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Effect of multiple-phase regional intra-arterial infusion chemotherapy on patients with resectable pancreatic head adenocarcinoma

JIN, Chen; YAO, Lie; LONG, Jiang; FU, De-liang; YU, Xian-jun; XU, Jin; YANG, Feng; NI, Quan-xing

Section Editor(s): QIAN, Shou-chu; LIU, Huan

doi: 10.3760/cma.j.issn.0366-6999.2009.03.009
Original article
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SDC

Background Regional intra-arterial infusion chemotherapy (RIAC) has been more valuable to improve prognosis and quality of life of patients with inoperable pancreatic adenocarcinomas, and adjuvant RIAC plays an important role in prolonging survival and reducing risk of liver metastasis after radical resection of pancreatic cancer, but the effect of preoperative or multiple-phase RIAC (preoperative combined with postoperative RIAC) for resectable pancreatic cancers has not been investigated. In this prospective study, the effect of multiple-phase RIAC for patients with resectable pancreatic head adenocarcinoma was evaluated, and its safety and validity comparing with postoperative RIAC were also assessed.

Methods Patients with resectable pancreatic head cancer were randomly assigned to two groups. Patients in group A (n=50) were treated with new therapeutic mode of extended pancreaticoduodenectomy combined with multiple-phase RIAC, and those in group B (n=50) were treated with extended pancreaticoduodenectomy combined with postoperative RIAC in the same period. The feasibility, compliance and efficiency of the new therapeutic mode were evaluated by tumor size, serum tumor markers, clinical benefit response (CBR), surgical complications, mortality and toxicity of RIAC. The disease-free survival time, median survival time, incidence of liver metastasis, survival rate at 1, 2, 3 and 5 years were also observed. Life curves were generated by the Kaplan-Meier method.

Results The pain relief rate and CBR in group A was 80% and 84% respectively. Serum tumor markers decreased obviously and tumors size decreased in 26% of patients after preoperative RIAC in group A. No more surgical complications, mortality or severe systemic side effects were observed in group A compared with group B. The incidence of liver metastasis in group A was 34% which was lower than 50% in group B. The disease-free survival time and median survival time in group A were 15.5 months and 18 months respectively. The 1-, 2-, 3- and 5-year survival rates were 54.87%, 34.94%, 24.51% and 12.25% respectively. There was no significant difference of survival time or survival rates between two groups.

Conclusions Multiple-phase RIAC is effective in combined therapy of resectable pancreatic head carcinomas by enhancing inhibition of tumor growth and reduction of liver metastasis, without negative effect on patients' safety or surgical procedure.

Edited by

Pancreatic Disease Institution, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China (Jin C, Yao L, Long J, Fu DL, Yu XJ, Xu J, Yang F and Ni QX)

Correspondence to: Dr. FU De-liang, Pancreatic Disease Institution, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China (Email: surgeonfu@yahoo.com.cn)

JIN Chen and YAO Lie contributed equally to this paper. The research was supported by grants from Shanghai Committee of Science and Technology, China (No. 054119504 and No. 004119009).

(Received July 1, 2008)

Pancreatic carcinoma is a malignancy with poor prognosis, and its overall 5-year survival rate is below 5%. Radical resection of tumor at an early stage is considered the only chance for a cure; but even in patients who have undergone resection of the tumor the median survival time is rarely longer than 12 to 18 months, depending on the selection criteria for the resected lesions. There is a strong evidence that multimodality therapy could prolong the survival in patients with pancreatic adenocarcinoma.1 Chemotherapy is one of the most promising combined-modality therapies for pancreatic adenocarcinoma; but the tumor is relativly resistant to systemic chemotherapy. Regional intra-arterial infusion chemotherapy (RIAC) has been found to be superior to systemic chemotherapy in improving prognosis and quality of life in patients with inoperable pancreatic adenocarcinoma.2 The adjuvant RIAC in patients after pancreatic cancer resection could prolong the survival with low toxicity, and reduce the risk of liver metastasis.3 Nevertheless, there is no reliable evidence to prove the efficiency of preoperative or multiple-phase RIAC for the patients with resectable pancreatic cancers. To evaluate the effect and safety of multiple-phase RIAC in the combined-modality treatment for patients with pancreatic carcinoma, we prospectively studied multiple-phase RIAC in patients with resectable pancreatic head adenocarcinoma after pancreaticoduodenectomy.

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METHODS

Patients

From January 2000 to December 2006, patients with resectable pancreatic head carcinoma undergoing extended pancreaticoduodenectomy in Pancreatic Disease Institute, Department of Surgery, Huashan Hospital, Fudan University were enrolled in the study. All patients were diagnosed by serum tumor markers such as CA19–9, CA50, CA125 and CA242, multi-detector row helical computed tomography (MDCT), and/or nuclear magnetic resonance imaging (MRI). They had good function of the heart, liver, and kidney. Routine blood test showed the results were within normal limits. They had no history of prior chemoradiotherapy. Patients with obstructive jaundice at initial presentation received endoscopic palliation (biliary plastic stent) for the restoration of liver function or a total bilirubin level <50 μmol/L before they were enrolled.

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Eligibility criteria and exclusion criteria of the patients

Inclusion criteria: patients aged 25–75 years with resectable pancreatic head cancer; tumor stage II or III (according to International Union against Cancer (UICC) 2002) without adjacent vascular invasion judged by CT or MR; reconfirmed diagnosis by histologically proven adenocarcinoma of the pancreas; normal liver function; no prior cancer therapy; and Karnofsky performance score (KPS) >60, expected survival >3 months.

Exclusion criteria: not histologically proven adenocarcinoma of the pancreas; unresectable tumors or distant metastasis; surgical procedure without radical resection of the tumor; any condition not allowed to continue the protocol; withdrawal requirements from the patients.

Eligible patients were randomized into two groups: group A treated with extended pancreaticoduodenectomy combined with multiple-phase RIAC, and group B treated with extended pancreaticoduodenectomy combined with postoperative RIAC only. Randomization was done using random numbers generated from a computer in a central registry for this study. Written informed consent was obtained from each patient, and the research protocol was approved by the Ethical Committee of Huashan Hospital, Fudan University, China.

Operative criteria for tumor resection were as follows: (1) absence of liver metastases; (2) no peritoneal dissemination or drop metastases in the pelvis; (3) lack of invasion of the transverse mesocolon; (4) absence of metastases to the celiac lymph node (No. 9); (5) no involvement of the superior mesenteric artery (SMA), celiac artery, or common hepatic artery; (6) the ability to obtain adequate vascular control of the superior mesenteric vein (SMV)/portal vein (PV), splenic vein, and inferior mesenteric veins for a safe venous reconstruction.

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Regional intra-arterial infusion chemotherapy

Patients in group A were given one cycle preoperative RIAC 2 weeks before extended pancreaticoduodenectomy and postoperative RIAC 4 weeks after the surgical procedure, one cycle every 6 weeks for 6 cycles. Patients in group B were only treated with extended pancreaticoduodenectomy and postoperative RIAC, the same as in group A.

For RIAC, 5-Fr Rosch hepatic catheters were placed using Seldinger's technique via the femoral artery, and the position was reconfirmed by digital subtraction angiography (DSA) with the tip into the hepatic artery or the SMA.4 Chemotherapy regimen was the same in the two groups, including 5-fluorouracil (600 mg/m2), mitomycin C (MMC 10 mg/m2) and gemcitabine (1000 mg/m2). The toxicity was evaluated and graded each cycle according to the WHO criteria.

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Surgical procedure with extended pancreaticoduodenectomy

Patients underwent surgery approximately 2 weeks after preoperative RIAC. All received an extended pancreaticoduodenectomy including the classic Whipple procedure plus extended lymph node dissection. Pancreaticoduodenectomy, either standard or pylorus sparing procedure, was used in this study. Anatomic dissections involved the hepatoduodenal ligament, pancreatic neck, duodenojejunal flexure, and uncinate process. Routine frozen-section examinations of margins of the pancreatic neck, bile duct, and retroperitoneal soft tissue were completed. If a positive pancreatic neck or bile duct margin was encountered, further resection was done to achieve a negative histological margin.

Regional lymph nodes of the major stations were routinely dissected (according to the second English edition of the Classification of Pancreatic Carcinoma proposed by the Japan Pancreas Society5): No. 5, suprapyloric lymph nodes; No. 6, infrapyloric lymph nodes; No. 7, lymph nodes along the left gastric artery; No. 8, lymph nodes in the common hepatic artery; No. 9, lymph nodes around the celiac artery; No. 11, lymph nodes along the splenic artery; No. 12, lymph nodes along the hepatic artery, the portal vein and the bile duct; No. 13, lymph nodes on the posterior aspect of the head of the pancreas; No. 14, lymph nodes along the superior mesenteric artery; No. 16, lymph nodes around the abdominal aorta; No. 17, lymph nodes on the anterior surface of the head of the pancreas; and No. 18, lymph nodes along the inferior margin of the pancreas.

If intraoperative assessment showed only localized tumors involving PV or SMV, venous resection was required for a radical resection. Vascular reconstruction with an interposition graft or patch venorraphy was performed using a continuous running suture of 5–0 Prolene with end-to-end anastomosis. If tumor was found unresectable during intraoperative exploration, biliaryenteric bypass and gastrojejunostomy were completed.

Antibiotics and supportive care were given to the two groups postoperatively. Data on intra-abdominal regional and distant metastases were obtained from operative findings. Information about tumor size, histological type, lymph node metastasis, and pathologic TNM stage was from the pathologic records.6,7 Surgical complications, peri-operative death and length of postoperative hospital stay were also recorded.

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Evaluation of therapeutic effects and follow-up

The effects of preoperative RIAC were assessed by clinical benefit response (CBR), change of serum tumor markers and tumor size before surgical procedure. MDCT was used to observe any change in the size of the tumor. The results of treatment were evaluated according to the WHO hypostatic tumor objective assessment standard: complete remission (CR: tumor disappears completely); partial remission (PR: the size of tumor reduced by 50%); stable disease (SD: tumor reduced or increased by no more than 25%); progressive disease (PD: tumor increased by more than 25% or new lesion). CR+PR was defined as responsive and SD+PD was defined as ineffective. Pain was assessed using a simple method of four-point rating scale (NRS) which included four levels as “no pain”, “mild pain”, “moderate pain” and “severe pain”. CBR score was defined by performance status, weight gain and pain control.

The influences of multiple-phase RIAC were evaluated with disease-free time, median survival time, incidence of liver metastasis, and survival rate. Serum tumor markers, chest X-ray plain film, and abdominal ultrasonography were performed each cycle, and CT scan conducted at the 3th, 6th cycle for detecting any recurrence of the tumor. All patients were followed up every three months postoperatively until March 2007.

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Statistical analysis

The Stata 9.0 software (2006, Stata Corp., USA) for Windows was used for statistical analysis. The quantitative data were assessed by Student's t test, and the counting data were assessed by the chi-square test. The survival rates were estimated by the Kaplan-Meier method. Statistical significance was established at P <0.05.

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RESULTS

Clinical characterization of patients

A total of 100 patients were enrolled in the study and randomized into the two groups. There were no significant differences in gender, age, and UICC stage between the two groups. Vascular invasion was confirmed pathologically in 4 patients in group A and 3 patients in group B who needed vascular reconstruction (Table 1), and all patients were treated with extended panreaticoduodenectomy.

Table 1

Table 1

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Surgical complications

Recorded surgical complications consisted of infection (intra-abdominal or wound infection), bleeding (intra-abdominal or anastomotic stoma), anastomotic stoma leakage or fistula (pancreatic, biliary or gastrointestinal anastomotic stoma) or others (dysfunction of the heart or lung (such as adult respiratory distress syndrome), chylous leakage or delayed gastric emptying (DGE). Diagnostic criteria of bleeding included hemoglobin level of draining fluid (intra-abdominal or gastrointestinal) higher than 1/2 peripheral blood, and the total draining volume more than 400 ml/24 hours. Pancreatic fistula was defined as the persistent drainage of >50 ml amylase rich fluid (more than 3-fold elevation above upper limit of normal in serum amylase) on or after postoperative day 10, or pancreatic anastomotic disruption demonstrated radiologically. Pancreatic leakage was defined as the amylase level of drainage fluid more than 3-fold elevation above the upper limit of normal value in serum amylase within 5 days after operation. The incidences of these complications are listed in Table 2. There were no differences in the incidence of postoperative complications between the two groups. The postoperative length of hospital stay (LOS) of group A was (18.6±6.3) days, and was similar to that of group B ((21.2±7.1) days, P=0.469, Student's t test). The postoperative RIAC of 11 (22%) patients in group A and of 9 (18%) in group B was deferred because of surgical complications (P=0.617, chi-square test).

Table 2

Table 2

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Toxicity of RIAC

A total 314 cycles of RIAC were performed in group A with mean 6.28 cycles per patient, including 50 cycles of preoperative RIAC. There were no serious toxic effects on the liver, kidney, heart or bone marrow prior to surgery, and preoperative RIAC neither delayed the surgical procedures nor aggravated the side-effects of postoperative RIAC. In group B, 276 cycles of postoperative RIAC were performed with a mean of 5.52 cycles for each patient. No severe local side-effects were noted at the catheter insertion site. Prominent side-effects of RIAC were nausea, vomiting, diarrhea, and myelosuppression. The majority of patients had toxicities of WHO grades 1 and 2, and a few had grade 3 toxicities (Table 3). All side-effects were well controlled by symptomatic treatment, and no irreversible toxicities were observed. Treatment with colony stimulating factor (CSF) was required only for some patients with myelosuppression. There was no significant difference in the incidence of toxicities of postoperative RIAC between the two groups (P >0.05, chi-square test).

Table 3

Table 3

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Therapeutic effects of preoperative RIAC

Tumor size

Forty-seven (94%) cases of SD and 3 (6%) cases of PD after one cycle of preoperative RIAC were re-evaluated by CT scan in group A. But tumor shrinkage within 25% was observed in 13 (26%) SD patients, and an obvious inflammation gap was detected between tumors and adjacent blood vessel in 10 (20%) patients with partial involvement of the SMV/PV. No new lesion was observed in 3 PD cases.

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Alteration of serum tumor markers

On admission, elevated serum levels of CA19–9 were observed in 42 (84%) patients, CA50 in 11 (22%), CA125 in 13 (26%) and CA242 in 10 (20%). These tumor markers decreased obviously after preoperative RIAC (P <0.05, Student's t test) (Table 4).

Table 4

Table 4

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Pain relief and CBR

Pain relief was objectively evaluated with a NRS before and after preoperative RIAC (Table 4). The rate of pain relief was 80%. Pain relieved in 70% of the patients usually 1 or 2 days after preoperative RIAC. 42% patients had a weight gain of <10% from baseline, and CBR was 84%.

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Survival and liver metastasis

Median disease-free survival in groups A and B was 15.5 months and 14.0 months respectively (P=0.4262, Student's t test). No significant differences were noted in the median survival time between groups A and B (18.0 vs 16.5 months, P=0.8667, Student's t test). The 1-, 2-, 3-, and 5-year survival rates were 54.87%, 34.94%, 24.51%, 12.25% in group A and 56.85%, 36.06%, 24.73%, 11.89% in group B, respectively (Figure). The incidence of liver metastasis was lower in group A (34%) compared with group B (50%), although the difference was not statistically significant (χ2=2.63, P=0.105, the chi-square test).

Figure.

Figure.

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DISCUSSION

RIAC for pancreatic carcinoma

As reported, regional chemotherapy via an arterial port-catheter drug delivery system could elevate the regional concentration of the drug in the pancreas, thus combating the antidrug mechanism of the tumor and improving the therapeutic effect. There is a positive correlation between the therapeutic effect and the duration of drug action or the drug concentration. Since tumor cells grow more quickly than normal cells and require more oxygen and blood supply, there are abundant vascular bed and slower blood flow in the tumor. If chemotherapeutic drugs could congregate and achieve a high concentration in tumor tissue, they would be absorbed and metabolized by tumor cells, which could inhibit or kill the tumor cells directly. It has been confirmed that regional intervention chemotherapy induces apoptosis of tumor cells, which is an effective approach to comprehensive therapy for pancreatic carcinoma. 5-FU is proved to easily penetrate pancreatic tissue into the pancreatic secretions, remaining there at high concentrations, and MMC penetrates pancreatic tissue more easily when given locally.8 Local and international researches have confirmed the benefits of changing the route of drug delivery.9

Pancreatic cancer is a notably chemo-resistant malignant disease. A large number of clinical trials failed to show significant improvement of systemic chemotherapy. Recently, several centers have reported promising results of RIAC for pancreatic cancer. The inefficacy of systemic chemotherapy lies in poor tumor perfusion because of the hypovascular nature of pancreatic cancer and the multidrug resistance gene (MDR1). To increase the local regional drug concentration within the tumor is to directly infuse the tumor and the tumor-bearing region via its arterial blood supply. It has been verified by animal experiment that regional intra-arterial infusion could deliver a high dose of anticancer agents into pancreatic tissue, and prolong the retention and action time of drugs for the enhancement of drug efficacy.10 Meanwhile, it could decrease the drug concentration in non-cancerous tissues, reduce side effects, and increase the tolerance of chemotherapy compared with systemic chemotherapy. Furthermore, drugs not taken up on the first pass effect through the tumor-bearing region may be redelivered to the liver via the portal venous system, thus administration through the celiac trunk and SMA would get a better result in killing scattering cancer cells in the portal venous system or liver.2 Although the mechanism remains unclear, RIAC is benefitial to CBR and life quality with a lower toxicity for advanced pancreatic cancer.

RIAC for unresectable pancreatic carcinoma has been reported with definite positive effect on survival time and life quality. The total median survival time of unresectable patients is about 9.2 months when treated by RIAC, with 10.5 months for patients in stage III and 6.6 months for stage IV.11 The efficiency of RIAC as an adjuvant therapy for resected pancreatic carcinoma has already been proved. Beger et al 3 found that the median survival time of the patients with resected pancreatic carcinoma followed by postoperative RIAC was much better than that by systemic chemotherapy (23 months VS 10.5 months), could reduce the risk of liver metastasis (the occurrence in the RIAC group going down to 17%) and increase the 4-year survival of resected pancreatic cancer patients (54% vs 9.5%). Postoperative RIAC is also advantageous in enhancing anticancer drug delivery into tumor tissue and reducing the side effects of a comparable level of systemic treatment.12 But there is no clinical trial about preoperative RIAC or multiple-phase RIAC for resectable pancreatic head cancer.

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Neoadjuvant RIAC for pancreatic cancer

Neoadjuvant (preoperative) chemoradiation has several advantages as compared with adjuvant chemoradiation:13,14 (1) radiotherapy is more effective for intact vascularization; (2) preoperative chemoradio-therapy might reduce cancer cell seeding during tumor manipulation; (3) the potential retardation of postoperative recovery would not postpone neoadjuvant therapy; and (4) the effect of neoadjuvant therapy is identifiable in histopathological examination of the operative specimen.

The application and efficiency of neoadjuvant chemotherapy in pancreatic cancer have been advocated and verified recently. Neoadjuvant chemotherapy seems to downstage the tumor, thus increase the resectability of “unresectable pancreatic cancer”. Kastl et al15 found 16 of 27 patients with unresectable pancreatic cancer underwent surgical procedure after neoadjuvant chemotherapy 5 weeks later, and 10 of them succeeded in a radical excision. Wanebo et al16 reported in 14 patients who had palliative surgery before chemotherapy, 11 underwent laparotomy for the second time after 2 months of chemotherapy and 9 patients had tumors successfully resected. In the other hand, neoadjuvant chemotherapy might have no significant impact on resectability of locally advanced pancreatic cancer. Only 3 of 87 patients with local aggressive pancreatic carcinoma who received neoadjuvant chemotherapy in the Memorial Sloan-Kettering Cancer Center (MSKCC) were found downstaged to potentially resectable disease by CT-scan re-evaluation, and only 1 patient had the tumor resected.17

Neoadjuvant therapy of pancreatic carcinoma is able to increase the resectability with clear margins (R0-resection)18,19 and to decrease the rate of local relapse.20 Additionally, the therapy may decrease the rate of metastastic lymph nodes (30%-48%)20,21 compared to initial surgery (60%-80%).22,23 These effects improve the prognosis of patients with pancreatic carcinoma. Furthermore, neoadjuvant therapy is better tolerated than adjuvant therapy resulting in a higher number of patients who will tolerate the intended therapy.24 Neoadjuvant chemotherapy also has a positive effect on drug resistance and reduction of the incidence of pancreatic leakage.25 At least 25%-30% of the patients would avoid delayed adjuvant therapy because of surgical complications,18 as was seen in this study. The effect of downstage may be found in a minority of unresectable tumors after neoadjuvant chemotherapy.17

The effect and feasibility of preoperative RIAC for locally advanced pancreatic cancer have been investigated in our institute. We found that the serum tumor markers decreased obviously, and the rate of pain relief and CBR increased significantly after preoperative RIAC.4 These results also demonstrate that preoperative RIAC is able to increase the resectability, and could be used safely without delayed surgical procedure and delayed postoperative RIAC.

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Multiple-phase RIAC for resectable pancreatic cancer

Few studies focus on neoadjuvant RIAC or multiple-phase RIAC for resectable pancreatic cancer. According to our previous experience, preoperative RIAC could increase resectablity of locally advanced pancreatic head cancer.4,26 In this study of multiple-phase RIAC for resectable pancreatic cancer, tumors diminished in 26% of patients and the relationship between tumor and adjacent blood vessels changed in 20% of the patients after one cycle of preoperative RIAC, which helps to complete successfully a radical resection. Similar results were seen in the French SFRO-FFCD 97–04 Phase II trial.27

In this study, even preoperative RIAC was beneficial in pain relief and reduction of serum tumor markers, 3 patients with tumor PD were observed after preoperative RIAC, but no new lesion was found. These patients might experience rapid progression because of aggressive tumor biology, not only during or after neoadjuvant therapy but also after primary resection. They would be spared futile morbidity of Whipple's procedure if new lesion was found as restaged by image diagnosis.

Although adjuvant RIAC has been found to be effective in prolonging survival for patients after pancreatico-duodenectomy, the role of multiple-phase RIAC for resectable pancreatic cancer is not clearly identified. In this prospective trial we evaluated the new therapeutic mode of multiple-phase RIAC combined with extended panreaticoduodenectomy. In a previous study of a small sample, the tumor cell apoptosis was enhanced, and the expression of tumor metastasis-related genes (nm23-h1, MBD1, E2F5, RB) decreased significantly in the multiple-phase RIAC group.28 The feasibility and safety of the new therapeutic mode were confirmed, but the 5-year survival rate and the incidence of liver metastasis were not evaluated after multiple-phase RIAC in patients with resectable pancreatic cancer. In this study, the encouraging results were obtained as the number of patients enrolled increased. The median survival time, the median disease-free time, the incidence of liver metastasis and the 5-year survival rate were 18 months, 15.5 months, 34% and 12.25% respectively, showing an inspiring trend compared with the control group, especially in patients after panreaticoduodenectomy with portal vein resection.29 Although there was no statistical difference in the survival time and the incidence of liver metastasis at present, multiple-phase RIAC is an effective therapy for resectable pancreatic carcinomas. It is imperative to optimize the efficiency of multiple-phase (preoperative combined with postoperative) RIAC in the treatment of resectable pancreatic carcinomas, and strict randomized prospective trails with much more patients are needed in the future.

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Keywords:

pancreatic adenocarcinoma; neoadjuvant chemotherapy; multiple-phase; intra-arterial infusion chemotherapy

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