Running title:Combination of cryosurgery and 125iodine seed implantation for pancreatic cancer

Ke-Cheng Xu, Li-Zhi Niu, Yi-Ze Hu, Wei-Bing He, Yi-Song He, Ying-Fei Li Jian-Sheng Zuo

Ke-Cheng Xu, Li-Zhi Niu, Wei-Bing He,Yi-Song He, Jian-Sheng Zuo, Cryosurgery Center for Cancer, Fuda Cancer Hospital Guangzhou, Guangzhou 510300, Guangdong Province, China

Yi-Ze Hu, Department of Hepato-biliary Surgery, GuangzhouMedicalCollege, Guangzhou 510300, Guangdong Province, China

Ying-Fei Li,Department of Gastroenterology, Nanfang Hospital, Nanfang Medical university, Guangzhou, Guangdong Province, China

Author contributions:Xu KC made study plan, managed patient data and wrote the paper, Niu LZ, Hu YZ and He WB performed cryosurgery procedure, He YS performed 125iodine seed implantation, Li YF performed statistical analysis, Zuo JS supervised the trial process

 Supported by: the Science-development Grand of Science-technology Department of GuangdongProvince and Grand of Health Department of Guangdong Province

Correspondence to: Ke-Cheng Xu, Cryosurgery Center for Cancer, Fuda Cancer Hospital Guangzhou, No 167, West Xingang Road, Guangzhou 510300, Guangdong Province, China. xukc@vip.163.com

 Telephone: +86-20-84196175Fax: +86-20-84195515

Received: July 11, 2007Revised: December 29, 2007

 Abstract

AIM：To study the therapeutic value of combination of cryosurgery with 125iodine seed implantation for locally advanced pancreatic cancer.

 METODS:Forty-nine patients with locally advanced pancreatic cancer, male 36 cases and female 13 cases, with the median age of 59 years old, were enrolled in this study. Twelve cases had liver metastases. The tumors of all cases were considered to be unresectable through a comprehensive evaluation. The therapy included cryosurgery, which was performed intraoperatively or percutaneously under guidance of ultrasound and /or CT, and 125iodine seed implantation，which was performed during cryosurgery process or post-cryosurgery under guidance of ultrasound and /CT. There were a few patients who received regional celiac artery chemotherapy.

 RESULTS: Thirteen patients received intraoperative cryosurgery and 36 patients received percutaneous cryosurgery. Part of patients underwent the repeat cryosurgery. 125Iodine seed implantation was performed during freezing procedure in 35 cases and with 3-9 d after cryosurgery in 14 cases. Twenty patients in which 10 had hepatic metastases received regional chemotherapy. At the 3 mo after therapy，CT follow-up was performed to estimate the tumor response to therapy. In the most of the cases tumors had varying degrees of necrosis. Complete response (CR) of tumor was seen in 20.4% of patients, partial response (PR), in 38.8%, stable disease (SD), in 30.6% ,and progressive disease (PD), in 10.2%. The adverse effects associated with cryosurgery mainly included pain of upper abdomen and increased serum amylase activity. Acute pancreatitis was seen in 6 patients in whom one presented severe pancreatitis. All adverse effects were controlled by medical management with no poor outcome. There was no therapy-related mortality. During the followed-up of median 18 mo (range of 5-40) median overall survival was 16.21 mo and there were 26 cases (53.1%) whose survival was 12 mo or more. Overall 6-,12-, 24-and 36-month survival rates were 94.9%、63.1% 22.8% and 9.5%, respectively. There were 8 cases that had survival of 24 mo or more. The patient with the longest survival is surviving without evidence of recurrence for 40 mo.

 CONCLUSION: The cryosurgery, due to far less invasive than conventional pancreas resection , and the low rate of adverse effects ,should be choice modality for most of the patients with locally advanced pancreatic cancer.125Iodine seed implantation can destroy the residue survival cancer cells after cryosurgery. Hence, combination of both modalities has a complementary effect.

Key words: Pancreatic cancer; Cryosurgery; Cryoablation; 125iodine seed implantation

 Xu KC, Niu LZ, Hu YZ, He WB, He YS, Li YF, Zuo JS. A pilot study on combination of cryosurgery with 125iodine seed implantation for treatment of locally advanced pancreatic cancer. World J Gastroenterology

INTRODUCTION

Pancreatic cancer grows rapidly and is near universally fatal. The majority of patients with pancreatic cancer are detected at a late stage of the illness, and the minority of patients are candidates for curative surgical resection. Overall 1-and 5-year survival rates are 20% and 5% only, respectively [1-3].Paclitaxel and gemcitabine have been considered to be effective agents for pancreatic cancer, but their response rates are no more than 20%, the effectiveness is lasted less than 6 mo [4,5]. Therefore, it is necessary to seek for novel modality [6,7]. This report is the first to look specifically at the value of combination of cryosurgery and 125iodine seed implantation for the treatment of locally advanced pancreatic cancer.

MATERIALS AND METHODS

Patients

Since March 2001 to November 2007, forty-nine patients with locally advanced pancreatic cancer underwent cryosurgery with combination of 125iodine seed implantation. They were 36 males and 13 females, aged 28-89 years old, with a median age of 59 years. Tumor size ranged 2.2-7.1cmin the largest diameter. Twelve patients had hepatic metastasis. Diagnoses in all patients were based on ultrasound, CT and MRI imaging, and there were 38 patients whose diagnoses were proved by histology. Before hospitalization, 14 cases have received 4-6 cycles of chemotherapy (gencitabine, cisplatin , 5-FU). The tumors in all patients received a comprehensive evaluation and were considered to be unresectable.

All patients were given information of cryosurgery guidelines, and the study received ethical approval.

Cryosurgery

The procedure of cryosurgery was performed with intraoperative or percutaneous approaches.

Intraoperative cryosurgery: Before the surgical procedure, patients were administrated a general anaesthesia and positioned for an upper abdominal incision. The involved pancreas was exposed by trans-peritoneal mobilization of the bowel and stomach. Once the specific pancreatic mass was identified, an 18-gauge Tru-Cut biopsy needle was used to obtain one to two cores of tissue from solid mass. If it was discovered that the tumor was unresectable through a thorough investigation, cryosurgery was performed in direct vision and under the guidance of ultrasound. A variable number (one to three) of 2- or 3-mm cryoprobes were placed directly into the pancreatic mass and positioned under ultrasound guidance. Generally, lesions smaller than 3cm could be reliably frozen with a single, centrally placed, 3-mm probe, and large lesions required multiple probes. A double cycles of freeze/thaw procedure was used with an argon gas –based cryosurgical unit (EndoCare, Inc., CA, USA). Each cryoprobe was cooled to -160 C and the resulting iceball monitored with ultrasound until frozen region encompassed the entire mass of the tumor with at least a “0.5-cm safe border”. The tissue was then allowed to slowly thaw to 0 C.A second cycle of freezing/thawing was performed after any necessary repositioning of the cryoprobes. After the freezing process was completed, the cryoprobes were removed and the still-frozen tract made by the cryoprobe was packed with thrombin-soated Gelfoam to control bleeding. For the metastases of the liver, the cryosurgery was performed simultaneously[8,9].

Percutaneous cryosurgery: The procedure was performed under local anaesthesia and under guidance of untrasound or CT. Insertion of cryoprobe was often done through the retroperitoneal approach based on the location of the tumor. Generally, the 2- or 3-mm cryoprobe was used. For the tumor more than 3cm, 2 to 3 probes may be used. For liver metastases, simultaneous cryosurgery was performed using additional cryoprobes which were inserted through right intercostal space. The cryosurgery procedure was the same as in intraoperative cryosurgery[9].

Seed implantation: The procedure was performed during the process of cryosurgery, or was done through percutaneous approach under guidance ultrasound or CT after cryosurgery. The 125iodine seeds were implanted at the border line of the tumor. The number of seeds was depended on the size of the tumor, and every seed was implanted in between the distance of 0.5cm.

Postoperative management: The patients were being instructed to stop diet for at least 3d. An analogue of somatostatin was given intravenous infusion, generally for 3 -4 d, or extended until alleviation of abdominal pain and repristination of the elevated serum amylase levels. Aprotinin ( Trasylol ), an inhibitor of pancreatic enzymes, and proton pump inhibitor were given intravenous infusion in patients with abdominal pain and increased serum amylase levels.

Adjuvant regional chemotherapy: Infusion of chemotherapeutic drugs began at one wk after cryosurgery, and was performed via catheters in celiac artery and/or hepatic artery .The prescription was 5-FU 500mg(m2 , mitomycin C 8.5 mg(m2andgemcitabine 500 mg(m2,for once in every 2 wk as a cycle.

Follow-up

Postoperative follow-up was obtained at the one month after treatment and in every 3 mo thereafter by assessment of tumor markers, abdominal ultrasonography, and CT. Some of the patients received follow-up with positron emission tomography-CT (PET-C). Efficacy of cryosurgery was evaluated according to the evolution of tumor size and survival of the patients. Changes in tumor mass were measured according to The Response Evaluation Criteria in Solid Tumors (RECIST) protocol [10], which based on objective measurements of lesion size before and after treatment. Complete response(CR) means all targeted lesion disappearance (scar) or less than 25% of original size. Partial response(PR) means a greater than 30 % decrease in the sum of the largest diameter of all targeted lesions. Stable disease (SD) means less than 30% decrease in the sum of the largest diameter of all targeted lesions. Progressive disease(PD) means an increase of greater than 20% in the sum of the largest diameter of all targeted lesions.

All radiologic studies were reviewed by the same radiologist with a expertise in pancreas imaging. For lesions suspecious of recurrence, an ultrasound-guided biopsy was performed for histologic study. Subsequent re-cryosurgery was performed if histology showed positive result. A persistent nodule on radiologic imaging, without tumoral activity shown on PET-CT, or with the reducing and normal tumor markers (CA19-9) ,or no changes in the absence of other treatment for an interval of at least 6 mo since cryosurgery, was considered as a remnant. Tumor recurrence was estimated either by positive histology, or by the combination of increase of the cryotreated lesion size on ultrasound, CT or PET-CT imaging and increased tumor markers or by the discovery of metastases.

Statistical analysis

Survival was calculated using the Kaplan-Meier method[11]. Possible prognostic factors for influence on survival were tested using the Log-rank, Tarone-Ware or the Breslow test which were used for univariate analysis, and Cox regression[12](Cox’s proportional hazard model)with the forward-stepwise method(likelihood ratio) which was used for multivariate analysis with various covariates. A significant difference was assumed for a probability value <0.05.Statistical analysis was performed using SPSS version 11.5 (SPSS, Chicago, USA).

RESULTS

Thirteen patients received intraoperative cryosurgery, and 36 patients underwent percutaneous cryosurgery. Among the patients that received percutaneous cryosurgery, 17 cases received the second session of cryosurgery, 3 cases received the third session of cryosurgery. 125Iodine seeds implantation was performed during cryosurgery in 35 cases, and was done within the 3-9 d after cryosurgery in 14 cases. The number of 125 iodine seeds implanted for every patient was 34 in median with range of 18-54 seeds. Twenty patients, in whom 10 had hepatic metastases, received adjuvant regional chemotherapy. Five patients received 1 cycle of chemotherapy, 10 cases 2 cycles, 3 cases 3 cycles, 2 cases 4 cycles.

Response to treatment:According to the results of CT at 3 mo after treatment, the tumors in most of the patients had varying degrees of necrosis, CR, PR, SD and PD were 20.4% (10/49), 38.8% (19/49), 30.6% (15/49) and 10.2% (5/49), respectively.

Adverse Reactions: As showing in Table 1, 69.4% of patients had the abdominal pain, which subsided usually in 2-3 d. About half of the patients (51.0%) had an elevated serum amylase levels, which generally ranged 1-2 times of the normal reference values for 5 -7 d. Acute pancreatitis with acute abdominal pain, elevated serum amylase levels to four times or more was seen in 6 patients (12.2%),in whom one patient developed severe pancreatitis with intraabdominal fluid effusion, and serum amylase levels as high as 12 times ofnormal reference values. All patients with pancreatitis were cured by conservative management. Three patients (6.1%) had abdominal bleeding, however, the abdominal liquid drawed out by paracentesis had no obvious increased levels of amylase activity. The bleeding was disappeared within four d. More than half of patients (53.1%) had fever of 38 -39.5 C, with temporary chill. Fever was persisted for 3 -4 d, generally less than 7 d. Two patients had pulmonary infection, recovered with antibiotic therapy within 7 -10 d. Two cases aged 78 and 91 years old, respectively, had cerebral infarction and myocardial infarction, respectively. No treatment-related mortality occurred.

Overall survival

During a median follow-up of 18 mo (range of 5-40 mo), the median of over all survival was 16.2 mo. Twenty-six patients who (53.1%) survived 12 mo or more,8 of whom had survival of 24 mo or more. The patient with the longest survival is surviving without evidence of recurrence for 40 mo. There were 36 patients of death, in whom 17 died of cancer spread, 11 hepatic metastases died of liver failure, 5 cardio - cerebral vascular diseases, 3 unknown causes. The 6-,12-,24- and 36-mo overall survival rates were 94.9%、63.1% 22.8% and 9.5% (Figure 1 A).

A univariate analysis for possible factors influencing survival was performed (Table 3). Of the 5 variables tested, adjuvant chemotherapy and hepatic metastases were associated with a poor prognosis. The mode of cryosurgery (intra-operative vs percutaneous), tumor size (</= 4 cm vs >4cm), and location(headvs body or tail) were not proven to be independent significant for prognosis (Figure1 A and B).

The median survival in different subgroup of patients with pancreatic cancer was showed in Table 4. The following factors were associated with a longer median survival: cancer of pancreatic head, absence of hepatic metastases and no adjuvant chemotherapy.

A Cox model for multivariate regression analysis showed that of six factors apart from adjuvant chemotherapy, including patient’s age, sex, tumor size, location, mode of cryosurgery, number of 125iodine seed implanted and hepatic metastases, only hepatic metastases was independent prognostic factor(p= 0.007).

There were six examples of the cases as follows:

Case 1. Male,80 years old, Ultrasound found an occupying lesion of 3 X 3 cm in size within pancreatic neck. Biopsy showed a cystadenocarcinoma. Patient underwent percutaneous cryosurgery with 125 iodine seed implantation under CT guidance. Three mo after treatment, CT scan found that there was tumor necrosis, in which contained 125 iodine particles. Current ultrasound and CT scan shows that the original tumor was decreased to 1.5 x 1.1 cm in size (Figure 2). The patient has recurrence-free survival for 40 mo.

Case 2 Male, 61 years old. CT scan showed a low-density areas of 4 cm х5.5 cm in size in body of pancreatic and 3 intrahepatic lesions with sizes ranging from 2-5cm. Biopsy showed adenocarcinoma. The Serum CA19-9 was 512 IU. The patient underwent percutaneous cryosurgery and 125iodine seed implantation under guidance of CT / ultrasound for pancreatic lesion and hepatic metastases. Repeat CT scan showed the tumor shrinkage and stability of lesions in both pancreas and liver (figure 3).Ultrasound-guided biopsy showed no evidence of cancer.CA19-9 levels were decreased to below 40 IU. The patient is alive for 27 mo.

Case 3Male, 36 years old. Ultrasound and CT revealed the mass of pancreatic head with dilated common bile duct. Serum CA19-9 210 IU/L. The patient underwent laparotomy which discovered the mass of 5cm X 5 cm in size within pancreatic head. Biopsy showed moderate differentiation of adenocarcinoma. The palliative cholecystojejunostomy was performed for improvement of obstructive jaundice, and cryosurgery was performed for pancreatic tumor under direct vision and ultrasound guiding. CT follow-up at three mo after the treatment showed the shrinkage and necrosis of the pancreatic mass with “honeycomb”-like change (Figure 4).CA19-9 was decreased to 48 IU. The patient had survival of 19 mo.

Case 4Male, 67 years old, was detected obstructive jaundice and received CT examination, showing that the mass of 5X3cm in size in pancreatic head and dilated common bile duct and gallbladder. He received percutaneous cryosurgery and 125iodine seed implantation for pancreatic mass. Biopsy ofmass showed moderately well-differentiated mucinous adenocarcinoma. CT at 8 mo after treatment showed the shrinkage and necrosis of the pancreatic mass (Figure 5).

Case 5Female, 59 years old. CT examination discovered a mass of 4X3 cm in size in pancreatic tail. Biopsy proved to be pancreatic adenocarcinoma. Percutaneous cryosurgery with 125iodine seed implantation was performed (Figure 6 ).The follow-up at 14 mo after treatment showed

the stability of pancreatic tumor and the patient is surviving for 28 mo.