Pancreatic cancer is one of the most frequent causes of cancer-related deaths in the western world. The overall 5-year survival rate after potentially curative resection does not exceed 15% in most series [
In 1985 the Gastrointestinal Study Group showed that adjuvant chemoradiation offers significant survival benefit after surgical resection in patients with pancreatic cancer [
The sites of recurrence after curative resection are the liver in 50–60%, the peritoneal surfaces in 40–50%, and the pancreatic bed in 50% of the cases [
The purpose of the study is to identify the potential benefits of hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC) with gemcitabine in patients that undergo R0 resection for pancreatic cancer.
From April 2007 until August 2011, 21 patients with resectable pancreatic cancer, without distant metastatic lesions as assessed by routine preoperative staging (physical examination, CT-scan, MRI, and bone scanning) were enrolled in the study. The study was approved by the Ethical Committee of the hospital and patients signed an informed consent prior to accepting this therapeutic approach.
The diagnosis was possible by physical examination, hematological-biochemical examination, tumor markers (CEA, CA 19-9, CA-125), CT abdominal and thoracic scan or MRI, and bone scanning. No preoperative histological examination was performed.
Patients between 16–90 years of age, with satisfactory cardiopulmonary function, satisfactory renal function (blood urea level <50 mg/dL and creatinine level <1.5 mg/dL), satisfactory liver function (other than hepatobiliary obstruction), with white blood cell count >4000/mL, platelet count >150.000/mL, and acceptable performance status (Karnofsky performance status >50%) were included in the study.
Patients with evidence of distant metastatic disease (liver, osseous, brain and pulmonary), with prior antitumor therapy, with prior malignancy at risk for recurrence (except for basal cell carcinoma or in situ carcinoma of the cervix adequately treated), with poor performance status (Karnofsky performance status <50%), with psychiatric diseases or addictive disorders, and pregnant women were not included in the study.
Patients with periampullary tumors were not included in the study. Patients with resectable pancreatic cancer and limited peritoneal metastases for whom CC-0 or CC-1 cytoreduction could be possible, were included in the study.
Patients with cancer of the head of the pancreas underwent subtotal pancreatoduodenectomy (Kausch-Whipple procedure). Distal pancreatectomy was used for cancer of the body or the tail of the pancreas. After tumor resection and before the reconstruction of the alimentary tract, HIPEC was performed for 60 min at 42–43°C with gemcitabine at a dose of 1000 mg/m2. HIPEC was administered using the open (Coliseum) technique. A heater circulator with two roller pumps, one heat exchanger, one reservoir, and an extracorporeal system of two inflow and two outflow tubes, and 4 thermal probes was used for HIPEC (Sun Chip, Gamida Tech, France). A prime solution of 2-3 liters of normal saline was instilled prior to administration of the cytostatic drug and as soon as the mean abdominal temperature reached 40°C gemcitabine was instilled in the abdomen.
During perfusion adequate fluids were administered in addition to dopamine at a diuretic dose of 3
The reconstruction of the alimentary tract was performed after the completion of HIPEC. After subtotal pancreatoduodenectomy the reconstruction was always made with an end-to-side pancreato-jejunal anastomosis, end-to-side choledocho-jejunal anastomosis, followed by a Roux-en-Y gastrointestinal anastomosis with a second jejunal loop.
Cytoreductive surgery with standard peritonectomy procedures was used for the treatment of peritoneal metastases whenever they were found [
All resected specimens were sent for histopathological examination and complete staging. Stage III patients received additional systemic chemotherapy with gemcitabine and 5-FU.
All patients were followed up at 3-month intervals with physical examination, hematological, and biochemical examinations, tumor markers (CEA, CA 19-9, CA-125), and thoracic and abdominal CT. Recurrences and the sites of recurrence were recorded.
The proportion of patients with a given characteristic was compared by chi-square analysis or by Pearson’s test. Differences in the means of continuous measurement were tested by the Student’s
The mean age of the patients was
Patients’ general characteristics.
Male/Female | No. of patients | % |
---|---|---|
9/12 | 42.9/57.1 | |
Tumor anatomic distribution | ||
Head | 17 | 81 |
Body | 1 | 4.8 |
Tail | 3 | 14.3 |
Performance status | ||
90–100% | 15 | 71.4 |
70–80% | 5 | 23.8 |
50–60% | 1 | 4.8 |
Tumor infiltration | ||
T1 | 1 | 4.8 |
T2 | 3 | 14.3 |
T3 | 17 | 81 |
Nodal infiltration | ||
N0 | 9 | 42.9 |
N1 | 12 | 57.1 |
TNM stage | ||
I | 3 | 14.3 |
II | 6 | 28.6 |
III | 12 | 57.1 |
Degree of differentiation | ||
G1 | 4 | 19 |
G2 | 9 | 42.9 |
G3 | 8 | 38.1 |
Residual tumor | ||
R0 | 20 | 95.3 |
R1 | 1 | 4.7 |
The hospital morbidity rate was 33.3% (7 patients). The recorded complications are listed in Table
Postoperative complications.
No. of patients | % | |
---|---|---|
Postoperative bleeding | 1 | 4.8 |
Anastomotic leak | 2 | 9.5 |
Acute respiratory distress syndrome | 2 | 9.5 |
Sepsis | 1 | 4.8 |
Grade II neutropenia | 1 | 4.8 |
The 5-year survival rate was 23% and the median survival 11 months (Figure
Overall survival of 21 patients with pancreatic cancer treated with complete resection plus hyperthermic intraoperative intraperitoneal chemotherapy.
Currently 8 patients (38.1%) are alive without evidence of disease, 10 patients (47.6%) died because of recurrence, and 3 patients (14.3%) died of other causes unrelated to cancer.
Although the pathophysiology of local-regional recurrence is unclear it has been assumed that the resection of a tumor located within narrow margins of resection may result in tumor dissemination because of interstitial tissue trauma, or severed lymphatics leaking cancer cells, or from venous blood loss contaminated by cancer cells. The disseminated cancer emboli are trapped in fibrin, stimulated by growth factors, and give rise to local-regional recurrent tumors within months-years after initial surgical manipulations [
Gemcitabine as systemic adjuvant treatment has been proved to be very effective in high risk patients undergoing potentially curative resection [
The theoretical advantage of intraperitoneal gemcitabine has been confirmed by clinical and laboratory studies. Pharmacokinetic studies of intraperitoneal administration in a rat model have demonstrated that the area under the curve ratio of intraperitoneal to systemic drug exposure is closely related to the intraperitoneal dose and tissue samples showed increased drug concentration when administered with heat [
Our preliminary results in the resection of pancreatic cancer with HIPEC using gemcitabine have shown that there may be a survival advantage even in patients with nodal involvement.