGC. They found that the objective response rates (complete and partial response) were higher in the mDCF group (30.0 vs. 13.3 %, p = 0.19). While toxicity was acceptable in both groups, the most common grade 3–4 toxicities were anemia in 3.3 and 5.0 %, neutropenia in 20 and 7.5 %, FN in 6.7 and 5.0 %, and diarrhea in 3.3 and 5.0 % in the CFF and mDCF groups, respectively. Median PFS was 4.4 and 6.2 months (p = 0.85), and median OS was 6.5 and 8.7 months (p = 0.88) in the CFF and mDCF groups, respectively. Inal et al. [19] performed a retrospective comparative analysis which evaluated the efficacy and tolerability of the original DCF regimen and mDCF. They found that grade 3–4 neutropenia (48.2 vs. 13.6 % p = 0.003), anemia (21.2 vs. 4.5 % p = 0.06), nausea (44.7 vs. 13.6 % p = 0.008), and vomiting (31.8 vs. 4.5 %, p = 0.01) were higher in the original DCF arm. However, the rate of response was similar in both arms. Among patients with the original DCF and mDCF arm, the rate of overall response (46 vs. 47 %), median PFS (7.4 vs. 6.5 months), and median OS (9.9 vs. 8.6 months) did not show statistically significant

difference. Despite the same schedules used in the present study as in Kos et al. and Inal et al., response rate and survival were more favorable in our study. This may be because more patients had poor performance status in Kos et al. and Inal et al. studies. In conclusion, various modified weekly, 2-weekly, and low-dose 3-weekly DCF regimens are promising without lack of effectiveness. Modified DCF is an active treatment alternative with high efficacy in terms of tumor response rate, PFS, and OS. In our opinion, modified DCF should represent a valid treatment option in AGC and a platform for future regimens. Conflict of interest of interest.

The authors declare that there are no conflicts

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