10.1245/s10434-006-9110-0
Annals of Surgical Oncology 14:190-194 (2007)
© 2007 Society of Surgical Oncology
Clinical Results on Intra-arterial Adjuvant Chemotherapy for Prevention of Liver Metastasis Following Curative Resection of Pancreatic Cancer
Akira Hayashibe, MD1,
Masao Kameyama, MD1,
Masaya Shinbo, MD2 and
Shinichiro Makimoto, MD2
1 Department of Surgery, Bell Land General Hospital, 500-3, Higashiyama, Sakai City, Osaka 5998247, Japan
2 Department of Surgery, Kishiwada Tokushukai Hospital, 4-27-1 Kamori, Kishiwada City, Osaka 596-8522, Japan
Correspondence: Address correspondence and reprint requests to: Akira Hayashibe, MD; E-mail: akirah1{at}hotmail.com
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ABSTRACT
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Background: We report here the clinical results of intra-arterial adjuvant chemotherapy for the prevention of liver metastasis following curative resection of pancreatic carcinoma.
Methods: Twenty-two patients with pancreatic cancer underwent the radical operation between January 1999 and April 2005. Intra-arterial adjuvant chemotherapy with cisplatin (CDDP) and 5-fluorouracil (5FU) was selectively performed on nine patients; the remaining 13 patients did not receive chemotherapy and comprised the control group.
Results: Demographics and clinical characteristics were almost identical in the two groups. Liver metastasis occurred in three of nine patients (33%) in the chemotherapy group and in seven of 13 patients (54%) in the control group. The intra-arterial adjuvant chemotherapy had the tendency to suppress the rate of liver metastasis. The median survival period was 15.8 months for the nine patients who underwent the intra-arterial adjuvant chemotherapy following surgery and 13.4 months for the 13 patients of the control group who were curatively resected without the intra-arterial adjuvant chemotherapy. Cumulative survival rate was improved by the intra-arterial adjuvant chemotherapy.
Conclusions: In patients with pancreatic cancer who underwent the curative operation, the intra-arterial adjuvant chemotherapy had the tendency to suppress the rate of liver metastasis and improve cumulative survival.
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INTRODUCTION
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Despite the recent progress that has been made with respect to diagnostic imaging techniques, the detection of early pancreatic cancer is still difficult, and the majority of pancreatic cancer patients are already in the advanced stages at the time of diagnosis. In addition to the difficulty in making the initial diagnosis of early pancreatic cancer, even if the radical operation can be carried out, the patients cannot be guaranteed long-term survival because of local recurrences and liver metastasis which can occur shortly after surgery. Under present conditions, it would seem that a histologically curative operation and effective chemotherapy for the prevention of early recurrence are very important to improve the prognosis of the pancreatic cancer patients.
We report here for the first time the results of a clinical investigation on intra-arterial adjuvant chemotherapy for the prevention of liver metastasis. In this investigation, we administered cisplatin (CDDP) and 5-fluorouracil (5FU) to patients with pancreatic carcinoma who underwent the radical operation.
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METHODS
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The study cohort consisted of 22 patients with pancreatic cancer who underwent the radical operation between January 1999 and April 2005. There were ten males and 12 females, and the mean age of the patients was 63.3 years (range: 51–76 years). Seventeen of these patients had pancreatic carcinoma of the head, three had pancreatic carcinoma of the head and the body, and two had pancreatic carcinoma of the body and the tail. In all patients, the diagnosis was confirmed by histologic examination. Clinicopathological features of the 22 patients are shown in Table 1
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TABLE 1. Clinicopathological features in patients of the pancreatic cancer who underwent the radical operation between January 1999 and April 2005 (Patient No.1–9: chemotherapy group. Patient No.10–22: control group)
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Following surgery, we performed a series of tests on the patients [blood analyses, (dynamic) contrast-enhanced computerized tomography (CT) imaging, and Ultrasonography] that were repeated every 4 months. All data were analyzed according to the latest versions of the Japanese classification system (JCS).1 A comparison of the principal points in the JCS with those in the Union Internationale Contre le Cancer (UICC) system2 is as follows.
With respect to T category, in the JCS the T factor is a function of nine independent factors, including tumor size (TS), distal bile, duct invasion (CH), duodenal invasion (DU), serosal invasion (S), retro-peritoneal tissue invasion (RP), portal venous system invasion (PV), arterial system invasion (A), extra-pancreatic nerve plexus invasion (PL), and invasion of other organs (OO). These factors are described as present (yes) or absent (no), with the exception of tumor diameter size, which is described as TS1 (
2 cm), TS2 (2.1–4.0cm), TS3 (4.1–6.0cm), TS4 (>6.0 cm).
UICC defines a tumor that invades the celiac or superior mesenteric artery (SMA) as T4 irregardless of portal vein, peripancreatic plexus, or organ invasion, while JCS regards them as T4, independently of celiac or SMA invasion. As for N category, the JCS defines lymph nodes removed in a conventional resection as group 1, and the other lymph nodes are categorized into groups 2 and 3, depending on lymph flow, lymph node metastasis rate. UICC defines lymph node metastasis as N1 irregardless of the distance from the primary tumor. Metastasis of group 3 nodes is considered to be equivalent to distant metastasis.
Lymph node dissection is defined by the D factor as follows: D0, no dissection of group 1 lymph nodes; D1, dissection of group 1 lymph nodes alone; D2, dissection of groups 1 and 2 lymph nodes; D3, dissection of group 1, 2, and 3 lymph nodes. JCS regards group 3 lymph node metastasis (N3) as distant metastasis. Stage classification of the JCS is demonstrated in Fig. 1. According to JCS criteria nine patients had Stage III pancreatic carcinoma according to the JCS, while the remaining 13 patients were diagnosed to have Stage IVa pancreatic carcinoma.
A pancreaticoduodenectomy was performed on 20 patients, while a distal pancreatectomy was carried out on the remaining two patients. Regional lymph nodes were dissected in all patients; these nodes were classified as group 2 according to the JCS. In eight of 22 patients, the portal vein involved in the pancreatic cancer was resected circularly and reconstructed in an end-to-end fashion. The wedge-shaped resection for the inferior vena cava was performed in only one patient.
Intra-arterial adjuvant chemotherapy was selectively administered to nine patients who gave their informed consent. Patients who had hepatic arterial anomaly, renal failure, and postoperative stenosis of the hepatic artery were excluded from the study as were those patients over 75 years of age. The control group (who underwent the resection without adjuvant chemotherapy) consisted of 13 patients. Age, gender, staging of the disease (according to the JCS), resection of the portal vein, postoperative radiotherapy as demographics, and clinical characteristics were compared in the two groups.
Statistical Analysis
Continuous variables were reported as the mean ± standard deviation and compared using Students t-test. Categorical variables were compared using the chi-squared test. A two-sided P value <0.05 was considered to be statistically significant.
Intra-arterial Adjuvant Chemotherapy (into the Properhepatic Artery)
The catheter was placed using Seldinger’s technique into the proper hepatic artery via the right femoral artery 4 weeks after surgery. The catheter was connected to the arterial infuser port which was buried under the skin in the right femoral region. The intra-arterial infusion chemotherapy was started soon after. The protocol of the chemotherapy was as follows: intra-arterial bolus injection of CDDP (10 mg/body) and continuous intra-arterial infusion (for 180 min) of 5FU (500mg/body). We repeated this regimen weekly as much as possible at an outpatient department.
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RESULTS
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Toxicity
There were no local side effects at the site of the arterial infuser port. During the treatment, no severe systemic and/or abdominal complications were observed, but anorexia [grade 1 according to Common Terminology/Criteria for Adverse Events (CTCAE)] occurred in two patients, bone marrow suppression [grade 1 (CTCAE)] occurred in one patient, and epigastric pain [grade 1 (CTCAE>] occurred in one patient.
Demographics and Clinical Characteristics
Demographics and clinical characteristics were almost identical in the two groups with the exception of the resection of the portal vein (Table 2). The chemotherapy group had significantly more patients with resection of the portal vein than the control group. Liver metastasis occurred in three of the nine (33%) in the chemotherapy group and in seven of 13 patients (54%) in the control group (Table 3). The intra-arterial adjuvant chemotherapy had the tendency to suppress the rate of liver metastasis, but there was no difference statistically between the two groups in this respect.
In the chemotherapy group, three of the nine patients died of liver metastasis, and one died of peritoneal seeding. In the control group, seven of the 13 patients died of liver metastasis, two died of peritoneal seeding, and one died of the other disease. The causes of the patient deaths were statistically similar in the two groups (Table 4).
Survival
The Kaplan-Meier regression analysis of the nine patients who underwent intra-arterial adjuvant chemotherapy subsequent to the curative operation revealed that the median survival term was 15.8 months. Comparatively, the Kaplan-Meier regression analysis of the 13 patients who were curatively resected without the intra-arterial adjuvant chemotherapy revealed that the median survival period for these patients was 13.4 months. Consequently, while there was a tendency towards an improvement in the cumulative survival rate in the patients who underwent intra-arterial adjuvant chemotherapy, the difference was not statistically significant (Fig. 2).
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FIG. 2. A comparison of the overall survival rate between the chemotherapy group and the control group (Kaplan-Meier estimates).
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With respect to recurrence-free survival, there was no difference between the chemotherapy group and control group statistically: the chemotherapy group had a mean recurrence-free survival period of 13.3 months; the control group had a mean recurrence-free survival period of 11.3 months) (Fig. 3).
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FIG. 3. The disease-free survival rate between the chemotherapy group and the control group (Kaplan-Meier estimates).
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DISCUSSION
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Morbidity and mortality following any radical operation has declined with modern advances in diagnostics, improved operative techniques for patients with pancreatic cancer, and developments in managing postoperative complications.3–8 However, these advances do not provide satisfactory results with respect to long-term survival in patients with pancreatic cancer who undergo the curative operation. To improve the prognosis of patients who undergo the radical operation for pancreatic cancer, various adjuvant chemotherapy and radiation therapy regimens have been developed for use following the surgical treatment.9–11 To date, post-operative systemic chemotherapy has not been accepted as a standard procedure in patients who undergo the pancreatic resection for pancreatic cancer.12 Postoperative chemoradiation based on systemic chemotherapy with 5-FU was introduced by the GITSG. Its value in treating patients with pancreatic cancer is now recognized.13 With respect to intra-arterial adjuvant chemotherapy, there is currently no evidence demonstrating its beneficial effect on the long-term survival and recurrence rate of liver metastasis of pancreatic cancer patients.
In the present study, the intra-arterial adjuvant chemotherapy regimen could be performed safely as it has been reported that the toxicity or adverse effects of intra-arterial chemotherapy would be extremely low.14 In our study, liver metastasis occurred in three of the nine patients (33%) in the chemotherapy group and in seven of the 13 patients (54%) in the control group. The intra-arterial adjuvant chemotherapy regimen showed a tendency to suppress the rate of liver metastasis. Furthermore, the median survival term was 15.8 months for the nine patients who underwent the intra-arterial adjuvant chemotherapy following surgery in comparison to 13.4 weeks for the 13 patients who were curatively resected without the intra-arterial adjuvant chemotherapy.
This tendency towards an improved cumulative survival rate following intra-arterial adjuvant chemotherapy suggests the possibility that the appropriate intra-arterial adjuvant chemotherapy can suppress liver metastasis and provide long-term survival.
Received for publication May 25, 2006.
Accepted for publication May 25, 2006.
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REFERENCES
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- Yeo CJ, Adams RA, Grochow LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival: a prospective, single-institution experience. Ann Surg 1997; 225:621.[CrossRef][Medline]
- Ishikawa O, Ohigashi H, Yamada T, et al. Adjuvant regional infusion therapy: a two-channel chemotherapy to prevent hepatic metastasis after extended pancreatectomy for adenocarcinoma of the pancreas: The Osaka Experience. Pancreatic Cancer 2002; 23:269–274.
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ABSTRACT
INTRODUCTION
