Transcript Effect of multiple-phase regional intra

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 Xianjun, XU Jin, YANG Feng, NI Quan-xing
Pancreatic Disease Institution, Department of General
Surgery, Huashan Hospital, Fudan University, Shanghai
200040, China
Pancreatic Carcinoma
Poor 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
RIAC

Regional 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 preop or multiple-phase RIAC for patients with
resectable pancreatic CA

Objectives
To evaluate the effect and safety of
multiple-phase RIAC in the combinedmodality treatment for patients with
pancreatic carcinoma
 Prospective cohort study: multiple-phase
RIAC in patients with resectable
pancreatic head CA after
pancreaticoduodenectomy

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
Patients


Jan 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).
Patients
Good function of the heart, liver and
kidney
 Routine blood test: normal
 No history of prior chemoradiotherapy
 Px 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 Criteria
25–75 y/o
Resectable 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 function
 no prior cancer therapy
 Karnofsky performance score (KPS) >60,
expected survival >3 mos


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.

Methods

Eligible 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
Resection
(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
chemotherapy

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
chemotherapy



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.
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 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.

Surgical procedure with extended
pancreaticoduodenectomy
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.
Surgical procedure with extended
pancreaticoduodenectomy
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, biliary- enteric
bypass and gastrojejunostomy were completed.

Surgical procedure with extended
pancreaticoduodenectomy



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.
Surgical complications, peri-operative death
and length of postoperative hospital stay
were also recorded.
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).

Evaluation of therapeutic effects 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 effects 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 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.

Results
Discussions
RIAC for Pancreatic 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 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 Carcinoma

It has been verified that regional intraarterial 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 noncancerous tissues
◦ reduce side effects
◦ increase the tolerance of chemotherapy
compared with systemic chemotherapy.
RIAC for Pancreatic 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 4year survival of resected pancreatic cancer
patients (54% vs 9.5%).

RIAC for Pancreatic Carcinoma

But there is no clinical trial about
preoperative RIAC or multiple-phase
RIAC for resectable pancreatic head
cancer.
Neoadjuvant RIAC for 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 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 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.
 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 Resectable
Pancreatic 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 Resectable
Pancreatic 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 Resectable
Pancreatic Cancer
The median survival time, the median disease-free
time, the incidence of liver metastasis and the 5year 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.

Recommendations

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.