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10.1245/ASO.2005.05.028
Annals of Surgical Oncology 12:629-636 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Feasibility and Efficacy of Combination Therapy With Preoperative and Postoperative Chemoradiation, Extended Pancreatectomy, and Postoperative Liver Perfusion Chemotherapy for Locally Advanced Cancers of the Pancreatic Head

Hiroaki Ohigashi, MD1, Osamu Ishikawa, MD1, Hidetoshi Eguchi, MD1, Yo Sasaki, MD1, Terumasa Yamada, MD1, Shingo Noura, MD1, Kohei Murata, MD1, Ko Takachi, MD1, Isao Miyashiro, MD1, Yuichiro Doki, MD1, Shingi Imaoka, MD1, Tsutomu Kasugai, MD2 and Kinji Nishiyama, MD3

1 Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan
2 Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan
3 Department of Radiotherapy, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan

Correspondence: Address correspondence and reprint requests to: Hiroaki Ohigashi, MD; E-mail: oohigasi-hi{at}mc.pref.osaka.jp.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The outcome after resection of advanced pancreatic cancers is extremely poor because of the high incidence of the postoperative development of liver metastasis and local recurrence. We performed a combination of chemoradiation and liver perfusion chemotherapy and extended pancreatectomy.

Methods: Nineteen patients with T3 pancreatic head cancers were enrolled. A total of 24 Gy in 12 fractions of 10-MV x-rays with a concurrent intravenous infusion of 5-fluorouracil (5-FU; 3 g/12 days) was administered to the pancreatic head area. An extended pancreaticoduodenectomy was performed, and catheters were placed into the gastroduodenal artery and the superior mesenteric vein. During the first 28 postoperative days, 5-FU was continuously infused via the hepatic artery and portal vein (3.5 g/28 days x 2). Finally, 36 Gy in 18 fractions with 5-FU (3 g/6 days) was applied to the pancreatic bed.

Results: After preoperative chemoradiation, four patients did not undergo surgical resection because of distant metastases. Fifteen patients underwent pancreaticoduodenectomy, liver perfusion chemotherapy, and postoperative chemoradiation. No patient developed grade 3 toxicity as a result of preoperative chemoradiation, but one patient (7%) developed grade 3 leukopenia during the postoperative treatments. The morbidity rate was 20% (3 of 15 patients), and the mortality rate was 0%. The overall 3-year survival rate was 53%. The 3-year disease-free survival rate was 66% in patients who pathologically responded well (>50%), versus 0% in patients with poor responses (P = .04).

Conclusions: A combination of preoperative and postoperative chemoradiation plus postoperative liver perfusion chemotherapy with an extended pancreatectomy is feasible, and the long-term outcomes are also promising.

Key Words: Pancreatic carcinoma • Neoadjuvant treatment • Chemoradiation • Liver perfusion chemotherapy • Extended pancreatectomy • Feasibility


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Despite the recent advances in radiological imaging, adenocarcinomas of the pancreas are diagnosable only at the advanced stage. Even if they have no distant metastasis macroscopically, most of the primary pancreatic tumors extend beyond the confines of the pancreas (T3 or T4 by International Union Against Cancer criteria). The long-term survival rate after resection of such locally advanced cancers remains very poor. The 5-year survival rate has been reported to be 7% by Nitecki et al.,1 12% by Sperti et al.,2 21% by Yeo et al.,3 and 34% by Manabe et al.4 in patients with T1 and T2 disease. Because the common sites of cancer recurrence consist of the pancreatic bed (local recurrence) and liver (metastasis),5,6 it is necessary to eradicate these two types of cancer relapse by adding some well-balanced therapies to surgical resection. In reviewing the previous reports, the Gastrointestinal Tumor Study Group first clarified that postoperative chemoradiotherapy resulted in a modest improvement in patient survival.7 Thereafter, the prognostic benefit of preoperative or postoperative radiotherapy has been supported by some authors,8–10 but many of them8–10 indicated that radiotherapy shifted the mode of cancer recurrence from local recurrence to distant (mainly liver) metastasis. Breslin et al.9 reported that liver metastases developed as the first treatment failure in 41 (70%) of 58 patients who had recurrences, whereas local recurrence occurred in 10% of them.

Thus, for the further improvement of patient survival, we should add some treatments that would be effective in preventing the postoperative development of liver metastasis with chemoradiation plus surgery. Although Yeo et al.11 and Evans et al.12 performed a prophylactic irradiation of the entire liver and primary pancreatic tumors, they failed to improve patient survival because of excessive toxicity. However, our previous report showed that the incidence of liver metastasis was decreased significantly by prospective liver perfusion chemotherapy in which 5-fluorouracil (5-FU) was continuously infused via both the portal vein and the hepatic artery for 28 postoperative days after pancreaticoduodenectomy. During this regional chemotherapy, the concentration of 5-FU was estimated to be as high as .14 µg/mL, not only in the portal vein, but also in the hepatic artery, although the infused dose of 5-FU was not high (250 mg/day). With this in mind, a combination of preoperative chemoradiation, pancreatic resection, and postoperative liver perfusion chemotherapy was considered as one of the most promising approaches for the treatment of T3 cancers. However, because of the lack of previous reports on such combination therapy, we feared that a full dose of preoperative chemoradiation might make it more difficult to complete the postoperative liver perfusion chemotherapy without delay. Thus, we carefully divided the chemoradiation schedule into preoperative and postoperative courses. The purpose of this study was to determine the feasibility of our new type of combination therapy for T3 cancer of the pancreas.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility Criteria
During 1995 to 1997 and 2000 to 2002, we implemented our regimen among a limited number of patients with locally advanced (T3 in the International Union Against Cancer classification, 6th edition) cancer of the pancreatic head. Before treatment, radiological imaging (thin-section and contrast-enhanced computed tomography and arteriography) indicated the presence of a pancreatic head tumor involving the retropancreatic soft tissues and sometimes the superior mesenteric/portal vein, whereas the liver, lung, and neighboring major arteries, such as the celiac truncus, common hepatic artery, or superior mesenteric arteries, were all intact. Also, for the purpose of practicing postoperative liver perfusion chemotherapy, it was confirmed that the gastroduodenal artery and both the right and left hepatic arteries were all branched from the common hepatic artery. By the cytology conducted on the pancreatic juice collected during endoscopic retrograde pancreatography, pancreatic adenocarcinoma was proven. Patients were excluded when their performance status (Eastern Cooperative Oncology Group criteria) was below grade 2 or when they had a history of serious disease.

Treatment Schedule
This protocol consisted of preoperative chemoradiation, pancreaticoduodenectomy, postoperative liver perfusion chemotherapy, and postoperative chemoradiation, in sequence (Fig. 1Go).


Figure 1
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  		FIG. 1. Preoperative radiation of 24 Gy with 5-fluorouracil (5-FU) was performed for 16 days. Patients without distant metastasis at restaging after preoperative treatments underwent laparotomy. Pancreaticoduodenectomy with lymphatic and connective tissue clearance was followed by liver perfusion chemotherapy and postoperative chemoradiation (36 Gy in 18 fractions for 4 weeks). V, vein; A, artery.

 
Preoperative Chemoradiation
A total of 24 Gy in 12 fractions of 10-MV x-rays irradiated the pancreatic head area, including the superior mesenteric artery, celiac artery, and aorta. An intravenous infusion of 5-FU (3 g/12 days) was concurrently performed during the period of irradiation.

Pancreaticoduodenectomy
A laparotomy was performed 7 ± 3 days after the final fraction of the preoperative irradiation. When neither liver metastasis nor peritoneal implantation was detected by macroscopic inspection, a pancreaticoduodenectomy was performed. The retroperitoneum and underlying tissue, containing both lymphatic and connective tissue, were detached from the vena cava, bilateral renal veins, and aorta. The upper margin was the inferior margin of the hepatic caudal lobe or the aortic hiatus, the inferior margin was the origin of the inferior mesenteric artery, the right margin was the hilum of the right kidney, and the left margin was 2 to 3 cm outside of the aorta. Both lymphatic and connective tissue were removed along the superior mesenteric vessels and celiac truncus, and these vessels were skeletonized.5 The portal/superior mesenteric vein was resected when it was not isolated from the pancreatic head. When the portal/superior mesenteric vein could be isolated, a touch smear was obtained from the disclosed vein wall and used for the intraoperative cytodiagnosis.13 When a positive result was thereby gained, the portal/superior mesenteric vein was additionally resected, and reconstruction was accomplished with end-to-end anastomosis. The cut margin of the pancreas was proven to be negative in cancer cells by an intraoperative frozen-section histology, and it was then anastomosed to the posterior wall of the stomach by using an invagination procedure.

Liver Perfusion Chemotherapy
Before the abdomen was closed, one catheter was placed in the gastroduodenal artery, and another was placed in one of the branches of the superior mesenteric vein.14,15 Immediately after operation, a continuous infusion of 5-FU (125 mg/day) via each of the two catheters was initiated. The infusion was continued for 28 postoperative days with an infusion pump, but no further infusion was performed thereafter.

Postoperative Chemoradiation
Three to five weeks after operation, 36 Gy in 18 fractions of 10-MV x-rays was applied to the pancreatic bed, including the superior mesenteric artery, celiac artery, and aorta. Concurrently, 5-FU (500 mg/day) was infused for 3 days at the beginning and end of postoperative radiation.

Evaluation of Resectability and Toxicity
All patients were followed up by routine physical checkups, including performance status and body weight. Computed tomography was performed before and after preoperative chemoradiation and after the completion of the entire treatment schedule. Laboratory examinations, such as a complete blood cell count (weekly) and the serum levels of carcinoembryonic antigen and CA 19–9 (twice a month), were also repeated. The grades of treatment toxicity were determined according to the Common Terminology Criteria for Adverse Events version 3.0.16 In our initial schedule, the treatment was interrupted when any grade 3 adverse effects developed. After leaving the hospital, all patients were followed up at our outpatient clinic with the aid of computed tomography/ultrasound (three times a year) and laboratory examinations (carcinoembryonic antigen, CA 19–9, liver function, and so on; monthly or every 2 months). Complications, the survival period, the cause of death, and other postoperative indicators were estimated.

Pathologic Assessment of Response
The resected specimens were fixed in a 10% formalin solution, sliced into 5-mm sections, and embedded in paraffin blocks. A 4-µm section was obtained from each block, stained with hematoxylin and eosin, and observed microscopically by two expert pathologists. The degenerated cancer cells (DCCs) were defined as those with absent, pyknotic, or irregularly shaped nuclei with acidophilic, swollen, or vacuolated cytoplasm. The population of DCCs was determined for each case (Table 1Go), and the fibrotic areas were excluded from this evaluation when they included islet cells left behind in the pancreatic parenchyma.


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  		TABLE 1. Toxicity profile (preoperative and postoperative chemoradiation)
 
Statistical Analysis
Survival was calculated as the time from registration until death. Disease-free survival was calculated as the time from registration to recurrence or death. Survival curves were estimated with the Kaplan-Meier method,17 and differences were assessed with the log-rank test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Twenty-eight consecutive patients were matched to the above-mentioned criteria at the Osaka Medical Center for Cancer and Cardiovascular Disease. With informed consent, 19 patients (60%) consented to receive our multimodal therapy (Fig. 2Go). The other nine patients were excluded from this study: three patients did not agree to receive this schedule, and six patients were not suited to receive postoperative liver perfusion chemotherapy because their hepatic arteries were partly branched from the superior mesenteric artery or their gastroduodenal arteries were not available for catheterization. These consisted of 11 men and 8 women with a median age of 56 years (range, 41–71 years). All patients tolerated preoperative chemoradiation without interruption. When the restaging was performed thereafter by radiological imaging, no patient revealed noteworthy changes in the size of the primary pancreatic tumor, but two had newly developed distant metastases (liver metastasis in one patient and lung metastasis in one patient) and were excluded from this study. Consequently, the 17 remaining patients were able to receive laparotomy, but then 2 of those patients were found to have unsuspected liver metastases. In these two patients, pancreatic resection was abandoned, and palliative bypass procedures (gastrojejunostomy and choledochojejunostomy) were performed. Finally, 15 (79%) of 19 patients underwent extended pancreaticoduodenectomy. According to intraoperative inspection with the aid of cytological examination as described previously, the portal/superior mesenteric vein was resected in ten patients and preserved in the other five patients. Immediately after operation, liver perfusion chemotherapy was initiated and was followed by postoperative chemoradiation. During these two types of postoperative treatment, no patient needed treatment interruption because of grade 3 or 4 toxicity.


Figure 2
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  		FIG. 2. Of the 19 enrolled patients, 2 patients did not undergo a laparotomy because of distant metastasis detected by preoperative restaging. During laparotomy, two other patients were judged as unsuitable candidates for surgical resection because of unsuspected and clinically occult liver metastases. Finally, 15 patients completed the initial treatment schedule.

 
Toxicity and Early Postoperative Complications
During the preoperative chemoradiation, none of the 19 patients experienced nausea/vomiting, appetite loss, thrombocytopenia, liver dysfunction, renal dysfunction, or clinical signs of hemorrhage. Their performance status was maintained at grade 0 or grade 1. Only two patients developed either grade 1 or grade 2 leukopenia (Table 1Go), but it did not delay the operative timing. During postoperative chemoradiation, only 1 (7%) of 15 patients developed grade 3 leukopenia, 6 patients (40%) developed grade 1 or grade 2 leukopenia, and 6 patients (40%) experienced grade 1 or grade 2 vomiting/nausea. In addition, one patient each developed cholangitis, ulcer formation at the site of gastrojejunostomy, and liver infarction, with a 20% morbidity rate. However, no patient died as a result of postoperative complications (the mortality rate was 0%).

Histopathologic Findings
Histopathologic study of the resected specimens revealed a wide variation in the population (20%–90%) of DCCs. Nine patients (60%) showed that the population of DCCs were more than 50% (responders), whereas the other six patients (40%) showed fewer than the number of DCCs in the population (nonresponders). No patient had a complete response. With regard to the histology of residual cancers, well-differentiated adenocarcinoma was seen in 2 patients (13%), moderately differentiated adenocarcinoma in 11 patients (74%), and poorly differentiated adenocarcinoma in 2 patients (13%). Nodal involvement was seen in 6 patients (40%), and direct invasion beyond the pancreatic confines was seen in 12 patients (80%). The surgical margin was judged as negative (R0) in 12 patients (80%) and as positive (R1) in 3 patients.

Long-Term Results Including Survival Rates and Causes of Death
In the 15 patients who underwent pancreatectomy, the postoperative follow-up period ranged from 32 to 117 months (median, 87 months). To date, six patients have developed cancer recurrence (two locoregional [13%], one liver [7%], one peritoneal [7%], one pleural [7%], and one bone [7%]), and four patients have died of other diseases without any evidence of cancer recurrence (one lung cancer, one lung thrombosis, one accident, and one pneumonia) (Table 2Go). The overall 3-year survival rate in these 15 patients with resected disease reached 53%, and their median survival period was 62 months (Fig. 3Go). All 3 patients who had no retropancreatic invasion are still alive without recurrence (range, 32–78 months), and the other 12 patients, who had extrapancreatic invasion, had a 41% 3-year survival rate. When the 12 patients with pathologic retropancreatic invasion were classified into 2 subgroups (responder vs. nonresponder), the 3-year survival rate was 0% in the nonresponder group and 66% in the responder group (P = .04; Fig. 4Go).


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  		TABLE 2. Pathologic responses and patient outcomes
 

Figure 3
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  		FIG. 3. The 5-year survival rate was 53% in the 15 patients who completed the treatments.

 

Figure 4
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  		FIG. 4. In 12 patients with retropancreatic extension, portal vein/superior mesenteric vein involvement, or both, the disease-free 3-year survival was 66% in the patients whose tumor populations consisted of <50% of degenerated cancer cells (>50%; open circle), whereas no 3-year survivors were found in the nonresponder group (≤50% of degenerated cancer cells; P = .0012).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Despite the recent advances in operative techniques and perioperative management, the postoperative morbidity rate after pancreaticoduodenectomy is still high: 27% according to Pellegrini et al.,18 39% according to Grace et al.,19 and 41% according to Yeo et al.20 Although Evans et al.21 and Yeo et al.11 added preoperative chemoradiation to pancreaticoduodenectomy without increasing the morbidity rate, excessive toxicity developed when whole-liver radiation was added to this combination.12 Therefore, before starting our combination therapy including chemoradiation and pancreaticoduodenectomy with a wide resection of the lymphatic and connective tissue and prophylactic liver perfusion chemotherapy,14,15 we paid careful attention to its feasibility. To achieve this safely, we decided to divide the chemoradiation schedule into preoperative and postoperative courses because of the following theoretical advantages: we would be able to avoid the full dose of radiation toward healthy stomach and duodenum, which are radiosensitive organs, and we could easily interrupt both the postoperative irradiation and liver perfusion chemotherapy if any serious complications developed after operation. With regard to the liver perfusion chemotherapy, our previous study showed that the concentration of 5-FU was as low as .01 to .02 µg/mL in the systemic blood circulation during the period when 125 mg/day of 5-FU was continuously infused via the portal vein and the hepatic artery. With such considerations, our protocol resulted in only one grade 3 toxicity and a 0% of mortality rate. Excluding the 4 patients who were not able to undergo pancreatic resection because of distant metastasis, all of the other 15 patients completed the full course of the planned schedule. After operation, 3 (20%) of the 15 resected patients developed complications, but this rate was not higher than that in patients who undergo surgery alone.18–20 Likewise, their complications were not life threatening. Thus, we conclude that our combination therapy is feasible with an acceptable rate of complications.

Whether survival was remarkably improved by the preoperative full dose of chemoradiation is still controversial because of the lack of a prospective randomized study.22 However, most authors have recognized that the incidence of local recurrence was thereby decreased, and local recurrence was observed in 10% and 11% of cases reported by the Fox Chase Cancer Center23 and the M. D. Anderson Cancer Center,24 respectively. In parallel with this fact, remarkable pathologic responses were observed in their resected specimens. Evans21 observed the destruction of 51% to 90% of tumor cells in 7 of 17 patients. A total of 30% and 22% pathologic complete responses were reported by Snady and Mehta, respectively. Likewise, 0% to 29% of patients showed negative resection margins in several studies; 0% at Stanford University, 12% at the M. D. Anderson Cancer Center, and 29% at the Fox Chase Cancer Center. A higher incidence of negative nodal involvement was also reported. Evans reported a 71% negative nodal involvement, and 70% of the incidence was investigated by White.25 Pendurthi et al.26 reported significantly fewer involved nodes in the preoperative chemoradiation group than in the postoperative chemoradiation group (28% vs. 56%).

It is not strange that their response rates were higher than ours, because our resected specimens had been preoperatively treated with only 24 Gy of irradiation with 5-FU. However, our patients received an additional 36 Gy or an overall 60 Gy of irradiation toward areas including the celiac truncus, superior mesenteric vessels, and aorta: these are common sites of local recurrence after pancreaticoduodenectomy. Consequently, our study resulted in a 12% local recurrence, and such a low incidence seems to be by no means inferior to the above-mentioned data23,24 in the preoperative full dose of chemoradiation.

The purpose of adjuvant chemoradiotherapy is to strengthen the locoregional control after pancreaticoduodenectomy. However, to improve the patient’s survival, many authors have described the need for some additional therapies that could prevent liver metastasis. Because our previous report indicated that our method of liver perfusion chemotherapy was able to successfully decrease the incidence of hepatic metastasis in patients who had received pancreaticoduodenectomy alone, we decided to include this regional chemotherapy in the present protocol. The dose of 5-FU was not high (250 mg/day: 125 mg from each of the two routes) and differed from the other types of regional chemotherapies for macroscopically visible tumors. However, the concentration of 5-FU was ≥.14 µg/mL in the portal vein and ≥.33 µg/mL in the hepatic artery during this chemotherapy. Shimoyama and Kimura27 reported that .10 µg/mL of 5-FU was sufficient to kill cancer cells if the 5-FU infusion continued for >2 weeks. Ackerman28 found that the blood supply into hepatic micrometastases was attributable to both portal blood and arterial blood, but more to the arterial blood flow than to the portal blood flow as it grew in the hepatic parenchymal tissues. Beger et al.29 also performed regional chemotherapy via the celiac artery after pancreatectomy and reported that the 3-year survival rate in the group of stage III pancreatic cancers was improved from 5% to 30% by way of decreasing the incidence of liver metastasis. Their method is similar to ours in that anticancer drugs might have reached the liver via the hepatic artery and portal vein, because the drug delivered via the splenic artery would have returned to the portal vein. Consequently, our study resulted in a 17% occurrence of liver metastasis, and this figure is significantly lower compared with the reported incidences ( 50%10 to 54%9) of liver metastasis in patients treated with surgery plus chemoradiation. Recently, Picozzi et al.30 added interferon alfa to chemoradiation plus surgery, and this resulted in a 64% 2-year survival rate; however, they reported neither the pattern of failure nor the incidence of liver metastasis. Whether interferon-based chemoradiation can prevent newly developing liver metastasis is a very interesting question, and future studies are needed to elucidate the role of interferon in preventing hepatic metastasis.

Although our study was preliminary, with only a small number of patients and a limited follow-up period, the 3-year survival rate reached 53%. Considering that they were all T3 cancers, this protocol is promising. This combination approach of chemoradiation and liver perfusion chemotherapy would be worthwhile to pursue in future studies.

Received for publication May 28, 2004. Accepted for publication February 22, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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