EUS -guided implantation

The values of EUS have been expanded from diagnosis to the treatment area. Because the resolution of EUS in local anatomy is better, and the puncture path has many advantages, EUS-guided implant treatment has been carried out and is demonstrated with broad application.

Radiotherapy Position

HK Kim et al reported the use of EUS-guided implantation of gold particles in abdominal radiation. The previous positioning of radiation required CT-guided percutaneous placement of some location marks. The process was often difficult because it was necessary through some abdominal organs, important ducts and vessels, etc. Under the guidance of EUS, some gold particles were implanted in the pancreas and liver tumors with 19-gauge fine needle. All cases were successful with no complications. EUS-guided implantation of gold particles is a more convenient and effective way of locating.

EUS-guided iodine 125I implantation in pancreatic cancer

By searching the Pubmed with the strategy of “brachytherapy”, “seeds”, “endoscopy” and “pancreatic cancer” from 2000 Jan to 2010 July, a list of 9 reports were summarized in Table 1.

The radioactive seeds recommended in brachytherapy are iodine-125, iridium-192 or palladium-103. Compared with the later two sources, iodine-125 has a longer half-time of 59.7 days, which is appropriate in targeting the rapidly growing tumor such as pancreatic cancer. Iridium-192 is always introduced in in brachytherapy for gynecological malignancies such as endometrial cancer, with a similar survival rate as the external beam radiotherapy. Palladium-103 has been widely accepted as a standard particle in brachytherapy for prostate and breast cancers. Iodine-125 source is Na125I, and the package is a titanium alloy tube sealed by laser. Each seed source is 4.5mm in length and 0.8mm in diameter, with a mean photon energy of 27–35 KeV gamma ray, an initial dose rate of 7 cGy/h, and a mean radioactivity of 0.694±0.021 mCi (25.6 MBq). As mostly concerned, the penetration distance in the human tissue for each seed is only 1.7cm, which allows localizing the energy inside the tumor instead of irradiating the surrounding organs. For the same reason, the implanted seeds are harmless to the patient's relatives. 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 radiation of low dose rate can maintain enough radiation dose in target while minimizing damage to surrounding normal tissue. About how to choose the right radioactive sources, some experts considered that Pd103 I125 is more suitable than others in pancreatic cancer through theoretical analysis. Currently, the most common radioactive seeds was 125I in clinic. When the doubling time of pancreatic cancer cell was short, it was difficult to reach the adequate treatment dose in a short time after implantation. The effects of treatment of radioactive particles may also be less than ideal. At this time, external beam radiotherapy or external beam radiotherapy combined brachytherapy should be chose.

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. Due to the resemblance of anatomy and physiology to human, pig becomes the most suitable animal to build up the model. Sun et al pioneered the EUS-mediated implantation, with 4 iodine-125 (125I) seeds in each pig. All the tested six pigs tolerated the trial and the median diameter of the lesion around the seed was 3.8cm after sacrifice. The surrounding pancreas was sonographically normal, and no seed migration occurred. Most importantly, localized tissue necrosis and fibrosis were only achieved in seed-contained pancreas, without significant complications. The usage of 18 or 19 gauge needles was proved to be safe during the puncture of 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.

By now the only available two clinical trials on EUS-guided brachytherapy came from China. The number of patients enrolled in these two studies was 15 and 22, respectively, with stage III or IV pancreatic cancer in a majority of cases. The study conducted by Sun et al. reported an estimated median survival time of 10.6 months and 27% 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 et al 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 improved 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 one-year survival rate at 27.3%. Moreover, the visual analogue scale pain score significantly dropped from 5.07 to 1.73 one week after brachytherapy and maintained for one 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 single brachytherapy as reported by Sun et al, the seed-drug combined treatment did not show a better tumor response and long-term effect. Single gemcitabine chemotherapy provides a median one-year survival rate of 21% (11.0%-37.2%). Following the proved safety and feasibility in human, next upcoming randomized controlled trials with long-term follow-up are expected 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.

EUS-guided celiac ganglion radiation for pain relief

Partial pain relief can be achieved simultaneously when the radioactive seeds release the tumor-killed ray inside the tumor. It is the physician's duty to retrieve the patient from the unbearable pain which leads to the poor living condition accompanied within the rest of the survival life. Celiac plexus neurolysis (CPN) and celiac plexus block (CPB) have been considered the first-line adjuvant therapies for the treatment of pain in pancreatic cancer patients. Gunaratnam et al. reported that EUS-guided CPN reduced pain in 78% pancreatic cancer patients. However, CPN can only relieve the pain in a limited degree, lasts a short period, and the analgesic effect is inversely correlated with the extent of invasion of celiac ganglia. EUS-guided brachytherapy with the implantation of iodine-125 seeds beside the celiac ganglion seems to be another choice for the pain relief. Recently, Wang et al. performed a pilot trial in a porcine model. Four pigs in each group were implanted with one 0.4 mCi or 0.8 mCi iodine-125 seed in either side of the celiac ganglion area with the help of EUS. Pigs implanted with non-radioactive seeds were used as controls. All animals were sacrificed and the celiac ganglions were checked on days 14 and 60. Compared with the control group, neuronal apoptosis in the ganglion was seen in both brachytherapy groups, and the intensity of necrosis increased with the radiation dose increasing. More apoptotic cells (index as 0.53 and 0.94, respectively) were seen on day 60 of irradiation than on day 14 (0.27 and 0.76, respectively) in both 0.4 mCi and 0.8 mCi groups. There were no significant complications during the experiment. This is the first preliminary evidence for the feasibility and safety of EUS-guided celiac neuron brachytherapy. The new technique may introduce an alternative treatment for pain accompanied pancreatic diseases in human. However, iodine-125 seeds, which own a long period of decay and thus may lead to the maintenance of analgesia, can not reach a rapid effect as CPN or CPB. More animal and clinical trials are needed to determine whether celiac ganglion radiation is superior to classic CPN, and whether the technique can be applied eventually in clinical practice.

Jin reported iodine-125 seeds under EUS guidance were implanted beside the celiac ganglion in 15 patients with 0.7 mCi (group 1) and 15 were treated with pharmacological therapy (group 2). Immediate and long-term efficacy, mean analgesic consumption, mortality and morbidity were evaluated. A mean number of four radioactive seeds per patient were implanted into the celiac ganglion. Immediately after the precedure, pain relief and analgesic consumption did not differ between two groups. Inversely, three patients reported pain exacerbation. But 10 days latter, patients in group 1 reported significant pain relief compared with those in group 2. Mean analgesic consumption was lower in group 1. There were no deaths. No complications such as transient diarrhoea, hypotension or infection occured. Drug-related adverse effects were constipation (6 of 15 patients in group 1 versus 13 of 15 in group 2), nausea and/or vomiting (four of 15 patients in group 1 versus 12 of 15 in group 2).

The efficacy of radioactive seeds implantation

EUS-guided radioactive seeds implantion has been found to be effective that may improve quality of life and survival in patients with advanced unresectable pancreatic cancer. The evaluation of it's effects remains a challenging clinical problem. Liu et al. reported the evaluation value of fuzzy classification of EUS texture features in radioactive seeds-implanting treatment in pancreatic cancer. The seeds treatment effect was evaluated through comparing the probability of cancer about before-treatment and after-treatment cases. 22 texture features are extracted according to the digital image processing algorithm. 216 EUS images are used as the train set and test set to perform several random experiments. Then the other 360 EUS images of 25 patients including before-treatment and after-treatment states are classified fuzzily according to the preceding best training results. Then the tumor's volumes' change, CA19–9's variation, and variation of probability of cancer (both before-treatment and after-treatment) are comparing to patients' survival time (whether more than 3 months). 19 patients' variation of probability of cancer vary with the patients' survival time (whether more than 3 months), which is much higher than the rates of volumes' change (14 patients in 25) and CA19–9's variation (9 patients in 25).

Problems and future

The common radioactive seeds in clinic have the size limitation, which is approved by SFDA and FDA. This has resulted in the difficulties in implanting seeds in pancreatic head and uncinate process, where EUS endoscopy was bended over in site. The radioactive seeds is relatively difficult to go through the fine needle. However, in the pancreatic neck, body and tail lesions, the operation is relatively easy. The development of new radioactive particle with smaller size, even for radioactive liquid is a follow-up research of EUS-guided implantation.

Although the exact seed number needed in the therapy can be calculated by the three-dimension computer system, the excise model for EUS-guided implantation has not been set up yet. But under EUS guidance, the evenly arrangement of radioactive seeds in the three-dimensional space is very difficult or even impossible. Therefore, the development of a new treatment planning system based on ultrasound image is very important.