Patient information
The medical records of 62 patients with unresectable hilar cholangiocarcinoma confirmed by pathology and/or imaging in our hospital from January 2014 to March 2019 were analyzed and summarized. The study was approved by the ethics committee of our hospital. The inclusion criteria were as follows: signed informed consent; confirmed locally advanced hilar cholangiocarcinoma who lost the opportunity for surgery; expected survival more than 3 months; and no prior external beam therapy. The exclusion criteria were as follows: allergic to iodinated contrast agent, unable to perform cholangiography; cholangiography showed complete biliary obstruction, unable to perform biliary stent implantation; accompanied by severe vital organ insufficiency, unable to tolerate treatment; expected survival less than 3 months; poor compliance, not cooperating with treatment.
Treatment method
The patients in the treatment group first received percutaneous hepatobiliary stent implantation and then underwent external beam radiotherapy. After external beam radiotherapy, 192Ir brachytherapy (Figure 1) and concurrent chemotherapy were performed for 1 to 2 cycles, including 7 cases of gemcitabine combined with cisplatin chemotherapy, 16 cases of single-agent gemcitabine chemotherapy, and 9 cases of single-agent capecitabine chemotherapy. The patients continued to receive 2 to 4 cycles of chemotherapy after radiotherapy – mainly gemcitabine combined with cisplatin – and they could not tolerate combined chemotherapy with a single-agent gemcitabine or capecitabine regimen. Patients in the control group received external beam radiotherapy after percutaneous biliary stent placement and concurrent chemotherapy for 1 to 2 cycles. Among these patients, 5 were treated with gemcitabine combined with cisplatin chemotherapy, 14 were treated with single-agent gemcitabine chemotherapy, and 11 were treated with single-agent capecitabine chemotherapy. After radiotherapy, the method of selecting the chemotherapy regimen was the same as that of the treatment group.
Percutaneous hepatobiliary stent implantation
The patient is placed in a supine position, and oxygen inhalation, ECG monitoring, and preoperative pain relief are performed. The drape is routinely disinfected, and the 10-11 intercostal space in the right axillary is selected as the puncture point. After local anesthesia, the expanded peripheral hepatobiliary duct is selected under fluoroscopy guidance. After the puncture needle enters the expanded hepatobiliary duct, the needle core is removed, and the contrast agent is injected. After part of the bile duct tree is developed, it is sent into the sheath under the guidance of the microguide wire, the stasis is fully aspirated, and the bile duct is washed repeatedly with gentamicin saline. The angiography again fully shows the occlusion of the common bile duct. After exchanging the balloon to dilate the diseased bile duct, the length of the lesion and the diameter of the normal biliary tract are measured, an appropriate type of stent is placed, and the internal and external drainage tubes are placed.
External beam radiotherapy
Patients can be treated with external beam radiotherapy after receiving percutaneous hepatobiliary stents and drainage. All patients received intensity-modulated radiotherapy, and the radiotherapy equipment was an Elekta Synergy medical linear accelerator. The prescribed dose of PTV in the treatment group was 45 Gy/1.8 Gy/25 f, 5 times/week. The prescribed dose of PTV in the control group was 60 Gy/2 Gy/30 f, 5 times a week. First, the patient is positioned by CT, lying supine on a special positioning frame for radiotherapy, fixed by a polymer low-temperature hydrolyzed plastic body membrane, and subjected to enhanced CT scan under calm breathing, with a thickness of 5 mm. The scan range is from the diaphragm to the level of the lower pole of the kidney, and the image is transmitted after the scan Go to the Monaco5.0 planning system to outline the target area and plan the design. The tumor area (GTV) locates the CT image combined with the tumor area that can be seen by abdominal MRI. The clinical target area (CTV) is obtained from GTV, with 0.5 cm outward expansion in the left and right chest and back directions and 1.0 cm outward expansion in the head and feet direction, including drainage areas along the bile ducts and lymph nodes, pancreaticoduodenal and abdominal trunk lymphatic drainage areas, which should be properly repaired when covering important organs. The planned target area (PTV) is CTV with an external expansion of 1.0 cm; the liver, small intestine, and stomach are also delineated, along with the spinal cord and other crisis organs. The 95% iso-dose line surrounds the PTV, liver Dmean<20 Gy, duodenum V50<5%, small intestine Dmax<52 Gy and V45<195 cm3, stomach Dmax<54 Gy and V50<10%. During radiotherapy, routine blood, liver and kidney function and other indicators are monitored.
192Ir brachytherapy
After the patient ends external beam radiation therapy, brachytherapy can be performed. First, fluoroscopic intervention is performed, followed by radiotherapy catheter preplacement. The patient is supine, anesthetized and punctured until the biliary tract is inserted into a single 8Fr vascular sheath. The tip is placed at the proximal end of the duodenal Chua’s ligament. After implanting the tube and the false source, the position of the implant tube was adjusted to satisfaction under fluoroscopy. The implant tube and postinstallation radiotherapy catheter were wrapped with sterile accessories to ensure a stable position. If it is a type IV patient, place it on the other side in the same way. By positioning the CT scan, the scanned image is transmitted to the afterloading radiotherapy planning system, the tumor target area GTV is delineated, and the prescribed dose is 20 Gy/5 Gy/4 f. The radiotherapy plan is developed, D100, D90, V100, and V90 are evaluated, and the duodenum and liver are evaluated. The D2cc of the stomach and small intestine, combined with the exposure dose of external radiation, limits the safe dose range. After the plan is passed, the 192Ir high-dose rate afterloading treatment machine (MicroSelectron V3) will be connected for treatment 2 times per week. After brachytherapy, the radiotherapy catheter was withdrawn, and the bile internal and external drainage tubes were implanted again. After brachytherapy starts, anti-inflammatory agents should be actively given, and nutrition should be strengthened to prevent possible complications.
Efficacy evaluation and follow-up
The RECIST 1.1 standard is used for the efficacy evaluation. After treatment, upper abdominal enhanced CT or MRI was regularly reviewed. The first 3 months after the end of the treatment, the monthly review is performed, and the review is performed every 3 months after the end of the treatment. Observe and record the survival status. PFS was defined as the time from signing informed consent to recurrence and metastasis, OS was defined as the time from signing informed consent to death, and statistics of local control rate, PFS and OS were obtained. Changes in TBIL, DBIL, ALT, AST and CA19-9 indices before treatment and 3 months after treatment in the two groups. Adverse reactions were evaluated using the RTOG injury grading standard. The follow-up time began after signing the informed consent form, and the follow-up was once a month.
Statistical analysis
For statistical analysis, quantitative data with a normal distribution are presented as the mean ± standard deviation. Student’s t-test was used to compare continuous variables, and the Mann–Whitney U test was used to compare for nonnormally distributed variables. Categorical variables were compared using the χ2 test. Overall survival time was analyzed using the Kaplan–Meier method and log-rank test. All data analyses were performed using statistical software (SPSS V.25.0).