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Original Research |
1 Department of Radiology, Nara Medical University, 840 Shijo-cho, Kashihara,
634-8522 Japan.
2 Department of Radiation Oncology, Nara Medical University, Kashihara,
Japan.
Received January 12, 2007;
accepted after revision March 28, 2007.
Address correspondence to T. Tanaka
(toshihir{at}bf6.so-net.ne.jp).
Abstract
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MATERIALS AND METHODS. One or two catheters were placed into the pancreas-supplying arteries angiographically. To obtain adequate drug distribution, the positions of the catheters were determined in accordance with the results of CT during arterial injection of contrast material. A dose of 333 mg/m2/d of 5-FU was continuously infused for 5 days a week for 5 weeks, with concurrent radiation therapy (50 Gy at 2.0 Gy per fraction). Twenty patients with unresectable pancreatic cancer were enrolled in this study.
RESULTS. Of the 20 patients, 19 (95%) completed the scheduled course of this combined therapy. Fourteen patients showed a partial response (response rate, 70%). Serum cancer antigen 19-9 (CA 19-9) levels were reduced by more than 50% in 16 of 18 patients (80%). The 1-year and 3-year survival rates were 40% and 17%, respectively, with a median survival time of 11.0 months. Grade 3 or worse nonhematologic toxicity was observed in 11 patients (55%), but there were no life-threatening toxicities or complications.
CONCLUSION. Arterial infusion of 5-FU combined with concurrent radiation therapy is tolerable and can produce a high response rate with encouraging survival duration for unresectable pancreatic cancer.
Keywords: arterial infusion • chemoradiotherapy • chemotherapy • 5-fluorouracil • interventional radiology • pancreatic cancer
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Recently, gemcitabine (2-2-difluorodeoxycytidine) has become the mainstay of chemotherapy for unresectable pancreatic cancer, and in the 2006 National Comprehensive Cancer Network (NCCN) guidelines, both chemoradiotherapy encompassing systemic 5-FU plus radiation therapy and systemic chemotherapy using gemcitabine are described as standard treatments for locally unresectable pancreatic cancer [5]. However, the therapeutic results achieved with these regimens, namely a response rate of 5-10% and a median survival time of 6-10 months, are far from satisfactory, and the undertaking of clinical trials aimed at the development of novel therapeutic approaches has been strongly advocated [6, 7].
To deliver anticancer drugs more selectively to the cancer tissue, thereby achieving higher concentrations of the antineoplastic agents in the tumor mass, arterial infusion chemotherapy has been tried. However, these trials have all been small in scale and have not proven the efficacy of this approach. Extremely high response rates of 57-77% have also been reported, and much is expected of this new therapeutic strategy for unresectable pancreatic cancer [8-11].
To improve the therapeutic results of unresectable pancreatic cancer, it is vital to optimize local control of the pancreatic primary tumor and suppress liver metastases, which frequently constitute the major factor determining prognosis [12, 13]. We designed a pilot study for patients with unresectable pancreatic cancer in which an arterial infusion of 5-FU was delivered to the pancreatic primary tumor and liver and concurrently extrabeam radiation therapy was administered to the pancreatic primary tumor. We report our experience here.
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Additional eligibility criteria contraindications included performance
status (PS) of 2 or lower according to the Eastern Cooperative Oncology Group
(ECOG) level; not more that 75 years old; no prior chemotherapy, hormone
therapy, or radiation therapy; adequate bone marrow (WBC 
4,000/mm3, absolute neutrophil count 1,500/mm3, and
platelets 100,000/mm3); kidney function (serum creatinine 
1.5 mg/dL); and liver function (serum bilirubin 3.0 mg/dL and
transaminases level three times the upper normal limit). Percutaneous
biliary drainage was performed in patients with obstructive jaundice, and
patients were required to have a total serum bilirubin level of less than 3.0
mg/dL before the initial treatment
[5]. The pancreatic tumor or
liver metastasis was proven to be an adenocarcinoma by cytologic or histologic
examination of a sonography-guided biopsy specimen.
The present protocol was contraindicated in cases showing extrahepatic distant metastases such as peritoneal or pulmonary metastases on CT. Cases with abdominal nodal metastases that could be included in the radiation field were not excluded from the protocol even if classified as having distant metastases according to the UICC classification.
Catheter Placement for Arterial Infusion Chemotherapy
Before the catheter placement, the vascular anatomy of the celiac and
superior mesenteric arteries and their following pancreatic arteries was
confirmed using 5.5-French angiographic catheters (High-Flo Torcon, Cook).
Then, CT was performed during arterial injection of contrast material via both
the celiac and superior mesenteric arteries. According to the scanning
protocol, iopamidol, 300 mg I/mL, was injected from the catheter at a speed of
0.5 mL/s (range of total contrast volume, 10-15 mL), and imaging was performed
from 15 seconds after the start of the injection so as to cover the liver and
the entire pancreatic tumor.
According to the results of CT during arterial injection of contrast material, placement of the catheter was planned so that the anticancer drugs would be distributed to both the entire pancreatic tumor and the liver. Namely, in cases in which the pancreatic tumor was enhanced on CT during arterial injection of contrast material from both the celiac artery and the superior mesenteric artery, two catheters were inserted, whereas in cases in which the entire pancreatic tumor was enhanced via either the celiac artery or superior mesenteric artery alone, a single catheter was placed in the supplying vessel [16]. In cases with locally advanced pancreatic cancer without liver metastasis as well, drugs were distributed to the liver to prevent liver metastases.
For intraarterial indwelling catheters (Fig. 1), 3.3-French polyurethane catheters coated with a hydrophilic heparinized polymer (Anthron PU catheter, Toray Medical) or 3.3-French W-Spiral catheters (Piolax Medical Devices) were used [17, 18]. A single catheter was inserted from a unilateral femoral artery, and when two catheters were used, they were inserted from the bilateral femoral arteries. When a catheter was to be placed in the celiac artery, the catheter tip was inserted into the splenic, hepatic, or left gastric artery, and the side hole placed at the origin of the celiac artery. When a catheter was to be placed in the superior mesenteric artery, the catheter tip was inserted into the jejunal artery and the side hole placed at the origin of the superior mesenteric artery. The catheter was connected to an implanted port (Selsite Port, Toray Medical) and embedded subcutaneously. Considering the tumor location and arterial anatomy in individual cases so as to increase the supply of drugs to the tumor and decrease it to the stomach, the splenic, right gastric, left gastric, and right gastroepiploic arteries were embolized with Tornado embolization microcoils (Cook), interlocking detachable coils (IDC, Boston Scientific), and a mixture of N-butyl cyanoacrylate (NBCA) (Histoacyrl, Braun) and iodized oil (Lipiodol Ultrafluide, Laboratoire Guerbet).
During the period of arterial infusion chemotherapy, CT during arterial injection of contrast material via the implanted ports was performed once per week to confirm whether the drugs from the indwelling catheter were being appropriately distributed to the pancreatic tumor and the liver. When the drug distribution was found to be unacceptable due to factors such as catheter migration, the catheter was immediately repositioned or replaced and treatment continued.
Treatment Regimen
Arterial infusion chemotherapy consisting of 5-FU 333 mg/m2/d
was administered continuously for 5 days a week for 5 weeks. The 5-FU was
infused via ports using the Intermate SV1 (Baxter) continuous infusion device.
In cases in which catheters were placed in both the celiac and superior
mesenteric arteries, half doses were infused from each of the catheters.
Concurrent radiation therapy was delivered through three to four fields as a single course of 50 Gy in 25 fractions over 5 weeks, with 10-MV photons (Linear Accelerator ML20M, Mitsubishi). The radiation volumes were decided based on the planning CT axial image in the treatment position. The clinical target volume (CTV) covered the gross tumor volume of the pancreatic tumor and an area extended 3D by 0.5-1 cm and the pancreaticoduodenal and celiac axis lymph nodes. In cases in which paraaortic nodal metastasis was present, these nodes were also included in the CTV. The planning target volume (PTV) included the CTV plus a 0.5-1 cm uniform 3D expansion.
Because the arterial catheter-port system is not used after arterial infusion combined with radiation therapy, the system was removed when requested by the patient. From about 1 month after the completion of arterial infusion combined with radiation therapy, for outpatient maintenance chemotherapy, gemcitabine 0.7-1 g/m2 was infused systemically for 30 minutes on days 1, 8, and 15 at 4-week intervals. Systemic chemotherapy using gemcitabine was continued until disease progression was seen.
Patient Evaluation and Response Criteria
Treatment-related toxicity was determined every week during arterial
infusion combined with radiation therapy according to National Cancer
Institute Common Toxicity Criteria, version 2.0 (NCI-CTC V2.0)
[19]. Both arterial infusion
chemotherapy and radiation therapy were suspended if grade 3 toxicity other
than nausea and vomiting was encountered, and both were resumed when recovery
to grade 2 toxicity level was achieved. If there was a total of 2 weeks of
delay due to toxicity for any reason, arterial infusion combined with
radiation therapy was abandoned. The efficacy of this therapy was evaluated
according to the tumor response, change in tumor marker cancer antigen 19-9
(CA 19-9) level, progression-free survival time, and survival time.
Using pretherapy CT images as a baseline, tumor response was assessed on CT performed within 1 month after the completion of arterial infusion combined with radiation therapy according to Response Evaluation Criteria in Solid Tumors (RECIST) [20]. CT was performed by IV injection of iopamidol, 3 mL/s, scanning the pancreas after 40 seconds on the early phase and the entire abdomen, including the liver, after 90 seconds on the delayed phase. The early phase was reconstructed at 2-mm intervals and the delayed phase at 5-mm intervals on axial images.
In the RECIST criteria, measurable lesions were defined as those having a
longest dimension of 1 cm. In this study, target lesions were considered
to be measurable pancreatic primary tumors, liver metastases, and nodal
metastases. Complete disappearance of a target lesion was classified as
complete response (CR), 30% shrinkage of the sum of the longest dimension
of a lesion was classified as partial response (PR), the appearance of a new
lesion or 20% increase in the sum of the longest dimension of a target
lesion was classified as progressive disease (PD), and other patterns were
classified as stable disease (SD). Also, because with this therapeutic
protocol the therapeutic effect may differ between the pancreatic primary
tumor and liver metastasis, CR, PR, PD, and SD were evaluated separately for
pancreatic primary tumor and liver metastasis according to RECIST
criteria.
Change in tumor marker CA 19-9 was determined as the serum CA 19-9 level
before therapy and 1 month after arterial infusion combined with radiation
therapy by immunoradiometric assay using the Centocor Radioimmunoassay Kit
(Centocor, Inc.). A 50% decrease in the baseline CA 19-9 value was
defined as a tumor marker response.
During maintenance chemotherapy, the state of the tumor was evaluated as a rule on CT every 2 months, with serum CA 19-9 levels measured monthly. When the CA 19-9 level showed an increase or changes in the general state were apparent, CT scans were obtained more frequently.
Survival analyses were conducted by the Kaplan-Meier method. Actuarial
Kaplan-Meier overall survival time was generated from the time of treatment
initiation to the time of death. Actuarial Kaplan-Meier progression-free
survival time was generated from the time of treatment initiation to the time
of disease progression. Disease progression was defined as the appearance of
new areas of malignant disease on CT or 20% increase in the longest
dimension of evaluable tumor mass according to RECIST criteria. Median
survival times were generated for the overall, locally advanced, and
metastatic groups.
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In nine cases, percutaneous biliary drainage was performed because of obstructive jaundice. In eight of these, metallic stents were placed percutaneously, and in the remaining one case, cholangiojejunostomy was performed. Furthermore, in one case, food passage disturbance occurred due to invasion of the duodenum by the pancreatic cancer and was treated with gastrojejunostomy.
The location of the catheter determined on CT during arterial injection of contrast material, namely the location of the catheter from which drugs could be distributed to the entire tumor, was both the celiac arterial site and superior mesenteric arterial site in 17 cases, celiac artery alone in two, and superior mesenteric artery alone in one case. Both cases in which catheters were placed in the celiac artery alone had small body-tail cancers with localized tumor spread. The case in which a catheter was placed in the superior mesenteric artery alone had head cancer, with the vascular anatomy showing the hepatomesenteric type in which the common hepatic artery branched from the superior mesenteric artery. The positions of the catheter tips and side holes are listed in Table 2.
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In 10 cases, the splenic artery was embolized to increase the drug concentrations reaching the pancreatic tumor and liver. In addition, to reduce drug inflow to the stomach, the left gastric artery, right gastric artery, and gastroepiploic artery were embolized in 11, seven, and six cases, respectively (Table 2).
Treatment Outcome
In 19 cases (95%), the combined therapy was completed. In a single case
(case 6), after delivery of 46 Gy of radiation therapy and infusion of 11,500
mg of 5-FU, therapy was terminated because of the appearance of grade 3
diarrhea. The diarrhea ceased after 15 days, but the remaining arterial
infusion and radiation therapy were not administered, and from after 1 month,
maintenance chemotherapy with gemcitabine was provided.
In the evaluation according to RECIST criteria, in 14 of the 20 cases PR
was obtained, with SD noted in the remaining six cases (response rate, 70%)
(Figs. 2A,
2B,
2C,
2D,
2E,
2F and
3A,
3B,
3C,
3D). In the evaluation of the
pancreatic primary tumors alone, PR and SD were noted in 14 and six cases,
respectively (response rate, 70%), whereas in the six cases with liver
metastasis when evaluating the liver tumor alone, CR was seen in two cases, PR
in three, and SD in one case (response rate, 83%). Change in tumor marker CA
19-9 was evaluated in 18 cases in which the pretherapy baseline was 100
U/mL, with a tumor marker response noted in 16 cases (80%).
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In all cases, the cause of death was progression of the pancreatic cancer, with the Kaplan-Meier overall median survival time amounting to 11.0 months (95% CI, 10.0-11.9 months), and the 1-year and 3-year survival rates, respectively, 40% and 17%. The Kaplan-Meier curve of overall survival is shown in Figure 4. The median survival time according to stage was stage III, 11.0 months and stage IV, 10.7 months.
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Dislocation of catheters placed in the superior mesenteric artery occurred in six cases (30%), but in all cases the catheter position could be corrected with interventional radiology techniques, and therapy was completed.
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The study eligibility criteria included locally advanced pancreatic cancer and cases with liver metastasis. This was because hepatic arterial infusion chemotherapy for liver metastasis from pancreatic cancer, like that for liver metastasis from colorectal cancer, has been reported to achieve high response rates. Arterial infusion not limited to the pancreas but including the liver as well was thought to have the potential to control liver metastasis [8-10, 21]. On the other hand, Ishii et al. [22] administered 5-FU arterial infusion to liver metastasis alone and delivered radiation therapy to the pancreatic tumor. They concluded that the combined therapy results in a poor prognosis despite its high response for liver metastasis. Therefore, regional chemotherapy at the primary site should be performed.
We attempted to achieve local control of the pancreatic tumor and liver metastasis by administering arterial infusion to both the pancreas and liver. On the other hand, hepatic arterial infusion chemotherapy as adjuvant chemotherapy has also been administered for pancreatic cancer after curative resection, with the survival period reported to have been extended [12]. On that basis, the present protocol for locally advanced pancreatic cancer—hepatic arterial infusion—was administered to prevent liver metastasis and control micrometastasis.
Hepatic arterial infusion chemotherapy has been widely applied for liver cancer, and the technique of percutaneous catheter placement using interventional radiology techniques has been largely established [17, 18]. However, in the case of arterial infusion chemotherapy for pancreatic primary tumors, many unresolved issues remain regarding which artery should be selected for drug infusion and the optimal method of catheter placement. In most previous reports, arterial infusion chemotherapy for advanced pancreatic cancer has been limited to drug administration via the celiac artery, with no evaluation of the patterns of drug distribution to the tumor [23-27].
We previously reported that in the majority of cases of advanced pancreatic cancer, infusion from both the celiac and superior mesenteric arteries would be necessary [16]. In the cases entered into the present study as well, we similarly focused on drug distribution to the tumor, and in all cases before catheter placement, we performed CT during arterial injection of contrast material to place the catheter in such a way that the drugs would be distributed throughout the entire tumor. In this way, catheter placement in both the celiac and superior mesenteric arteries was found to be needed in 15 (94%) of 16 cases of head cancer and in two (50%) of four cases of body-tail cancer.
An extremely high response rate of 70% was achieved with the present arterial infusion of 5-FU combined with concurrent radiation therapy for pancreatic tumors. Compared with hitherto obtained response rates of about 10% achieved with chemoradiation with 5-FU systemic chemotherapy and radiation therapy [6], 5-FU pancreatic arterial infusion may achieve a higher local control effect than systemic infusion. The response rate of liver metastasis was extremely high as well at 87%, and as in previous reports [8-10, 22] 5-FU hepatic arterial infusion was considered to be effective. Furthermore, in two cases (10%) long survival times of 45 months, exceeding those usually obtained with surgical curative resection, were noted, proving that this therapy exerts a powerful effect on pancreatic tumor and liver metastasis [28].
In the present pilot study, peritoneal metastasis was one of the major determinants of prognosis. In nine (45%) of 20 cases, peritoneal metastasis appeared as the initial progression factor, and in the majority of these cases, the survival period was short. In the treatment of peritoneal metastasis, systemic chemotherapy plays the major role. In the present protocol, from 1 month after arterial infusion combined with radiation therapy systemic chemotherapy using gemcitabine was administered as maintenance therapy, but the median dose of gemcitabine was low at 14 g and may have been insufficient. Also, in two cases (cases 18, 20), ascites was detected on CT during the period of arterial infusion combined with radiation therapy, and in these cases, death resulted from peritoneal metastases at 6.8 and 4.5 months. We surmised that in these cases peritoneal metastases had already developed before or during arterial infusion combined with radiation therapy.
The diagnosis of peritoneal metastases before therapy can be difficult, and accurate diagnosis based on laparotomy or laparoscopy is essential. The second factor determining prognosis is the reprogression of liver metastases. In the present protocol, hepatic arterial infusion was administered only during the 5 weeks of arterial infusion combined with radiation therapy, with a switch made to systemic chemotherapy after catheter removal. In five of six cases (cases 8, 9, 11, 12, and 19) in which liver metastases were present before therapy, reprogression of liver metastases during systemic chemotherapy was seen as the initial manifestation of disease progression, and these become a determinant of prognosis. In light of this finding, in cases with liver metastases, further prolongation of survival may be achievable if hepatic arterial infusion is continued in the long term.
Life-threatening toxicity was not encountered, but a major drawback
remained the occurrence of grade 3 nonhematologic events in 55% of cases. When
delivering high concentrations of anticancer agents by arterial infusion to
pancreatic tumors, distribution of these agents to the stomach and duodenum
cannot be avoided, and thus in one half of cases grade 3 nausea and vomiting
developed, and in three cases, duodenal ulcers. Also, in 17 (85%) of 20 cases,
5-FU was infused from the superior mesenteric artery to distribute the drug to
the entire pancreatic tumor
[16]. For this reason, in
about 20% of cases grade 2 diarrhea or hypoalbuminemia was thought to
have occurred. Future studies must focus on the dosage of 5-FU, administration
schedule, and administration method.
In summary, arterial infusion of 5-FU and concurrent radiation therapy for unresectable pancreatic cancer can be implemented safely without life-threatening toxicity and may be a promising treatment providing an extremely high response rate. To obtain conclusive evidence of this, large phase 2 trials should be conducted after making minor changes to the treatment protocol.
Acknowledgments
We thank the Japanese Society of Implantable Port Assisted Regional
Treatment (JSIPART) for assistance in submitting this article.
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