DISCUSSION

Cryosurgery recently has provided a novel therapeutic approach and has been used for the treatment of many benign and malignant tumors, especially for unresectable tumors[13].Several publications have reported on trials using the modality for the treatment of liver cancer, prostate cancer, kidney tumors, and breast cancer, and showed encouraging results [14，15].

There are few of reports about cryosurgery for treatment of pancreatic cancer. Kovach [16] reported that 9 patients with unresectable pancreatic cancer underwent a total of 10 sessions of intraoperative cryosurgery under ultrasound guidance. There was no cryosurgery-related motality and no post-cryosurgery pancreatic fistulae and pancreatitis. Following the treatment, patients had alleviation of pain and decrease of analgetic dose. All patients could take normal diet at discharge from hospital. Patiutko[17]treated 30 patients with locally advanced pancreatic cancer with combination of cryosurgery and radiation. All patients had effective control of pain, decrease of CA 19-9, improvement of performance, increased survival rates. Korpan[18] summarized the experience of cryosurgery for pancreatic cancer, and showed that there was a good efficacy of the modality for most of the patients.

The effectiveness of cryosurgery is dependent upon the completeness ofcryoablation to all targeted tissue. The tumor persistence or occurrence at the site of cryoablation is often resulted from an incomplete destruction. Temperatures lower than -40 °C are assumed necessary to ensure the tumor ablation. Ice-balls larger than the target lesions are thus necessary for complete tumor ablation, because the outer few millimeters of the iceball circumference are at the nonlethal temperatures. The 1-cm ice-ball extension beyond the tumor borders should be often used as adequate for ablation [19，20].However, because the pancreas volume is relatively small, cancer often involves most of the glands, and over-freezing increases the complications, it is very difficult to ensure the “1 cm safe border”. Therefore, we decided to try to use the combination of cryosurgery with 125iodine seed implantation for the treatment of the pancreatic cancer.125Iodine with half-life of 59 d radiates a γ ray of short distance and results in death of targeted cells. Brachytherapy using 125iodine seed implantation has been successfully used for treatment of prostate cancer and metastatic or recurrent cancer[21－24].It is much more likely that 125iodine seed implantationis complementary to cryosurgery.

In this study, 49 patients with locally advanced pancreatic cancer underwent the combination of cryosurgery with 125 iodine seed implantation. There were 13 patients who underwent intraoperative cryosurgery and 36 patients who underwent percutaneous cryosurgery under guidance of ultrasound and CT. As a result, most of the tumors had a different degrees of necrosis, CR ,PR and SD were 20.4% ,38.8% and 30.6%,respectively,and only 10.2% presented PD. During the median follow-up of 18 mo (5-40 mo), the median survival was 16.21mo for all patients, in whom 26 patients(53.1%) survived 12 mo or more. The overall 6-,12-,24- and 36-momth survival rates were 94.9%, 63.1%, 22.8% and 9.5%,respectively.

At present, the conventional therapies for locally advanced pancreatic cancer are chemotherapy and radiotherapy. Early reports showed a median survival of 6-10 mo survival in patients with locally advanced disease treated with 5-FU-based chemoradiation compared to no treatment or radiation therapy alone. Patients with metastatic disease had a shorter survival (3-6mo)[1].Recently described combination regimen under investigation consists of gemcitabine,5-FU,cisplatin, capecitabine and /or radiation[25-34].These combinations produced a median progressive-free survival ranged 3-10 mo, and median survival 7-16 mo, the objective response rate of the tumors was 22%-40%,and 1-year survival was 20%-78% (less than 60% in the most reports)(Table 6).The results in our series are similar to that reported in the above reports. However, it is important that in this series there were 8 cases who had survival of 24 mo or more. The patient with the longest survival is surviving without evidence of recurrence for 40 mo. The fact appears that combination of cryosurgery and 125iodine seed implantation offers the possibility of complete remission.

In the univariate and multivariate analysis, hepatic metastases was an independent prognostic factor andassociated with poor outcome. It was surprised that patients who underwent adjuvant regional chemotherapy after treatment had a low survival. This could at least in part relate to patient selection. The patients receiving the chemotherapy had more severe illness, and half had hepatic metastases.

In the univariate analysis, it is shown that the patients with cancer of pancreatic head had longer median survival compared with that in patients with cancer of pancreatic body or tail. The reasons may be that cancer of pancreatic head is easy detected because of obstructive jaundice and undergo proper management in relatively early stage.

It is believed that the tumor size has special importance in cryotherapy[35], however, in our analysis it was not confirmed as an independent prognostic factor. This may be resulted from that the combination of cryosurgery and 125iodine seed implantation could effectively destroy whole or great part of targeted tissue, even for larger tumor.

A great attention is paid for the safety of cryosurgery of pancreatic cancer. Korpan [8] made an experimental study on dogs that received pancreatic cryosurgery with the disc cryoprobe. No animal developed cryosurgery-related mortality and complications. No post-cryosurgery bleeding, pancreatic fistulae or secondary infection were observed.In our series, there was no cryosurgery-related mortality. The main adverse effects were abdominal pain, fever and increased amylase levels. There were a few of the patients who developed acute pancreatitis, but all had no poor outcome.. In addition, 125iodine seed implantation, as a local therapy, may be performed at the same time of cryosurgery, and is not complicated such persistent adverse effects as in chemo-radiotherapy. As a whole, the combination therapy consisted of cryosurgery and 125iodine seed implantation is a less- or mini-invasive technique.

Korpan[8,18]pointed out that there were almost no known contraindication of cryosurgery for pancreatic cancer. For the most of pancreatic cancer, the cryosurgery can be the substitute of conventional surgery. The opinion is needed to be confirmed. According to our experiences, for unresectable pancreatic cancer, cryosurgery has the following advantages: (a)At laparotomy the pancreatic cancer is discovered to be unresectable, the conventional management is bypass operation without intervention for the tumor. The cryosurgery may make up the shortcoming of the conventional therapy, and the operation, therefore, become “radical” from “palliative” .(b)The cryosurgery is a less invasive technique, and has low rate of the complications compared with conventional resection. (c)The tumor that has been considered to be unresectable, may undergo percutaneous cryosurgery under ultrasound or CT, which has a similar efficacy as inintraoperative cryosurgery and far less invasive to the patient.(d)During percutaneous cryosurgery, the other modalities, such as 125iodine seed implantation, may be used simultaneously.(e) The metastatic masses out of pancreas may be treated using the combination technique simultaneously.(f)Immune enhancement or activation after cryosurgery may occur probably due to a quantitative and qualitative change in the surface antigen (component) of tumor cells[36]. That is called “cryoimmunity” [37]. (g)The cryoablated cancerous tissue had an increased sensitivity to chemo / radiotherapy[38,39].

A shortcoming in this study is absence of a standardized candidate who is adaptable for the treatment, and whether the patient has “locally advanced” tumor often depends upon physican’s subjective evaluation.

In conclusion, while these data are preliminary, they indicate that combination of pancreatic cryosurgery with 125iodine seed implantation could play an important role in the treatment of patients with locally advanced pancreatic cancer. These findings warrant further development of techniques for the procedure as well as controlled clinical studies to further define real value of the new modality for management of pancreatic cancer.

 COMMENT

Background

Pancreatic cancer is the fifth leading cause of cancer-related death for both men and women. Patient survival depends on the extent of disease and performance status at diagnosis. Patients who undergo surgical resection for localized nonmetastatic pancreatic cancer have a longer-term survival rate of approximately 20% and a median survival of 12-20mo, however patients with locally advanced disease have a shorter-term survival of 6-10 mo. Current chemoradiation, including gemcitabine, could not improve the outcome of this disease. Therefore, it is important to develop a modality which is able to improve local tumor control without increasing toxicity for normal tissue in patients with locally advanced pancreatic cancer.

Research frontiers

Cryosurgery recently has provided a new therapeutic approach for prostate cancer and liver cancer with encouraging results. But there are few experience of cryosurgery for treatment of pancreatic cancer.125Iodine seed implantation has not been reported to treat pancreatic cancer as well.

Innovations and breakthroughs

To our knowledge, this is the first report that combination of cryosurgery with 125iodine seed implantation is used for treatment of locally advanced pancreatic cancer. Both cryosurgery and 125iodine seed implantation are local ablation technique with different mechanism, and it is believed that their combination will play a complementary effect.

Applications

Cryosurgery and 125iodine seed implantation can be performed during operation or percutaneously, are miniinvasive modality and specially adaptable to treat unresectable tumor.In more than 80% of patients with pancreatic cancer surgical resection is not feasible at the time of diagnosis. Of the patients who undergo operation with curative intent, only 30%-50% have their tumors successfully removed. Therefore, cryosurgery and 125iodine seed implantation are of special significance for management of unresectable pancreatic cancer.

Terminology

Pancreatic cancer is mainly derived from ductal tissue with adenocarcinoma being the most common malignancy. There are a few pancreatic cancer which are classified as adenosquamous, giant cell cancers, and mucinous cystadenocarcinomas. Microscopically, these tumors may vary from well-differentiated to undifferentiated tumors. Seventy to 80 percent of respectable pancreatic cancer have spread into lymph nodes. Ultrasonography and CT are the principal means of diagnosis of pancreatic cancer.

Peer review

This is an interesting, well written paper with practical value. The presentation is adequate and easy to understand. The results of this paper, despite the limited case number and the shorter follow-up, suggest that a benefit exists for locally advanced pancreatic cancer,mainly when cryosurgery is associated with 125iodine seed implantation.

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