Surgery Today

, Volume 43, Issue 1, pp 33–39

Portal vein infusion chemotherapy with gemcitabine after surgery for pancreatic cancer

Authors

  • Chi-e Kitami
    • Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental Sciences
    • Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental Sciences
  • Yasuyuki Kawachi
    • Department of SurgeryNagaoka Chuo General Hospital
  • Koei Nihei
    • Department of SurgeryTsuruoka Municipal Shonai Hospital
  • Yoshiaki Tsuchiya
    • Department of SurgeryNiigata Cancer Center Niigata Hospital
  • Tatsuya Nomura
    • Department of SurgeryNiigata Cancer Center Niigata Hospital
  • Masahiro Minagawa
    • Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental Sciences
  • Kabuto Takano
    • Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental Sciences
  • Katsuyoshi Hatakeyama
    • Division of Digestive and General SurgeryNiigata University Graduate School of Medical and Dental Sciences
  • Niigata study group of pancreatic cancer
Original Article

DOI: 10.1007/s00595-012-0179-8

Cite this article as:
Kitami, C., Kurosaki, I., Kawachi, Y. et al. Surg Today (2013) 43: 33. doi:10.1007/s00595-012-0179-8
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Abstract

Purposes

Pancreatic cancer still has a poor prognosis even after curative resection because of the high incidence of postoperative liver metastasis. This study prospectively evaluated the feasibility and tolerability of portal vein infusion chemotherapy of gemcitabine (PVIG) as an adjuvant setting after pancreatic resection.

Methods

Thirteen patients enrolled in this study received postoperative chemotherapy with PVIG. The patients received intermittent administration of gemcitabine (800 mg/m2) via the portal vein on days 1, 8, and 15 after surgery. The tolerability and the toxicity of PVIG were closely monitored.

Results

The PVIG was started on an average of 3.1 days after surgery. Complete doses of chemotherapy (three sessions of portal infusion) were accomplished in 11 of the 13 patients. Grade 3 or 4 leukocytopenia was observed in three patients (23 %), and liver dysfunction was found in one patient (7.7 %). Grade 2 sepsis developed in two cases due to bloodstream infection. Liver metastasis was the first site of recurrence in only two patients.

Conclusions

PVIG can be administered to the liver with acceptable toxicity, but myelosuppression is similar to the systemic use of gemcitabine. Careful observation is required even for locoregional chemotherapy.

Keywords

Portal vein infusion chemotherapyGemcitabineAdjuvant chemotherapyPancreatic cancerLiver metastasis

Introduction

Hepatic recurrence is one of the major causes of treatment failure after curative resection of pancreatic cancer. Minute or occult liver metastasis may have already formed at the time of surgery and may not be detected by standard imaging modalities [1]. Liver perfusion chemotherapy is aimed at the eradication of these potential liver metastases. Double-route liver perfusion chemotherapy via both the hepatic artery and portal vein was designed as postoperative adjuvant chemotherapy by Ishikawa et al. [2] in 1994. Double-route liver perfusion chemotherapy with 5FU produces remarkable reduction of the incidence of liver metastasis and improves the overall survival time; only 8 % died from hepatic recurrence 3 years after surgery in the treated group in comparison to 32–34 % in the non-treated historical control [3]. Furthermore, the present multicenter prospective study demonstrates that liver perfusion chemotherapy could be performed safely even after aggressive pancreatectomy [4]. However, liver perfusion chemotherapy is not widely accepted as common adjuvant chemotherapy. In pancreatic surgery, the pancreatic fistula occasionally causes secondary serious conditions, including abscess formation, erosion of the hepatic artery, arterial hemorrhage, etc. The possible risks related to pancreatic anastomosis may have made our surgeon hesitate to perform locoregional chemotherapy through the hepatic artery, especially early after surgery. In contrast, the cannulation into the portal vein can be performed without any technical difficulty and the tubes placed into portal vein can be removed when postoperative complications occur. [4] On the other hand, the systemic administration of gemcitabine is widely accepted as a first-line chemotherapy for pancreatic cancer, but the intraportal administration of gemcitabine has not yet been studied in detail.

Therefore, the present pilot study was conducted to investigate the feasibility and tolerability of the intraportal infusion of gemcitabine early after pancreaticoduodenectomy as a locoregional chemotherapy for the prevention of hepatic recurrence.

Materials and methods

Eligibility criteria

Thirteen patients from 5 institutions were enrolled in this study from September 2008 to June 2009. The eligibility criteria were: an age of less than 80 years with histologically proven ductal carcinoma of pancreas, no severe major organ dysfunction, and the performances status of 0–1 (World Health Organization). Radiological imaging indicated tumors for which margin-negative surgery could be performed. Patients were excluded if they had pretreatment with any chemotherapy or radiation therapy.

Written informed consent for the study protocol was obtained from 15 patients who fulfilled the eligibility criteria, but 2 of the 15 patients were not included because one was diagnosed with an endocrine tumor by frozen section, and another had dislocation of the catheter. This study was approved by the review board of each institution. Final microscopic staging of the tumor was determined by the International Union Against Cancer Tumor, Node, and Metastasis (TNM) staging system.

Calculation of the liver volume

A volumetric study was performed in all patients using CT scans. Each slice of the liver was traced with a cursor and the corresponding area was calculated. The whole liver volume was calculated by multiplying the area of each part by the interval thickness. The correlation between the grade of the adverse effects of liver dysfunction and the liver volume was evaluated.

Catheterization technique and chemotherapy schedule

A 16-gauge plastic catheter was inserted into one of the tributaries of the middle colic vein, and the catheter tip was placed in the portal vein. The catheter was fixed using elastic ligature and removed after the completion of PVIG. The PVIG was initiated as soon as possible after surgery. The criteria for starting PVIG were WBC > 3000/mm2, serum levels of AST and ALT > 5.0 × ULN, platelet count > 10 × 104/mm2, serum levels of total bilirubin <3.0 mg/dl, and no septic condition. The administration of PVIG was postponed if the patient developed high fever of more than 38 °C, septic conditions, or abnormality of liver function test, until the status was improved. A dose of gemcitabine, 800 mg/m2, was administered on days 1, 8, and 15. The patients received 500 mL of saline with 2000 IU heparin through the PVI route with an infusion pump for 24 h during the period of non-infusion of gemcitabine. The drug was dissolved in 100 ml of saline and given for 30 min after pretreatment with antiemetic drugs (5-hydroxytryptamine 3 receptor antagonists). The dosage of gemcitabine was reduced to 600 mg/m2 when grade 3 toxicity was observed. All patients were closely monitored for adverse effects and toxicity during the follow-up period. Complications related to chemotherapy were evaluated according to the toxicity criteria set out by the World Health Organization. The treatment was discontinued when: (1) objective disease progression was observed, (2) the patient’s general condition became worse because of adverse effects or rapid progression of the disease, and (3) patients withdrew their previous consent.

The systemic administration of 800–1000 mg/m2 gemcitabine was administered for approximately 1 year after hospital discharge. This systemic chemotherapy was left to the surgeon’s discretion and was not included in the protocol of this study. Tumor markers including carcinoembryonic antigen and CA19-9 were tested every 1–2 months. Objective tumor recurrence was estimated by chest X-ray, abdominal ultrasound, and computed tomography (CT). In addition, abdominal CT was performed every 4 months. These imaging examinations were conducted more frequently if necessary.

Results

Clinical course of patients

The preoperative, intraoperative, and postoperative findings are shown in Tables 1 and 2. The 13 patients included 10 males and 3 females with a mean age of 66.5 years. Ten pylorus-preserving pancreaticoduodenectomy, two pancreaticoduodenectomy, and one total pancreatectomy were performed with a mean operation time of 407 (SD 82) min and a mean blood loss of 689 (246) ml. Seven patients underwent combined resection of the portal vein. Intraoperative Doppler ultrasonography was used to evaluate the portal vein flow velocities. The seven patients that underwent portal vein resection showed no problems related to the portal vein reconstruction after surgery. Postoperative complications occurred in three patients (23 %). Intra-abdominal abscess and delayed gastric emptying was observed in one patient, and two patients experienced enteritis. One patient that was receiving anticoagulant therapy had an intraperitoneal abscess due to oozing after surgery, and underwent percutaneous drainage. No pancreatic fistulas were found, and no mortality or life-threatening complications related to the surgery were observed. Ten of the thirteen patients received systemic chemotherapy with gemcitabine after PVIG therapy.
Table 1

Patient characteristics

Case No.

Age/sex

Jaundice

Biliary drainage

BSA (m2)

Estimated liver volume (ml)

Chemotherapy start (POD)

1

52/M

Yes

ERBD

1.77

1400

1

2

70/F

Yes

PTCD

1.44

900

7

3

57/F

Yes

PTGBD

1.34

1090

6

4

76/M

No

Non

1.31

841

4

5

76/F

No

Non

1.48

913

1

6

72/M

Yes

PTCD

1.37

904

1

7

69/M

No

Non

1.63

1215

4

8

59/M

Yes

ENBD

1.66

1397

3

9

78/M

No

Non

1.54

896

2

10

76/M

No

ENBD

1.46

1100

5

11

55/M

No

Non

1.85

1891

1

12

58/M

No

ENBD

1.8

1309

3

13

69/M

Yes

ERBD

1.27

950

3

PTCD percutaneous transhepatic cholangio drainage, PTGBD percutaneous transhepatic gall bladder drainage, ENBD endoscopic nasobiliary drainage, ERBD endoscopic retrograde bile duct drainage, BSA body surface area, POD post operative day

Table 2

The surgical and pathological findings and outcome of 13 patients

Case no.

Operation

Portal vein resection

Postoperative complication

T

n

pStage

Curability

Outcome

1

PPPD

No

Non

3

0

IIA

R0

289 days

A

DF

2

PPPD

Yes

Non

3

1

IIB

R0

102 days

D*

 

3

PPPD

Yes

DGE, enteritis

3

1

IIB

R0

294 days

A

DF

4

PPPD

No

Non

3

1

IIB

R0

66 days

D*

 

5

PPPD

Yes

Non

3

0

IIA

R0

533 days

A

DF

6

PPPD

Yes

Non

3

1

IIB

R1(DPM)

275 days

D

Liver

7

PD

No

Non

3

1

IIB

R0

422 days

A

DF

8

PPPD

Yes

Non

3

1

IIB

R0

351 days

D

Liver

9

PPPD

No

Intra-abdominal abscess

3

1

IIB

R1(CY1)

228 days

D

Peritoneum, Liver

10

TP

No

Non

3

1(M1LYN)

IV

R1(M1)

393 days

D

Lung

11

PPPD

No

Non

2

0

IB

R0

550 days

A

DF

12

PD

Yes

Non

3

1

IIB

R0

270 days

A

DF

13

PPPD

Yes

Enteritis

3

1

IIB

R0

264 days

A

DF

PPPD pylorus preserving pancreaticoduodenectomy, PD pancreaticoduodenectomy, TP total pancreatectomy, DGE delayed gastric emptying, A alive, D dead, DF disease free, D* dead without recurrence

Toxicity and feasibility of chemotherapy

PVIG was started within 7 days after surgery in all patients, with a mean of 3.1 days. Complete doses of PVIG were accomplished in 11 of the 13 patients (84.6 %). The third course of PVIG (15th day after surgery) was not administered in two patients, because catheter-related sepsis was suspected. Both of those patients had severe diabetes mellitus. The intraportal catheter was removed and methicillin-resistant Staphylococcus aureus was detected from the culture test of the catheter tip placed in the portal vein. Table 3 shows that grade 4 leukocytopenia was observed in one patient (7.7 %), grade 3 leukocytopenia in two patients (15.4 %), and grade 3 liver dysfunction in only one patient (7.7 %) after the first administration of gemcitabine. The levels of AST and ALT were promptly normalized, and the second session of gemcitabine was given without liver dysfunction. This patient had not undergone biliary decompression for obstructive jaundice and showed severe fatty change of the liver preoperatively. Grade 3 nausea/vomiting was observed in two patients (15.3 %), anorexia in five (28.4 %), high fever over 38 °C in three (23 %) at the first administration of gemcitabine, and grade 3 fever in one (7.7 %). The course of the WBC count and the levels of AST/ALT are shown in Fig. 1. The third course of PVIG was delayed in three patients because of grade 4 leukocytopenia or Grade 3 liver dysfunction. The correlation between the liver volume and the grade of liver dysfunction is shown in Fig. 2. The liver volume of the patient with grade 3 liver dysfunction was estimated to be 1215 ml and the standard liver volume was calculated to be 1153 ml. Patients with a small liver volume tended to have a high grade of adverse effects, but there was no significant correlation between the liver volume and the grade of adverse effects.
https://static-content.springer.com/image/art%3A10.1007%2Fs00595-012-0179-8/MediaObjects/595_2012_179_Fig1_HTML.gif
Fig. 1

The course of the WBC count (a), and AST/ALT (b, c). GEM① the 1st course of gemcitabine, GEM② the 2nd course of gemcitabine, GEM③ the 3rd course of gemcitabine. Opentriangles the delay of the 2nd and 3rd course of gemcitabine in the case with grade 3 of liver dysfunction

https://static-content.springer.com/image/art%3A10.1007%2Fs00595-012-0179-8/MediaObjects/595_2012_179_Fig2_HTML.gif
Fig. 2

The correlation between liver volume and the grade of liver dysfunction [opensquares, opentriangles the grade of liver function test (AST/ALT)]

Table 3

Adverse effects of the portal vein administration of gemcitabine

Toxicity

Grade 1 (%)

Grade 2 (%)

Grade 3 (%)

Grade 4 (%)

Hematologic

 Leukocytopenia

4 (30.7)

7 (53.8)

1 (7.7)

1 (7.7)

 Anemia

7 (53.8)

6 (46.5)

0

0

 Thrombocytopenia

10 (76.9)

1 (7.7)

0

0

 Liver function test (AST/ALT)

7 (53.8)

3 (23)

1 (7.7)

0

Non-hematologic

 Nausea and vomiting

1 (7.7)

3 (23)

2 (15.4)

0

 Fatigue

5 (38.5)

1 (7.7)

0

0

 Anorexia

1 (7.7)

0

5 (38.5)

0

 Fever

1 (7.7)

1 (7.7)

1 (7.7)

0

AST serum aspartate aminotransferase, ALT serum alanine aminotransferase

Tumor pathology

The primary tumors included one pT2 (7.7 %) and 12 pT3 (92.3 %) tumors, with a mean maximal diameter of 3.0 (SD 0.7) cm. Lymph node metastasis was positive in 76.9 % of the patients, including one patient with positive paraaortic nodes. Portal vein invasion was seen in three of the seven patients who underwent portal vein resection. There were three non-curative operations due to a positive surgical margin (1), tumor-positive lavage cytology, and positive paraaortic node metastasis (1).

The treatment results

Four patients (30.7 %) had tumor recurrence during the 16-month (median) follow-up period, and six patients died of recurrent disease (n = 4) or other diseases (n = 2). Three of the four patients with recurrent disease had non-curative factor. Seven patients are alive without recurrence. The initial sites of recurrence were the lung in one patient (7.7 %), liver in two patients (15.3 %), and peritoneum and liver in one patient (7.7 %). Peritoneal dissemination was detected first in one patient, and then liver metastasis developed 2 months later. However, the cause of death in the patient was peritoneal metastasis. Liver metastasis was the first site of recurrence in only two patients. The overall 1-year survival rate was 63 % and the 1-year hepatic recurrence rate was 28 % (n = 3).

Two patients died of clinical conditions unrelated to pancreatic cancer after hospital discharge. One was a 76-year-old male who had pemphigoid, hypertension, and diabetes. He received 10 mg/day prednisolone for about 1 year. He died suddenly in his home, 66 days after surgery. Another was a 70-year-old female who had been re-hospitalized for emaciation and fever about 2 months after surgery. She died of septic shock from a urinary tract infection, 102 days after surgery, and Candida albicans was detected in the blood culture of this patient. Those two patients had received no adjuvant systemic chemotherapy, except for PVIG. They had not visited the hospital for more than a month after hospital discharge. Furthermore, there was no evidence that the administration of PVIG played a role in the patients’ death.

Discussion

Only a few studies have so far been conducted on adjuvant liver perfusion chemotherapy via the portal vein following resection of pancreatic cancer [5, 6]. Nakayama et al. [6] demonstrated that liver perfusion chemotherapy using 5FU via the portal vein was effective in the specific tumor that did not express intratumoral dihydropyrimidine dehydrogenase. On the other hand, gemcitabine has become a first-line chemotherapeutic agent for pancreatic cancer. Ohigashi et al. [7] reported that gemcitabine administration via portal vein therapy causes diminution of the incidence of liver metastasis in comparison to administration of only 5FU via the portal vein. In addition, they performed preoperative full-dose gemcitabine, concurrent radiation, and postoperative liver perfusion chemotherapy for the treatment of pancreatic cancer [7, 8]. The 5-year survival rate was 53 % in 31 patients that received preoperative chemoradiation and surgical resection followed by postoperative liver perfusion chemotherapy [8]. The 31 patients showed a cumulative rate of liver metastasis of 7 %, 5 years after surgery. They stressed that two types of treatment strategies, preoperative chemoradiation for strengthening local control and postoperative liver perfusion chemotherapy for reducing the incidence of liver metastasis, should be combined to improve the long-term outcomes after resection of pancreatic cancer. However, the complication or indications for PVIG after surgery have not been fully investigated.

Gemcitabine is a standard chemotherapeutic agent in a postoperative adjuvant setting. The administration generally starts approximately 4 weeks after surgery. Ottle et al. [9] recommended the start of gemcitabine administration at 2–6 weeks after surgery or after wound healing. In fact, it took a median of 36 days (28–43 days) to begin chemotherapy in their study [9]. JSAP-2, a Japanese study group of adjuvant therapy for pancreatic cancer, set the start of chemotherapy at 3–8 weeks after surgery [10]. Conversely, the infusion of gemcitabine into the portal vein can be given early after surgery. Micro-metastases of the liver are usually formed preoperatively, thus an early start of chemotherapy seems to have potential benefit for patients’ survival.

The major concerns regarding the intraportal administration of gemcitabine are the incidence and the degree of hepatotoxicity. The current study analyzed the relationship between liver volume and the expression of hepatotoxicity. However, serum AST or ALT levels were hardly influenced by the portal infusion of gemcitabine (Fig. 1b, c). Furthermore, there was no relationship between the estimated liver volume and the grade of liver dysfunction (Fig. 2). Gemcitabine hydrochloride, which is an antimetabolite agent, changes to dFdCDP/dFdCTP in the tumor tissue and expresses anti-tumor activity. The excess gemcitabine in the blood and dFdU is excreted in urine. Therefore, hepatocytes with slow cell kinetics appear to be unaffected by the conventional dose of gemcitabine, even when administered intraportally. Conversely, the expression of myelosuppression was similar to that of systemic administration. Leukocytopenia of ≥grade 3 was observed in three patients. Patients frequently develop serious leukocytopenia or thrombocytopenia with the administration of gemcitabine after surgery. However, the incidence or the degree of myelosuppression in the current series cannot be compared with other studies, because gemcitabine is not usually given intravenously within several days after pancreatic resection. In a study of liver perfusion chemotherapy using 5FU, Ishikawa et al. [2] investigated the concentration of 5FU in the portal blood flow. The minimum concentration of 5FU was as high as 0.14 μg/ml in the portal vein, but the maximum concentration of 5FU in the systemic circulation was as low as 0.02 μg/dl [2]. Unlike 5FU, the flow of unchanged gemcitabine into the systemic circulation was greater than expected when it was administered through the portal vein. Onoue et al. [11] reported that the administration of gemcitabine caused more severe leukocytopenia in patients after surgery, in comparison to non-surgical patients. They reported that the recommended dose of gemcitabine was 600 mg/m2 in patients who had undergone surgical resection [11]. The dosage was set as 800 mg/m2 for safety in the pilot study. However, fewer doses of gemcitabine seem to be desirable when it is administered in a postoperative adjuvant setting.

There is the minor risk of portal thrombosis, but intraportal infusion can be easily managed in comparison to intra-arterial administration [4]. The portal infusion of gemcitabine via one route is a simpler technique than the double-route method with continuous infusion of 5FU. However, the occurrence of catheter-related bloodstream infection is similar to the conventional intravenous infusion method. Catheter-related sepsis resulted in the discontinuation of the treatment. Furthermore, though catheter-related infection in liver perfusion chemotherapy has not been reported in the literature [24, 7, 8], it is one of the complications that requires careful observation in postoperative patients with decreased immunity.

Conclusion

PVIG with acceptable toxicity can be administered to the liver, but myelosuppression is similar to the systemic use of gemcitabine. Careful observation is required even for locoregional chemotherapy following surgery. Therefore, this study suggests that PVIG could become one of the components of promising neoadjuvant/adjuvant chemotherapy for pancreatic cancer.

Acknowledgments

The authors are grateful to Manabu Oyamatsu, MD, Sado General Hospital, for his valuable collaboration.

Conflict of interest

None.

Copyright information

© Springer 2012