DOI: https://doi.org/10.21203/rs.3.rs-1669627/v1
To evaluate the prognostic efficacy and safety of 192Ir brachytherapy combined with external beam radiation in the treatment of unresectable hilar cholangiocarcinoma.
The clinical data of patients with unresectable hilar cholangiocarcinoma admitted to Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine in Hebei Province from January 2014 to March 2019 were retrospectively analyzed. The treatment mode was concurrent chemoradiotherapy + biliary stent +/- brachytherapy. Survival was analyzed using the Kaplan–Meier method.
This study included 62 patients; 32 received 192Ir brachytherapy combined with external beam radiation and percutaneous hepatobiliary stenting as the treatment group, and 30 received external beam radiation and percutaneous hepatobiliary stenting as the control group. After 3 months of treatment, the complete remission rates (CRs) of the treatment group and the control group were 15.6% and 6.7%, respectively, the partial remission rates (PRs) were 78.1% and 63.3%, and the objective remission rates (ORRs) were 93.7% and 70%, respectively. The median progression-free survival (PFS) of the treatment group and the control group was 11.0 months and 8.5 months, respectively. The 1-year PFS rates for the treatment group and the control group were 37.5% and 6.3%, respectively, and the 2-year PFS rates were 16.7% and 0%, respectively. There was a statistically significant difference in the progression-free survival rate between the two groups (P < 0.05). The median overall survival (OS) of the treatment group and the control group was 14.5 months and 12.2 months, respectively. The 1-year OS rates for the treatment group and control group were 58.8% and 27.9%, respectively; the 2-year OS rates were 51.6% and 14.7%, respectively. There was no significant difference in the overall survival rate between the two groups (P > 0.05). TBIL, DBIL, ALT, AST and CA19-9 in the treatment group were significantly lower than those before treatment and 3 months after treatment in the control group, and the difference was statistically significant (P < 0.05). No serious complications, such as bile leakage or biliary tract hemorrhage, occurred.
192Ir brachytherapy combined with external beam radiation and biliary stenting might improve the local control rate of unresectable hilar cholangiocarcinoma, with reliable prognostic efficacy and tolerable adverse reactions, providing a feasible and safe treatment method for clinical practice.
Cholangiocarcinoma is divided into intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma and distal cholangiocarcinoma. Hilar cholangiocarcinoma refers to bile duct mucosal carcinoma involving the common hepatic duct, left and right hepatic ducts and their confluence, accounting for approximately 60–70% of extrahepatic cholangiocarcinomas. The incidence of hilar cholangiocarcinoma is approximately 0.01% (Clary et al. 2004), and surgical treatment is the only possible cure for long-term survival (Angelico et al. 2021), but the 5-year survival rate after cholangiocarcinoma is only 12% (Stremitzer et al. 2019; Tran et al. 2019), but 60%~70% of patients have lost the opportunity for surgery when they are diagnosed (Bridgewater et al. 2014). For patients with locally advanced hilar cholangiocarcinoma that cannot be surgically removed, interventional therapy, chemotherapy, radiotherapy, targeted therapy, and immunotherapy can benefit some patients(Belkouz et al. 2020; Bisello et al. 2019; Palmieri et al. 2020; Yang et al. 2018) but still cannot improve the treatment effect. External beam radiation therapy often fails to reach the ideal dose due to the limited number of organs at risk, resulting in local recurrence or uncontrolled disease progression. In clinical work, interventional therapy, brachytherapy and external radiotherapy are often used to improve the local control effect of hilar cholangiocarcinoma. At present, brachytherapy combined with external radiotherapy and biliary stent treatment of hilar cholangiocarcinoma are rarely reported.
The dose of 192Ir brachytherapy can decrease quickly, meeting the dose of the tumor target area and reducing the exposure to the surrounding organs at risk. Therefore, it is often used as a boosting therapy for external beam radiation therapy to achieve better tumor control. A biliary stent indwelling drainage tube can better reduce the yellow infarction. This study retrospectively analyzed the clinical data of our hospital using 192Ir brachytherapy combined with external beam radiation and biliary stents to treat unresectable locally advanced hilar cholangiocarcinoma, evaluated the prognostic efficacy and safety, and explored its clinical application value.
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).
Summary: From January 2014 to March 2019, 62 patients with 192Ir brachytherapy combined with external beam radiotherapy for hilar cholangiocarcinoma who were confirmed by pathology and/or imaging in Cangzhou Integrated Traditional Chinese and Western Medicine Hospital of Hebei Province were treated. The patients were divided into a treatment group (32 patients) and a control group (30 patients), which were comparable in terms of demographics and disease factors at baseline (Table 1).
| Clinical features | Treatment group N % | Control group N % | p |
|---|---|---|---|
| Sex Male Female | 24 75.0 8 25.0 | 23 76.7 7 23.3 | > .05 |
| Age > 65yr ≤ 65yr | 12 37.5 20 62.5 | 10 33.3 20 66.7 | > .05 |
| Bismuth-Corlette Type II Type Ⅲ Type Ⅳ | 3 9.4 22 68.7 7 21.9 | 4 13.3 20 66.7 6 20.0 | > .05 |
| Child-Pugh Class A Class B | 26 81.2 6 18.8 | 25 83.3 5 16.7 | > .05 |
| TNM stage IIIA IIIB IIIC | 14 43.7 11 34.4 7 21.9 | 12 40.0 12 40.0 6 20.0 | > .05 |
Follow-up lasted until July 2021. The follow-up period ranged from 7 to 28 months, and the median follow-up time was 16.3 months. Five patients survived, including 3 patients in the observation group and 2 patients in the control group. A total of 57 patients died, including 28 patients with liver metastasis, 18 patients with lung metastasis, and 11 patients with liver metastasis combined with lung metastasis. Local control was assessed 3 months after the end of treatment. In the treatment group, there were 5 cases of complete remission, accounting for 15.6% (5/32), 25 cases of partial remission, accounting for 78.1% (25/32), 2 cases of stable disease, accounting for 6.3% (2/32), and no cases of disease progression. The objective response rate was 93.7%. In the control group, there were 2 cases of complete remission, accounting for 6.7% (2/30), 19 cases of partial remission, accounting for 63.3% (19/30), 8 cases of stable disease, accounting for 26.7% (8/30), 1 case of progressive disease, accounting for 3.3% (1/30). The objective response rate was 70%. The median progression-free survival in the treatment group was 11.0 months, and the 1- and 2-year progression-free survival rates were 37.5% and 6.3%, respectively. The median progression-free survival in the control group was 8.5 months, the 1- and 2-year progression-free survival rates were 16.7% and 0%, respectively. There was a statistically significant difference in the progression-free survival rate between the two groups (P = 0.032). The median overall survival in the treatment group was 14.5 months, and the 1-year and 2-year overall survival rates were 58.8% and 27.9%, respectively. The median overall survival in the control group was 12.2 months, the 1- and 2-year overall survival rates were 51.6% and 14.7%, respectively. There was no significant difference in the overall survival rate between the two groups (P = 0.361). See Fig. 2–3.
Three months after treatment, TBIL, DBIL, ALT, AST and CA19-9 levels in the two groups were significantly lower than those before treatment; this indicated that the treatment was effective, and the difference was statistically significant (P < 0.01). TBIL, DBIL, ALT, AST and CA19-9 levels in the treatment group were significantly lower than those in the control group at 3 months after treatment, and the difference was statistically significant (P < 0.05). See Table 2 for details.
| Treatment group | Control group | t | p | |
|---|---|---|---|---|
| TBIL(umol/L) Before After | 251.47 ± 85.79 32.94 ± 19.19 | 232.69 ± 86.89 53.49 ± 25.77 | 0.856 -3.576 | 0.395 0.001 |
| DBIL(umol/L) Before After | 204.38 ± 67.81 27.95 ± 16.54 | 199.46 ± 64.42 39.73 ± 25.07 | 0.293 -2.198 | 0.771 0.032 |
| ALT(U/L) Before After | 161.31 ± 54.69 31.47 ± 13.13 | 176.40 ± 52.45 48.13 ± 16.02 | -1.107 -4.492 | 0.273 0.000 |
| AST(U/L) Before After | 174.03 ± 59.28 32.81 ± 17.82 | 190.97 ± 55.22 44.17 ± 17.59 | -1.162 -2.523 | 0.250 0.014 |
| CA-199(U/mL) Before After | 443.36 ± 213.44 203.72 ± 117.21 | 461.17 ± 206.98 268.03 ± 124.15 | -0.333 -2.098 | 0.740 0.040 |
There was no significant difference in adverse reactions between the two groups (Table 3). In the treatment group, 46.8% (15/32) of patients experienced grade 1–2 neutropenia, 12.5% (4/32) of patients experienced grade 3 or higher hematological toxicity. In the control group, 43.3% (13/30) of patients experienced grade 1–2 neutropenia, 13.3% (4/30) of patients experienced grade 3 or higher hematological toxicity, and they improved after treatment. In the treatment group, 40.6% (13/32) of patients experienced grade 1–2 thrombocytopenia, and 15.6% (5/32) experienced grade 3 or higher hematological toxicity; in the control group, 40% (12/30) and 10% (3/30) of patients experienced grade 1–2 thrombocytopenia and grade 3 or higher hematological toxicity, respectively. These reactions improved after treatment with platelet raising. In the treatment group, 34.4% (11/32) of patients experienced grade 1–2 nausea and vomiting, and 28.1% (9/32) experienced abdominal pain; in the control group, 33.3% (10/30) of patients experienced grade 1–2 nausea and vomiting, and 30% (9/30) experienced abdominal pain. Cholangitis occurred among 9.4% (3/32) of patients in the treatment group and 3.3% (1/32) of patients in the control group, and this reaction improved after anti-infective treatment. No serious complications, such as biliary fistula or biliary bleeding, occurred in the two groups during the treatment. See Table 3 for details.
| Variable | Treatment group(n = 32) | Control group (n = 30) | P Value |
|---|---|---|---|
| Neutropenia,n(%) Grade 1 ~ 2 ≥Grade 3 | 15 (46.8) 4 (12.5) | 13 (43.3) 4 (13.3) | 0.962 |
| Thrombocytopenia, n(%) Grade 1 ~ 2 ≥Grade 3 | 13 (40.6) 5 (15.6) | 12 (40) 3 (10) | 0.773 |
| Nausea and vomiting,n(%) Grade 1 ~ 2 ≥Grade 3 | 11 (34.4) 0 (0) | 10 (33.3) 0 (0) | 0.931 |
| Abdominal pain,n(%) | 9 (28.1) | 9 (30) | 0.871 |
| Cholangitis,n(%) | 3 (9.4) | 1 (3.3) | 0.652 |
| Bleeding,n(%) | 0 (0) | 0 (0) | |
| Biliary fistula,n(%) | 0 (0) | 0 (0) |
192Ir brachytherapy is a kind of brachytherapy that is different from the 125I radioactive particle therapy that has been more widely reported in clinical practice. To achieve an ideal dose distribution, the radiation radius is short, and the radiation dose can drop rapidly. When the dose of the tumor target area increases, the radiation dose to the surrounding organs at risk is small, and there is no leftover in the body. Therefore, it is often used as a booster treatment for external beam radiation therapy to achieve better local tumor control. Some studies have reported the use of 125I radioactive seeds in the treatment of unresectable hilar cholangiocarcinoma (Zhang et al. 2015), while the application of 192Ir brachytherapy has rarely been reported (Mukewar et al. 2015).
Kamphues(Kamphues et al. 2012) retrospectively analyzed 10 patients with intrahepatic or hilar cholangiocarcinoma recurrence after resection. All patients received at least one CT-guided 192Ir brachytherapy, and the 1-year survival rate after treatment was 77.1%. No serious complications were found to be a safe treatment. Mukewar(Mukewar et al. 2015) and others believed that external beam radiotherapy combined with 192Ir brachytherapy for unresectable hilar cholangiocarcinoma could downstage inoperable patients to meet the surgical standard and then performed liver transplantation and explored a neoadjuvant. The method of radiotherapy brings survival benefits, but the catheter is placed retrogradely under the endoscope, which is difficult to operate and prone to adverse reactions such as cholangitis, duodenal disease, and severe abdominal pain. Ba et al. (Ba et al. 2020) found that compared with ERCP, PTCD reduced the incidence of cholangitis and pancreatitis in patients with type II, type III and type IV hilar cholangiocarcinoma; in particular, the risk of type III and type IV cholangitis was significantly reduced, and reducing hospitalization costs is the preferred interventional drainage method for hilar cholangiocarcinoma. A number of studies(Dechao et al. 2016; Tan et al. 2015) have reported that percutaneous biliary stents combined with brachytherapy or percutaneous biliary stents combined with external beam radiotherapy in the treatment of unresectable hilar cholangiocarcinoma and biliary stent indwelling drainage tubes can better reduce the occurrence of yellow infarction and are a safe and effective palliative treatment method. External beam radiotherapy alone for hilar cholangiocarcinoma often results in dose limitation due to organs at risk (such as the liver or duodenum) and the amount required to achieve satisfactory dose gradient. Therefore, in this study, 192Ir brachytherapy combined with external irradiation and biliary stenting was used to treat locally advanced hilar cholangiocarcinoma that could not be surgically removed. Compared with external irradiation combined with biliary stents, it improved the patency of internal drainage, effectively reduced bilirubin, and relieved symptoms. Stem yellow can improve liver function and the local control rate of tumors, and the short-term efficacy is reliable. The median survival time of the treatment group was longer than that of the control group, and there was a trend of benefit, but no statistical significance was achieved.
According to the latest research report(Qi et al. 2020), 317 cases of hilar cholangiocarcinoma from 2004 to 2014 were selected from the SEER database, and the survival rate was analyzed by propensity matching with intrahepatic cholangiocarcinoma and hepatocellular carcinoma. The 1-year OS rate of hilar cholangiocarcinoma was 26.2%, and the 2-year OS rate was 10.7%, which were significantly lower than those of intrahepatic cholangiocarcinoma (1-year OS rate of 62.2%, 2-year OS rate of 36.4%) and hepatocellular carcinoma (1-year OS rate of 72.4%, 2-year OS rate of 48.5%)%), which had the worst prognosis. In particular, Bismuth–Corlette type III and IV patients are often inoperable and have a worse prognosis. The main treatment methods include interventional biliary drainage, chemotherapy, radiotherapy, photodynamic therapy and palliative support. Cassani LS (Cassani et al. 2019) and others believed that adequate biliary drainage could improve the overall survival rate of patients, with a median OS of 11.0 months and a 1-year OS rate of 48%. The success of stent implantation was significantly associated with longer OS. Shin DW(Shin et al. 2020) et al. reported that gemcitabine combined with cisplatin in the treatment of unresectable hilar cholangiocarcinoma resulted in a median OS of 12.8 months, which was significantly higher than that of the best support group of 6.1 months, and patients who were older (70 years old and above) did not have a higher risk of death than younger patients. Dumoulin FL(Dumoulin et al. 2007) and other studies analyzed that the median OS of photodynamic therapy for hilar cholangiocarcinoma was 9.9–21 months, and the median OS of brachytherapy was 9.4–24 months, but the median OS of most of them was approximately 12 months. Bisello S et al.(Bisello et al. 2019) reported that chemoradiotherapy was used for the treatment of hilar cholangiocarcinoma. Patients who received concurrent chemoradiotherapy accounted for 77.6%, and patients who received sequential chemoradiotherapy accounted for 22.3%. The chemotherapy regimen was gemcitabine or fluorouracil, and the OS rates at 1 and 2 years were 58.1% and 25.8%, respectively, and the median OS was 13.5 months. The median OS, 1-year OS rate, and 2-year OS rate in the treatment group in this study were slightly better than those previously reported.
Adverse reactions, such as hematological toxicity, nausea and vomiting, biliary tract infection, etc., all improved after symptomatic treatment. No serious complications (e.g., biliary leakage and biliary tract bleeding) occurred, and the adverse reactions were tolerable.
There are also many limitations in this study. Due to the low incidence of cholangiocarcinoma and the small number of cases collected, we conducted a retrospective study because a prospective randomized controlled study could not be performed. Additionally, the chemotherapy regimens were not uniform across all patients. This combined treatment mode is limited by the low penetration rate of brachytherapy equipment and requires certain practical abilities and clinical experience. In the future, we will continue to collect data, expand the number of clinical cases, and conduct further randomized controlled studies.
192Ir brachytherapy combined with external beam radiation and biliary stents might improve the local control rate of unresectable hilar cholangiocarcinoma, seems to prolong survival and is safe and tolerable, thus providing a feasible and safe treatment method for clinical practice.
Funding
This work was supported by Hebei Province Medical Science Research Project Program [20200608].
Declaration of competing interest
The authors have stated that they have no conflicts of interest.
Author Contributions
Wenbo Yang, Yang Li and Li Xiao were responsible for article writing,data collection and analysis. Fei Liu was responsible for statistics.Yunchuan Sun were responsible for article creation, correction and guidance.
Availability of data and material
The datasets used in this study are available from the corresponding author on reasonable request.