Cryosurgery has provided a novel therapeutic approach to the treatment of benign and malignant tumors, especially unresectable tumors[13
]. A number of clinical trials have been published using this modality for the treatment of liver cancer, prostate cancer, kidney tumors, and breast cancer, with encouraging results[14,15
There are few reports on the use of cryosurgery for the treatment of pancreatic cancer. Kovach[16
] reported 9 patients with unresectable pancreatic cancer who received a total of 10 sessions of intraoperative cryosurgery under ultrasound guidance. There was no cryosurgery-related mortality and no post-cryosurgery pancreatic fistulae or pancreatitis. Following treatment, patients experienced alleviation of pain and reduction in the use of analgesic agents. All patients were able to take normal diet at the time of discharge from the hospital. Patiutko[17
] treated 30 patients with locally advanced pancreatic cancer with a combination of cryosurgery and radiation. All patients had effective control of pain, reduction in CA19-9, improvement of performance, and increase in the survival rate. Korpan[18
] summarized the experience of cryosurgery for pancreatic cancer, and concluded that most patients obtained good results with this therapeutic modality.
The effectiveness of cryosurgery is dependent upon complete cryoablation to all the targeted tissue. Tumor persistence or recurrence at the site of cryoablation is often the result of incomplete destruction. Temperatures lower than -40°C are believed to be necessary for tumor ablation. Ice-balls targeted lesions are thus necessary for complete destruction of the tumor, because the outer several millimeters of the iceball circumference are at nonlethal temperatures. The 1-cm ice-ball extension beyond the tumor borders is required for adequate ablation[19,20
]. However, because the pancreatic volume is relatively small, cancer often involves most of the gland, and over-freezing increases the risk of complications, it is often difficult to ensure the “1 cm safe border”. Therefore, we decided to use the combination of cryosurgery with 125
iodine seed implantation for the treatment of the pancreatic cancer. 125
Iodine with a half-life of 59 d provides γ radiation for a short distance, resulting in the death of the targeted cells. Brachytherapy using 125
iodine seed implantation has been successfully used for the treatment of prostate cancer and metastatic or recurrent cancer[21–24
]. As a result, the use of 125
iodine seed implantation is likely to be complementary to cryosurgery .
In the present study, 49 patients with locally advanced pancreatic cancer were treated with a combination of cryosurgery and 125iodine seed implantation. Thirteen patients underwent intraoperative cryosurgery and 36 patients percutaneous cryosurgery under ultrasound and CT guidance. The tumors showed different degrees of necrosis, and the CR, PR and SD were 20.4%, 38.8% and 30.6%, respectively, and only 10.2% demonstrated PD. During the median follow-up of 18 mo (5-40 mo), the median survival was 16.2 mo, of whom 26 patients (53.1%) survived 12 mo or more. The 6-, 12-, 24- and 36-mo survival rates were 94.9%, 63.1%, 22.8% and 9.5%, respectively.
Currently, the conventional therapies for locally advanced pancreatic cancer are chemotherapy and radiotherapy. Previous reports showed a median survival of 6-10 mo in patients with locally advanced disease treated with 5-FU-based chemoradiation. Patients with metastatic disease had a shorter survival (3-6 mo)[1
]. A recently described combination regimen that is under investigation consists of gemcitabine, 5-FU, cisplatin, capecitabine and/or radiation[25–34
]. These combination therapies produced a median progression-free survival ranging from 3-10 mo, and median survival of 7-16 mo, the objective response rate of the tumors was 22%-40%, and 1-year survival was 20%-78% (less than 60% in most reports) (Table ). The results in our series were similar to those reported previously. However, it is important to note that in this series there were 8 cases who survived for 24 mo or more. The patient with the longest survival is living for 40 mo, with no evidence of recurrence. The findings indicate that combination of cryosurgery and 125
iodine seed implantation offers the possibility of complete remission.
Recent chemoradiation trials in patients with locally advanced pancreatic cancer
Using univariate and multivariate analysis, presence of hepatic metastasis was an independent prognostic factor and was associated with poor outcome. It was surprising to note that patients who were underwent to adjuvant regional chemotherapy had a lower survival. This finding could in part be related to patient selection; patients receiving chemotherapy had more severe illness, and one-half had hepatic metastases.
By univariate analysis, it was observed that patients with cancer of pancreatic head had longer median survival compared with patients with cancer of pancreatic body or tail. The reasons may be that cancer of pancreatic head is detected relatively earlier because of the development of obstructive jaundice.
It is believed that tumor size is of critical importance in cryotherapy[35
]. However, tumor size could not be confirmed as an independent prognostic factor in our analysis. This finding may be related to the possibility that the combination of cryosurgery and 125
iodine seed implantation may effectively destroy the entire tumor or a greater part of the targeted tissue, even in the presence of a large mass.
A great deal of attention has been paid to the safety of cryosurgery in the treatment of pancreatic cancer. Korpan[8
] performed an experimental study on dogs who received pancreatic cryosurgery using the disc cryoprobe. None of the animals developed complications and there was no cryosurgery-related mortality. Moreover, there was no post-cryosurgery bleeding, pancreatic fistulae or secondary infection. In our series, no cryosurgery-related mortality was observed. The main adverse effects were abdominal pain, fever and increased serum amylase levels. Some patients developed acute pancreatitis, but none had a poor outcome. In addition, 125
iodine seed implantation can be performed at the same time, and is not accompanied with the adverse effects observed with chemo-radiotherapy. As a whole, combination therapy of cryosurgery and 125
iodine seed implantation is a less invasive procedure.
] pointed out that there were almost no known contraindications to the use of cryosurgery for pancreatic cancer. For most patients with pancreatic cancer, cryosurgery can substitute conventional surgery. These observations need to be confirmed by more studies. According to our experience, cryosurgery has several advantages in the treatment of unresectable pancreatic cancer: (1) The conventional management of unresectable pancreatic cancer involves a bypass operation without removal of the tumor. Cryosurgery can make up this shortcoming of conventional therapy, by converting the surgery from “palliative” to “radical”. (2) Cryosurgery is less invasive, and has lower rate of complications compared with conventional resection. (3) Unresectable tumors can be treated with percutaneous cryosurgery under ultrasound or CT guidance, with similar efficacy as intraoperative cryosurgery and is much less invasive to the patient.(4) During percutaneous cryosurgery, other modalities, such as 125
iodine seed implantation, can be used simultaneously. (5) Metastatic tumors can be treated simultaneously, using the combination technique. (6) Immune enhancement or activation after cryosurgery may occur probably due to quantitative and qualitative changes in the surface antigen (component) of tumor cells[36
]. That is called “cryoimmunity”[37
]. (7) The cryoablated cancerous tissue has increased sensitivity to chemo/radiotherapy[38,39
In conclusion, although the present data is preliminary, it indicates that combination of cryosurgery and 125iodine seed implantation may play an important role in the treatment of locally advanced pancreatic cancer. These findings warrant further refinement of the technique as well as initiation of controlled clinical studies to better define the true value of combination treatment in pancreatic cancer.