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10.1245/ASO.2003.10.021
Annals of Surgical Oncology 10:927-934 (2003)
© 2003 Society of Surgical Oncology
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ORIGINAL ARTICLES

Intra-Arterial Infusion Chemotherapy With Angiotensin-II for Locally Advanced and Nonresectable Pancreatic Adenocarcinoma: Further Evaluation and Prognostic Implications

Hiroaki Ohigashi, MD, PhD, Osamu Ishikawa, MD, PhD, Shigekazu Yokayama, MD, PhD, Yo Sasaki, MD, PhD, Terumasa Yamada, MD, PhD, Shingi Imaoka, MD, PhD, Akihiko Nakaizumi, MD, PhD and Hiroyuki Uehara, MD, PhD

From the Departments of Surgery (HO, OI, SY, YS, TY, SI) and Internal Medicine (AN, HU), Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.

Correspondence: Address correspondence and reprint requests to: Hiroaki Ohigashi, MD, Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Nakamichi 1-3-3, Higashinari-ku, Osaka 537-8511, Japan; Fax: 6-6981-8055; E-mail: oohigasi-hi{at}mc.pref.osaka.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: For locally advanced and nonresectable cancer of the pancreas, we performed intra-arterial infusion chemotherapy with angiotensin-II (AT-II). In our preliminary report, this treatment resulted in a median of 14 months of survival without objective adverse effects. This study was designed to clarify the prognostic factor in this chemotherapy by using a larger number of cases.

Methods: For 32 patients, intra-arterial chemotherapy was performed: 1 or 2 catheters were intraoperatively placed into the pancreas-supplying arteries. The tissue blood flow and its change by AT-II infusion were determined. For intra-arterial chemotherapy, a mixture of methotrexate (50 or 100 mg/m2) and AT-II (.4 µg/kg/hour) was repeatedly infused from the catheter, mainly at our outpatient clinic.

Results: With our intra-arterial chemotherapy, the median survival period was 13 months. The median survival period was 19 months in patients without coexisting pancreatitis but was only 9 months in those with it (P = .0003). The presence or absence of coexisting fibrosis in the neighboring uninvolved pancreas offered the only prognostic indicator. The blood flow in cancerous tissue was increased during AT-II infusion, and this was characteristic in the patients whose neighboring uninvolved pancreas had normal parenchyma (nonatrophic) or higher blood flow before AT-II infusion.

Conclusions: Because the AT-II infusion played a role in shifting the blood flow from the surrounding uninvolved pancreas to the cancer tissues, we can speculate that cancer tissues might have thereby received a higher dose of anticancer drugs if the surrounding uninvolved pancreas had been nonfibrotic and more rich in tissue blood flow.

Key Words: Locally advanced pancreatic cancer • Angiotensin-II • Hemodynamic change • Coexisting pancreatitis • Intra-arterial infusion chemotherapy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although surgical resection offers the only curative strategy for adenocarcinoma of the pancreas, the fact remains that most patients are diagnosed at such advanced stages as that they are unsuitable for curative resection. For those with locally advanced and nonresectable cancers of the pancreas, either systemic chemotherapy1–6 or chemoradiation therapy7–9 has been widely performed as the standard treatment. Although many cytotoxic drugs were once expected to be effective against pancreatic cancer cells from their in vitro studies, none of them has succeeded in achieving a drastic improvement in patient survival. In reviewing the previous reports, the median survival period was <=6 months,3–5 which is still shorter than the 8 to 12 months resulting from a combination with radiotherapy.9–11 Although a few authors have treated this cancer by the conventional type of intra-arterial chemotherapy,12–16 their patients’ median survival periods did not exceed 7 months. Adenocarcinoma of the pancreas forms a poorly vascularized tumor,17 and thus, even when a high dose of cytotoxic drug is introduced into either the systemic circulation or the pancreas-supplying arteries, only a small amount of drug actually reaches the cancer tissues. The remainder of the cytotoxic drug might thus be distributed among the noncancerous tissues, increasing the likelihood of adverse effects.

In an attempt to solve this problem, we have treated nonresectable cancers of the pancreas by using an intra-arterial infusion of both cytotoxic drug and vasoactive drug.18 Briefly, one or two catheters were placed into the pancreas-supplying arteries (splenic artery, gastroduodenal artery, or both) during laparotomy, and methotrexate (MTX) was postoperatively infused together with angiotensin-II (AT-II), a potent vasoconstrictor. The use of AT-II was intended to distribute a higher dose of MTX into the cancer tissues but a lower dose into the noncancerous tissues, because it actively constricts the arterioles of the noncancerous tissues but not (or relatively dilates) the tumor-supplying arterioles. In our preliminary report,18 intra-arterial chemotherapy with AT-II resulted in 14 months of median survival (mean ± SD, 16 ± 9 months; range, 5–36 months), which was far better than the reported data, although MTX has not been highly appraised because of its lower sensitivity and response rates when used for systemic administration.

Since then, we have accumulated a larger number of patients who were treated by our intra-arterial infusion chemotherapy with AT-II. This study was designed to (1) clarify whether we can still gain an improved prognosis with a larger number of patients studied and (2) clarify whether any prognostic factors are associated with the hemodynamic alterations presumably caused by AT-II infusion.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Operative Procedure
From 1987 to 1996, 36 patients with locally advanced cancer of the pancreatic head, body, or both underwent laparotomy with a preoperative informed consent to receive either surgical resection or intra-arterial chemotherapy. Although neither hepatic metastasis nor peritoneal seeding had been detected by preoperative imaging diagnosis (computed tomography and ultrasonography) or intraoperative inspection, curative resection was abandoned because their primary pancreatic tumors invaded the retroperitoneal spaces involving not only the portal-superior mesenteric vein but also at least one of the following arteries: celiac artery, superior mesenteric artery, common hepatic artery, or aorta. A histological diagnosis of ductal adenocarcinoma of the pancreas was proven for all patients.

During laparotomy, for patients whose pancreatic tumors involved more areas of the caudal pancreas than of the cranial pancreas, the splenic artery was exposed at the splenic hilum. One catheter was inserted retrogradely into the splenic artery, and the tip of this catheter was introduced as near to the branching point from the celiac artery as possible (Fig. 1). A blue dye (indigo carmine; Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan) was injected into this catheter to determine how the pancreatic tumor was stained. If the cranial part of the tumor was not stained, another catheter was additionally placed into the gastroduodenal artery via the branching point from the common hepatic artery or via the right gastroepiploic artery. The catheter was connected to the reservoir, which was placed in the subcutaneous layer of the abdominal wall. When the tumor involved more areas of the cranial pancreas than of the caudal pancreas, one catheter was placed into the gastroduodenal artery first. If the caudal part of the tumor was not stained by the dye injection, another catheter was additionally placed into the splenic artery.



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  		FIG. 1. Schema of the intraoperative catheterization. During laparotomy, one catheter is placed into either the splenic artery (A.) or the gastroduodenal artery. When a part of the tumor is not stained after dye injection from this catheter, one catheter is placed additionally into another artery. When the tip of catheter is placed into the gastroduodenal artery, it is inserted via the branching point from the common hepatic artery or via the right gastroepiploic artery.

 
Choledochojejunostomy was then performed for patients with bile duct obstruction, and gastrojejunostomy was performed for patients whose duodenal wall was involved by cancer invasion. The uninvolved area of the pancreas occasionally had fibrotic changes (coexisting pancreatitis) and had lost its lobular pattern. Thus, the cancer-free area was macroscopically classified according to whether there was coexisting pancreatitis or not. In addition, for selected patients, the blood flow in the pancreatic cancer tissue was measured by using the hydrogen gas clearance method.19 Briefly, a needle type of electrode was inserted into the cancer tissue and connected to the monitor of the hydrogen-ionization equipment (Unique Medical Co., Tokyo, Japan). After hydrogen gas inhalation, the washout speed of the hydrogen gas was monitored and compared between before and during the injection of AT-II (5 µg/min) via the catheters.

Postoperative Treatments and Follow-Up
Intra-arterial infusion was repeated mainly at our outpatient clinic, weekly or biweekly. While the patient was lying on the bed, a thin needle was punctured into the reservoir placed in the subcutaneous layer of the abdominal wall. Then, a mixture of MTX (50 mg/m2; Lederle Co. Ltd., Tokyo, Japan) and AT-II (10 µg) dissolved in 20 mL of physiologic saline was infused continuously within 30 minutes by using an infusion pump (Syringe Pump; Terumo Co. Ltd., Tokyo, Japan). When the infusion was finished, the inner lumen of the catheter and reservoir were filled with heparin solution (1000 U/mL), and the needle was withdrawn. Two hours later, an intravenous bolus infusion of 5-fluorouracil (500 mg/m2) was performed. After this intravenous infusion was finished, the patient returned home and received oral administration of citrovorum factor (leucovorin 30 mg) for 1 day.

Before each infusion therapy, the patients received routine physical examinations with an aid of ultrasonography. The blood sampling was performed monthly to determine the complete blood count, plasma carcinoembryonic antigen (CEA) level, CA 19-9 level, liver function tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, cholesterol, lactate dehydrogenase, prothrombin time, and hepaplastin test), electrolytes, glucose, and so on. Computed tomography was routinely performed every 2 months to determine the size of the primary pancreatic tumor and to search for new lesions in the liver or other surrounding organs. The chest x-ray, bone or brain scintillation, and magnetic resonance imaging were also added as needed, such as when patients complained of symptoms that suggested lung, bone, or brain metastasis. A partial response (PR) was defined as a decrease >50% in the product of the greatest perpendicular dimension of lesions for at least 4 weeks. Minor response (MR) was defined as a decrease of at least 25% but <50% in the product of the greatest perpendicular dimension of lesions for at least 4 weeks. No change (NC) was defined as <50% reduction and <25% increase of local tumor lesions lasting for at least 8 weeks. Progressive disease (PD) was defined as an increase of at least 25% in the greatest perpendicular dimension of lesions or the appearance of any new manifestations of disease.

The degree of toxicity was determined according to the World Health Organization criteria,20 and the treatment was interrupted when an acute toxicity worse than grade 3 was observed. In addition, our intra-arterial infusion was abandoned when (1) local tumor progression (PD) was observed with or without distant metastasis, (2) the general condition took a turn for the worse because of rapid growth of distant metastasis, or (3) the catheter became occluded or dislocated.

Statistical Analysis and Informed Consent
The survival rate of the patients was estimated according to the Kaplan-Meier method, and survival curves for prognostic factors were compared by the log-rank and generalized Wilcox’s test. The statistical analysis of observed difference was assessed by unmatched t-tests and the {chi}2 method. P values of <.05 were considered significant. We obtained informed consent from all patients; approval to measure tissue blood flow and to perform a histological examination was also obtained.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Among 36 patients, 4 patients did not receive the following intra-arterial chemotherapy because of either dislocation or occlusion of catheters, whereas the remaining 32 patients received it (Table 1). They consisted of 20 men and 12 women, and the mean age was 60 ± 9 years (range, 43–73 years). None of them received any other therapies, such as radiation or other systemic chemotherapy. The pancreatic tumor was located dominantly in the pancreatic head for 13 patients, whereas 19 patients had tumors in the pancreatic body. Before laparotomy, 28 (88%) patients had severe abdominal and/or back pain, 28 (88%) exhibited increases in serum tumor markers (CEA >5 ng/mL or CA 19-9 >37 ng/mL), and 27 (84%) had a grade 0–1 performance status. The diameter of the pancreatic tumor was >=5 cm in 20 (60%) patients. All 32 patients showed cancer invasion of the celiac or superior mesenteric arteries, and 29 (91%) had cancer invasion of the portal and/or superior mesenteric vein. All tumors were classified as T4 (International Union Against Cancer 6th edition).20a According to the staining pattern from the intraoperative dye injection, a single catheter was placed for 10 patients, and double catheters were placed for 22 patients.


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  		TABLE 1. Patient characteristics
 
Treatment Periods and Toxicity
Our intra-arterial infusion chemotherapy was continued for 11 ± 9.6 months (range, 2–50 months), with 26 ± 23 (range, 4–108) cycles of treatment. The total dose of MTX was 1768 ± 1332 mg, and that of 5-fluorouracil was 12.6 ± 10.5 g. Nausea with or without vomiting was experienced by four patients, but it did not continue for >3 days after injection. Two patients developed grade 3 diarrhea after the chemotherapy had been continued for >=2 years, but it was so short that we did not interrupt our chemotherapy. Only one patient developed grade 1 leucopenia, which did not need special treatment. Another patient developed a duodenal ulcer, but this was easily cured by a histamine-2 receptor antagonist. Thrombocytopenia, renal dysfunction, and liver dysfunction was not seen in any patients. Thus, no patient required dose reduction or treatment interruption.

Response, Survival, and the First Site of Failure
Serial examinations of computed tomographic scans indicated PR for 2 patients (6%), MR for 8 (25%) patients, NC for 21 (66%) patients, and PD for 1 (3%) patient. The median survival period was 13 months (mean, 17 ± 11 months; range, 3–51 months), and the survival rates at 1, 2, and 3 years were 56%, 19%, and 6%, respectively. According to the maximum response of the primary tumor during the treatment period, 10 patients were grouped into PR/MR, 21 patients were grouped into NC, and 1 patient was grouped into PD. The median survival period of each group was 20, 11, and 5 months, respectively (P = .028 between PR/MR and NC). Our initial schedule had been to repeat this chemotherapy as many times as possible, discontinuing treatment after either tumor progression or catheter occlusion (Table 2). Twenty-three patients developed regrowth of the local (primary pancreatic) tumor, and eight patients developed distant metastasis, but the median survival period did not differ between these two subgroups. Among 23 patients who developed local failure, the median survival period of 11 patients whose treatment had been interrupted by the catheter occlusion was 20 months, which was significantly longer than 10 months for the other 12 patients whose treatment had been abandoned because of tumor progression.


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  		TABLE 2. First site of failure and survival periods
 

The patients were also classified according to whether they survived at least one postoperative year (18 patients) or not (14 patients; Table 3), and the background factors were compared between these two groups. The results indicated that sex, age, the location and size of the tumor, arteries involved, portal vein invasion, T4 status (International Union Against Cancer 6th edition), status of nodal involvement, histological differentiation, presence or absence of pain, performance status before laparotomy, and serum levels of tumor markers (CEA, CA 19-9, or both) were not significantly correlated with patient survival. Although the bypass procedure was not related to patient survival, the tumor grade response was related to patient survival (P = .0189). Among the 18 patients who survived for >=1 year, 9 (50%) showed either PR or MR. However, only 1 showed MR among 14 patients who died within 1 year (P < .05). The presence or absence of coexisting pancreatitis in the cancer-free area was also associated with 1-year survival. The coexisting pancreatitis was characterized by a disappearance of lobular pattern on the surface and a hard parenchyma. There were only two 1-year survivors among the 11 patients with coexisting pancreatitis, but there were sixteen 1-year survivors among the 21 patients without coexisting pancreatitis (P < .01).


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  		TABLE 3. Patient characteristics and survival periods
 
Figure 2 compares the survival rates between the two groups classified according to whether or not their cancer-free areas had a lobular structure. The 1-year survival rates were 76% and 18%, respectively (P < .05), and the median survival periods were 9 and 19 months, respectively. Likewise, a significant difference was seen in the median periods with a performance status of 0 to 2 (5 vs. 12 months, respectively) and in the median periods without disease progression (7 vs. 12 months, respectively).



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  		FIG. 2. Cumulative patient survival rates. The survival period of patients whose pancreatic parenchyma-bounding tumor was classified as nonfibrotic ({circ}) was 19 months but was only 9 months in those with fibrotic pancreatic parenchyma (•). There was a significant difference between these (P = .0003). The overall median survival was 13 months (mean, 17 ± 11; range: 3–51 months).

 
The blood flow of cancer tissues was measured for eight patients. In the three patients with coexisting pancreatitis in the cancer-free area, the tissue blood flow in the cancer was slightly increased from 26 ± 18 mL/min/100 g to 39 ± 14 mL/min/100 g during intra-arterial injection of AT-II. However, in the five patients whose cancer-free area did not show coexisting pancreatitis, the in-lesion blood flow was increased from 27 ± 12 mL/min/100 g to 69 ± 26 mL/min/100 g during infusion of AT-II. The blood flow in the cancer-free area was also measured for six patients. In the three patients with coexisting pancreatitis, tissue blood flow in the cancer-free lesion was slightly decreased from 37 ± 5 mL/min/100 g to 28 ± 4 mL/min/100 g during intra-arterial injection of AT-II, whereas the tissue blood flow in the cancer-free lesion was remarkably decreased from 78 ± 6 mL/min/100 g to 17 ± 10 mL/min/100 g in three patients whose pancreases were normal and did not show coexisting pancreatitis.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The response to anticancer chemotherapy depends on both drug delivery and chemosensitivity. Because pancreatic cancer is characterized by poor vascularity, we first tried to improve the drug delivery by using both intra-arterial administration and AT-II infusion before selecting the cytotoxic drug. At present, MTX, the main anticancer drug used in this study, is known to have an inferior chemosensitivity against human pancreatic cancer cells compared with some other anticancer drugs (5-fluorouracil, mitomycin C, doxorubicin and gemcitabine, and so on),21,22 and our dose of 5-fluorouracil was too small to directly produce certain anticancer effects. The leucovorin was used to soften or prevent systemic adverse effects of MTX. In our preliminary report on intra-arterial infusion of both MTX and AT-II, a very slight adverse effect and longer survival (16 ± 9 months; median, 14 months) were observed in 15 patients with locally advanced and nonresectable pancreatic cancers.18 This study consisted of 32 patients, including 17 additional patients with similar results, as expected: the adverse effect was almost negligible, and the survival period was 17 ± 11 months (median, 13 months). This figure was better than the 5 to 7 months of median survival observed in patients whose locally advanced pancreatic cancers had been treated by systemic chemotherapy (MTX plus 5-fluorouracil or doxorubicin plus 5-fluorouracil) during the same period in our institution.23 There have been very few reports of systemic chemotherapy in which the median survival period exceeded 12 months. In addition, considering that median survival periods were reported to be approximately 6 to 7 months in the systemic or traditional types of intra-arterial chemotherapies for pancreatic cancer,1,2,7,8,12–16 the prognostic benefit observed herein would have been attributed to the hemodynamic effect of AT-II rather than to drug sensitivity.

Some authors24–26 have infused either AT-II or norepinephrine concomitantly when intra-arterial chemotherapy had been performed for advanced carcinomas of the breast24 and liver.25 Noguchi et al.24 reported that the rate of patients with complete necrosis of breast tumors among the patients treated with AT-II was higher than that among patients treated without AT-II. Likewise, Sasaki et al.25,27 infused a mixture of AT-II and radioisotope from the hepatic artery for carcinoma of the liver and suggested that the AT-II infusion might have shifted the blood flow from the noncancerous area to the cancerous area. None of these researchers determined the absolute changes of blood flow, and they thus could not compare the relationships between response/prognosis and the blood flow changes due to AT-II among patients. However, we can speculate that intra-arterial chemotherapy with a concomitant infusion of AT-II would be more effective if the tissue blood flow were rich in the surrounding noncancerous tissues. In these results, first, the presence or absence of coexisting pancreatitis in the noncancerous pancreas around the cancer was the only factor associated with patient survival. Second, the presence or absence of coexisting pancreatitis was correlated not only with tissue blood flow (78 ± 6 mL/min/100 g versus 37 ± 5 mL/min/100 g), but also with decreased (difference of) blood flow during AT-II infusion. It is well known that a large number of acinar cells are replaced by the fibrous connective tissues in coexisting pancreatitis (chronic pancreatitis). Ishida et al.17 also reported that pancreatic blood flow was 88 ± 21 mL/min/100 g in the normal pancreas versus 58 ± 33 mL/min/100 g in chronic pancreatitis. Third, the cancer tissues that were close to the normal pancreas showed a larger increase of blood flow than the cancer tissues with coexisting pancreatitis.

Homma et al.28 recently developed a new type of intra-arterial chemotherapy for nonresectable cancer of the pancreatic head. Briefly, four pancreaticoduodenal arteries and the dorsal pancreatic artery were embolized superselectively with microcoils by using an interventional radiological technique. They infused 5-fluorouracil and cisplatin via the catheter placed in the splenic artery. The survival period was reported to be as long as 18 ± 10 months, and further improvement may be expected in the future if a concomitant infusion of AT-II is considered.

As described previously, more sensitive drugs than MTX or 5-fluorouracil have been developed in recent years for pancreatic cancer. In the near future, their effects will be compared and discussed on the basis of their systemic administration. However, far better patient survivals would be expected if the drugs were given via the arterial routes with an aid of AT-II infusion, especially for the patient whose uninvolved pancreatic parenchyma is nonfibrotic or nonatrophic. At the same time, a preoperative laparoscopy29 is also promising, not only in determining the presence or absence of the lobulated pattern in the uninvolved pancreas, but also in directly examining the blood flow. This approach would be useful to determine the suitable candidates for our type of intra-arterial chemotherapy with AT-II for nonresectable pancreatic cancer.


   ACKNOWLEDGMENTS
 
The acknowledgments are available online at www.annalssurgicaloncology.org.

Supported by a grant of the Foundation for Promotion of Cancer Research.


   FOOTNOTES
 
For locally advanced pancreatic cancer, intra-arterial chemotherapy was administered with angiotensin-II to shift the blood flow from the surrounding uninvolved pancreas to the cancer tissues. The presence of coexisting fibrosis offered the only prognostic factor, presumably because of reduced blood flow.

Received for publication September 23, 2002. Accepted for publication May 29, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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