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

JIN Chen, YAO Lie, LONG Jiang, FU De-liang, YU Xian-jun, XU Jin, YANG Feng, NI Quan-xingPancreatic Disease Institution, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China

Pancreatic CarcinomaPancreatic CarcinomaPoor prognosis; overall 5-year survival

rate <5%Cure: radical resection of tumor at an

early ◦ median survival time is rarely >12-18 months

strong evidence that multimodality therapy could prolong the survival in patients w/ pancreatic CA

Chemotherapy: a promising combined-modality therapy for pancreatic CA◦ Although tumor is relatively resistant to

systemic chemotherapy

RIACRIACRegional intra-arterial infusion

chemotherapy (RIAC)◦More superior to systemic chemotherapy in

improving prognosis and QOL in patients with inoperable pancreatic CA.

Adjuvant RIAC in patients after pancreatic cancer resection could prolong the survival with low toxicity, and reduce the risk of liver metastasis.

No evidence to prove the efficiency of pre-op or multiple-phase RIAC for patients with resectable pancreatic CA

ObjectivesObjectivesTo evaluate the effect and safety

of multiple-phase RIAC in the combined-modality treatment for patients with pancreatic carcinoma

Prospective cohort study: multiple-phase RIAC in patients with resectable pancreatic head CA after pancreaticoduodenectomy

In the Study…In the 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

PatientsPatientsJan 2000-Dec 2006, px w/ 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).

PatientsPatientsGood function of the heart, liver and

kidney Routine blood test: normalNo history of prior

chemoradiotherapyPx w/ 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.

Inclusion CriteriaInclusion Criteria25–75 y/oResectable pancreatic head cancer;

tumor stage II or III (according to International Union against Cancer 2002) without adjacent vascular invasion judged by CT or MR

Reconfirmed diagnosis by histologically proven adenocarcinoma of the pancreas

normal liver functionno prior cancer therapyKarnofsky performance score (KPS) >60,

expected survival >3 mos

Exclusion CriteriaExclusion Criterianot histologically proven

adenocarcinoma of the pancreasunresectable tumors or distant

metastasissurgical procedure without radical

resection of the tumorany condition not allowed to

continue the protocolwithdrawal requirements from the

patients.

MethodsMethodsEligible patients were randomized into two

groups: ◦ grp A: treated with extended

pancreaticoduodenectomy combined with multiple-phase RIAC

◦ grp 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 Operative Criteria for Tumor ResectionResection

(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(5) no involvement of the superior

mesenteric artery, celiac artery, or common hepatic artery

(6) the ability to obtain adequate vascular control of the superior mesenteric vein/portal vein, splenic vein, and inferior mesenteric veins for a safe venous reconstruction

Regional intra-arterial infusion Regional intra-arterial infusion chemotherapychemotherapy

Patients in group A were given:◦one cycle preoperative RIAC 2 weeks

before extended pancreaticoduodenectomy

◦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.

Regional intra-arterial infusion Regional intra-arterial infusion chemotherapychemotherapyFor 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.

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.

Surgical procedure with Surgical procedure with extended extended pancreaticoduodenectomypancreaticoduodenectomyPatients 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.

Surgical procedure with Surgical procedure with extended extended pancreaticoduodenectomypancreaticoduodenectomyAnatomic 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.

Surgical procedure with Surgical procedure with extended extended pancreaticoduodenectomypancreaticoduodenectomyIf 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, biliary- enteric bypass and gastrojejunostomy were completed.

Surgical procedure with Surgical procedure with extended extended pancreaticoduodenectomypancreaticoduodenectomyAntibiotics 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.

Surgical complications, peri-operative death and length of postoperative hospital stay were also recorded.

Evaluation of therapeutic Evaluation of therapeutic effects and follow-upeffects and follow-upThe 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).

Evaluation of therapeutic Evaluation of therapeutic effects and follow-upeffects and follow-up

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.

Evaluation of therapeutic Evaluation of therapeutic effects and follow-upeffects and follow-up

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.

Statistical analysisStatistical 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.

ResultsResults

DiscussionsDiscussions

RIAC for Pancreatic RIAC for Pancreatic Carcinoma Carcinoma Regional chemotherapy via an arterial port-

catheter drug delivery system could elevate the regional concentration of the drug in the pancreas, thus 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.

RIAC for Pancreatic RIAC for Pancreatic Carcinoma Carcinoma Pancreatic cancer is a notably chemo-

resistant malignant disease. A large number of clinical trials failed to

show significant improvement of systemic chemotherapy.

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.

RIAC for Pancreatic RIAC for Pancreatic Carcinoma Carcinoma It has been verified that regional

intra-arterial infusion could :◦deliver a high dose of anticancer agents

into pancreatic tissue, ◦prolong the retention and action time of

drugs for the enhancement of drug efficacy.

Meanwhile, it could also:◦decrease the drug concentration in

non-cancerous tissues◦reduce side effects◦ increase the tolerance of chemotherapy

compared with systemic chemotherapy.

RIAC for Pancreatic RIAC for Pancreatic Carcinoma Carcinoma The efficiency of RIAC as an adjuvant

therapy for resected pancreatic carcinoma has already been proved.

It has been 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%).

RIAC for Pancreatic RIAC for Pancreatic Carcinoma Carcinoma But there is no clinical trial about

preoperative RIAC or multiple-phase RIAC for resectable pancreatic head cancer.

Neoadjuvant RIAC for Neoadjuvant RIAC for Pancreatic Cancer Pancreatic Cancer Neoadjuvant (preoperative)

chemoradiation has several advantages as compared with adjuvant chemoradiation:◦Radiotherapy is more effective for intact

vascularization; ◦Preoperative chemoradiotherapy might

reduce cancer cell seeding during tumor manipulation

◦The potential retardation of postoperative recovery would not postpone neoadjuvant therapy

◦ the effect of neoadjuvant therapy is identifiable in histopathological examination of the operative specimen.

Neoadjuvant RIAC for Neoadjuvant RIAC for Pancreatic Cancer Pancreatic Cancer The effect and feasibility of preoperative

RIAC for locally advanced pancreatic cancer have been investigated:◦The researchers found that the serum tumor

markers decreased obviously, and the rate of pain relief and CBR increased significantly after preoperative RIAC.

◦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.

Multiple-phase RIAC for Multiple-phase RIAC for Resectable Pancreatic Resectable Pancreatic Cancer 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.

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.

Multiple-phase RIAC for Multiple-phase RIAC for Resectable Pancreatic Resectable Pancreatic Cancer Cancer In this study, even preoperative

RIAC was beneficial in pain relief and reduction of serum tumor markers, 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.

Multiple-phase RIAC for Multiple-phase RIAC for Resectable Pancreatic Resectable Pancreatic Cancer Cancer In this study the new therapeutic

mode of multiple-phase RIAC combined with extended panreaticoduodenectomy were evaluated.

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.

Multiple-phase RIAC for Multiple-phase RIAC for Resectable Pancreatic Resectable Pancreatic Cancer Cancer 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

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.

RecommendationsRecommendationsit 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.