Rationale

The radioactive seeds recommended in brachytherapy are iodine-125, iridium-192, or palladium-103. Compared with the latter two sources, iodine-125 has a longer half-time of 59.7 days, which is appropriate in targeting rapidly growing tumors, such as with pancreatic cancer. Iridium-192 is always introduced in brachytherapy for gynecologic malignancies, such as endometrial cancer, with a similar survival rate as external beam radiotherapy. Palladium-103 has been widely accepted as a standard particle in brachytherapy for prostate and breast cancers. Iodine-125 source is sodium iodide-125 and the package is a titanium alloy tube sealed by laser. Each seed source is 4.5 mm in length and 0.8 mm in diameter, with a mean photon energy of 27 to 35 keV gamma ray, an initial dose rate of 7 centigray per hour and a mean radioactivity of 0.694 plus or minus 0.021 MCi (25.6 megabecquerel). The spillover of radiation beyond the region of interest is certainly a potential concern. However, the penetration distance in human tissue for each seed is only 1.7 cm, which allows for precise localization of the energy inside the tumor instead of irradiating the surrounding organs. For the same reason, the implanted seeds are harmless to the patient’s close contacts. The potential harm to the operators can be minimized by adequate shielding.

The most notable feature of radioactive seeds is the low dose rate. The low dose rate can maintain enough radiation dosage in the target while minimizing damage to surrounding normal tissue. Currently, the most common radioactive seed used clinically is iodine-125. When the doubling time of pancreatic cancer cells is short, it may be difficult to reach the adequate treatment dose in a relatively short interval after implantation. The effects of treatment of radioactive particles may also be less than ideal. At this time, external beam radiotherapy (XRT) or XRT combined with brachytherapy should still be considered standard of care, unless maximal dosage has already been reached or access to conventional XRT is difficult.

Current Literature

The first reported cases of EUS-guided brachytherapy were applied to head and neck cancer and recurrent esophageal cancer in a mediastinal lymph node. By searching PubMed with the strategy of “brachytherapy,” “seeds,” “endoscopy,” and “pancreatic cancer” from January 2000 to July 2010, a list of nine reports were summarized. Before EUS-guided radioactive seeds implantation could be applied in human tumor treatment, animal studies were necessary to confirm the safety and to simulate the protocol. Owing to the resemblance of anatomy and physiology to humans, the pig represents a suitable animal model. Sun and colleagues pioneered the EUS-mediated implantation, with four iodine-125 seeds in each pig. All the six pigs tested tolerated the trial; the median diameter of the lesion around the seed was 3.8 cm after sacrifice. The surrounding pancreas was sonographically normal and no seed migration occurred. Most important, localized tissue necrosis and fibrosis were only achieved in seed-containing pancreas, without significant complications. The usage of 18 or 19 gauge needles was shown to be safe puncturing through the gastric wall. The study firstly confirmed that EUS-guided implantation of radioactive seeds was a safe and minimally invasive technique for interstitial brachytherapy.

Under EUS, the maximal diameter of the tumor is measured by real-time sector ultrasound and the relationship between the surrounding vasculature and the tumor is then identified. The puncture points should be determined by color Doppler technology to prevent the injury to the pancreatic duct or the vessels.

The only available two clinical trials on EUS-guided brachytherapy of the pancreas come from China. The number of patients enrolled in these two studies was 15 and 22, respectively, with stage III or IV pancreatic cancer in most of the cases. The study conducted by Sun and colleagues reported an estimated median survival time of 10.6 months and 27% of the patients reached partial tumor response toward a mean 22 seeds load per patient. Procedure-related pancreatitis or pseudocyst was only found in three patients, which was considered mild and easily managed. With the combination of gemcitabine, Jin and colleagues further evaluated the clinical efficacy and safety of EUS-guided interstitial implantation of radioactive iodine-125 seeds in advanced pancreatic cancer. Although the novel technique did not significantly improve the overall survival rate, it showed an estimated median survival time of 9.0 months, with a partial remission rate of 13.6%, and an estimated 1-year survival rate at 27.3%. Moreover, the visual analog scale pain score significantly dropped from 5.07 to 1.73 1 week after brachytherapy and maintained for 1 month. Therefore, these two reports show promising preliminary data that pancreatic cancer can be treated safely with EUS-brachytherapy. Additional larger studies are needed to establish this as an acceptable option for inoperable pancreatic cancer. Compared with brachytherapy monotherapy as reported by Sun and colleagues, the brachytherapy-chemotherapy combination treatment did not seem to show a better tumor response or long-term outcome. Single gemcitabine chemotherapy provides a median 1-year survival rate of 21% (11.0%–37.2%). Having shown initial safety and feasibility in these preliminary clinical trials, the next step is to conduct randomized controlled trials with long-term follow-up to evaluate the efficacy between single EUS-guided implantation and single standardized chemotherapy. It would also be of interest to compare the efficacy and tolerability between EUS-guided brachytherapy and conventional external beam radiation.

Rationale

The radioactive seeds recommended in brachytherapy are iodine-125, iridium-192, or palladium-103. Compared with the latter two sources, iodine-125 has a longer half-time of 59.7 days, which is appropriate in targeting rapidly growing tumors, such as with pancreatic cancer. Iridium-192 is always introduced in brachytherapy for gynecologic malignancies, such as endometrial cancer, with a similar survival rate as external beam radiotherapy. Palladium-103 has been widely accepted as a standard particle in brachytherapy for prostate and breast cancers. Iodine-125 source is sodium iodide-125 and the package is a titanium alloy tube sealed by laser. Each seed source is 4.5 mm in length and 0.8 mm in diameter, with a mean photon energy of 27 to 35 keV gamma ray, an initial dose rate of 7 centigray per hour and a mean radioactivity of 0.694 plus or minus 0.021 MCi (25.6 megabecquerel). The spillover of radiation beyond the region of interest is certainly a potential concern. However, the penetration distance in human tissue for each seed is only 1.7 cm, which allows for precise localization of the energy inside the tumor instead of irradiating the surrounding organs. For the same reason, the implanted seeds are harmless to the patient’s close contacts. The potential harm to the operators can be minimized by adequate shielding.

The most notable feature of radioactive seeds is the low dose rate. The low dose rate can maintain enough radiation dosage in the target while minimizing damage to surrounding normal tissue. Currently, the most common radioactive seed used clinically is iodine-125. When the doubling time of pancreatic cancer cells is short, it may be difficult to reach the adequate treatment dose in a relatively short interval after implantation. The effects of treatment of radioactive particles may also be less than ideal. At this time, external beam radiotherapy (XRT) or XRT combined with brachytherapy should still be considered standard of care, unless maximal dosage has already been reached or access to conventional XRT is difficult.

Current Literature

The first reported cases of EUS-guided brachytherapy were applied to head and neck cancer and recurrent esophageal cancer in a mediastinal lymph node. By searching PubMed with the strategy of “brachytherapy,” “seeds,” “endoscopy,” and “pancreatic cancer” from January 2000 to July 2010, a list of nine reports were summarized. Before EUS-guided radioactive seeds implantation could be applied in human tumor treatment, animal studies were necessary to confirm the safety and to simulate the protocol. Owing to the resemblance of anatomy and physiology to humans, the pig represents a suitable animal model. Sun and colleagues pioneered the EUS-mediated implantation, with four iodine-125 seeds in each pig. All the six pigs tested tolerated the trial; the median diameter of the lesion around the seed was 3.8 cm after sacrifice. The surrounding pancreas was sonographically normal and no seed migration occurred. Most important, localized tissue necrosis and fibrosis were only achieved in seed-containing pancreas, without significant complications. The usage of 18 or 19 gauge needles was shown to be safe puncturing through the gastric wall. The study firstly confirmed that EUS-guided implantation of radioactive seeds was a safe and minimally invasive technique for interstitial brachytherapy.

Under EUS, the maximal diameter of the tumor is measured by real-time sector ultrasound and the relationship between the surrounding vasculature and the tumor is then identified. The puncture points should be determined by color Doppler technology to prevent the injury to the pancreatic duct or the vessels.

The only available two clinical trials on EUS-guided brachytherapy of the pancreas come from China. The number of patients enrolled in these two studies was 15 and 22, respectively, with stage III or IV pancreatic cancer in most of the cases. The study conducted by Sun and colleagues reported an estimated median survival time of 10.6 months and 27% of the patients reached partial tumor response toward a mean 22 seeds load per patient. Procedure-related pancreatitis or pseudocyst was only found in three patients, which was considered mild and easily managed. With the combination of gemcitabine, Jin and colleagues further evaluated the clinical efficacy and safety of EUS-guided interstitial implantation of radioactive iodine-125 seeds in advanced pancreatic cancer. Although the novel technique did not significantly improve the overall survival rate, it showed an estimated median survival time of 9.0 months, with a partial remission rate of 13.6%, and an estimated 1-year survival rate at 27.3%. Moreover, the visual analog scale pain score significantly dropped from 5.07 to 1.73 1 week after brachytherapy and maintained for 1 month. Therefore, these two reports show promising preliminary data that pancreatic cancer can be treated safely with EUS-brachytherapy. Additional larger studies are needed to establish this as an acceptable option for inoperable pancreatic cancer. Compared with brachytherapy monotherapy as reported by Sun and colleagues, the brachytherapy-chemotherapy combination treatment did not seem to show a better tumor response or long-term outcome. Single gemcitabine chemotherapy provides a median 1-year survival rate of 21% (11.0%–37.2%). Having shown initial safety and feasibility in these preliminary clinical trials, the next step is to conduct randomized controlled trials with long-term follow-up to evaluate the efficacy between single EUS-guided implantation and single standardized chemotherapy. It would also be of interest to compare the efficacy and tolerability between EUS-guided brachytherapy and conventional external beam radiation.