Brachytherapy, Gallbladder Cancer

Anatomy and Physiology

The gallbladder is a small, pear-shaped hollow organ inferior to the liver in the abdomen, occupying the gallbladder fossa.[8] This organ measures around 7 cm to 10 cm in length and 4 cm in width. The gallbladder is part of the extrahepatic biliary system, where bile produced by the liver is stored and concentrated until it is needed for digestion. The cystic duct attaches the organ to the rest of the biliary system.

Anatomically, the gallbladder is divided into the fundus, body, and neck. The fundus is the wide, distal part that narrows into the main body. The body tapers into the infundibulum, which connects to the neck and cystic duct. The cystic duct aids gallbladder emptying in response to neural and hormonal signals.[9] The gallbladder's function is to store bile and release it during digestion. This process is stimulated by the secretion of cholecystokinin from the duodenum in response to gastric distension and fatty food content.[10]

Gallbladder cancer is often asymptomatic, leading to delayed detection and a poor prognosis due to significant disease progression at the time of diagnosis. Over a fifth of patients with this condition are diagnosed incidentally during surgical cholecystectomy for biliary colic and gallstones. The most common symptoms, usually present late in the disease, are abdominal pain (73%), nausea and vomiting (43%), jaundice (37%), anorexia (35%), and weight loss (35%).[11] Individuals with ascites, a mass on palpation, duodenal obstruction, or hematobilia usually have more advanced disease.

Indications

Brachytherapy is indicated for patients with gallbladder cancer in specific clinical scenarios. This procedure is particularly beneficial for individuals with localized gallbladder cancer who are not candidates for surgical resection due to medical comorbidities or have residual disease postsurgery. Brachytherapy may also be used as an adjuvant treatment following chemotherapy and external beam radiation therapy to improve local control and overall survival rates.[12] Additionally, this modality serves as a palliative treatment to manage symptoms and control local disease progression in patients with unresectable, locally advanced, or metastatic gallbladder cancer. Study results have shown that combining brachytherapy with chemotherapy can significantly increase median survival and improve local disease control.[13][14]

Contraindications

Contraindications to brachytherapy in gallbladder cancer include widespread metastatic disease where localized treatment would not provide significant benefit.[15] Patients who cannot tolerate the procedure due to poor overall health or severe comorbid conditions are also unsuitable candidates. Furthermore, anatomical variations that prevent effective catheter placement, such as in cases with complex biliary anatomy or severe obstruction that cannot be navigated, increase the risk of iatrogenic injury.[16] Brachytherapy is also contraindicated in cases where previous treatments have led to complications that increase a patient's vulnerability to this procedure's adverse events.

Equipment

Brachytherapy for gallbladder cancer requires several specialized tools and devices. High-dose-rate afterloaders and iridium-192 radioactive sources are essential for delivering precise doses of radiation directly to the tumor site.[16] Catheters, used for transhepatic or transduodenal placement, are crucial for accurately positioning the radioactive sources within the biliary system. Imaging tools such as computed tomography (CT), magnetic resonance imaging, and ultrasonography are necessary for visualizing the stenoses and guiding catheter placement to ensure accurate radiation dose delivery. Dosimetry software is also utilized to plan and optimize the radiation dose distribution, maximizing the therapeutic effect while minimizing exposure to surrounding tissues.[17]

Personnel

An interprofessional team is essential for successfully administrating brachytherapy in gallbladder cancer treatment. This team typically includes radiation oncologists, who oversee the treatment and ensure radioactive sources' correct dose and placement. Medical physicists are responsible for planning the radiation dose and ensuring the safety and accuracy of the treatment. Interventional radiologists perform the catheter placement using imaging guidance. Surgical oncologists may be involved in cases where surgical resection is part of the treatment plan. Radiation therapists assist in the treatment delivery and ensure the equipment's proper functioning. Specialized nursing staff provide patient care before, during, and after the procedure, managing side effects and monitoring for complications.

Preparation

Preparation for brachytherapy involves thorough patient evaluation to determine their suitability for the procedure. The process includes liver function tests, a complete blood count, and a comprehensive metabolic panel to assess the patient's overall health and detect potential issues that may complicate the treatment. Imaging studies such as CT, ultrasonography, and endoscopic ultrasonography are performed to determine the stage and extent of the cancer and to plan the catheter placement.[18][19]

Pretreatment simulations using CT scans help verify the catheter path and plan the dose to maximize therapeutic effects while minimizing exposure to nontarget tissues. The preparation process also involves coordinating with the interprofessional team to ensure that all necessary equipment and personnel are available and that the patient is adequately informed and prepared for the procedure. By adhering to these preparation protocols, the healthcare team can enhance the precision and effectiveness of brachytherapy for gallbladder cancer, ultimately improving patient outcomes.

Technique or Treatment

After imaging and evaluation, gallbladder cancer is staged using the Tumor, Node, and Metastasis system from the American Joint Committee on Cancer, eighth edition, with stages ranging from 0 to IV; management is determined based on the cancer stage. The 5-year survival rate decreases sharply with each stage, with survival rates of 81%, 50%, 29%, 7%, and 2%, respectively.[20] For patients diagnosed at stages 0, I, and II, surgical resection via cholecystectomy, along with removal of the bile duct, lymph nodes, and surrounding structures, is the first-line treatment. Individuals with resectable gallbladder cancer at stage II or higher are offered surgery followed by adjuvant chemotherapy.

One approach used gemcitabine 1000 mg/week for 4 weeks along with 5-fluorouracil (5-FU). This treatment produced a median overall survival of 43.1 months, a slight improvement over the 35.2 months observed in patients who received no chemotherapy, although the improvement was not statistically significant.[21] In the Southwest Oncology Group S0809 study, an adjuvant treatment combining chemotherapy with gemcitabine and capecitabine followed by radiotherapy showed effectiveness for biliary tract cancers, offering a 2-year survival rate of 65%. Patients received radiation doses of 45 Gy to regional lymphatics and up to 59.4 Gy to the tumor bed, reflecting a personalized treatment approach to maximize outcomes. Median survival reached 35 months, highlighting the treatment's potential.

Chemotherapy is the mainstay of management for unresectable locally advanced metastatic cancer. However, the efficacy of this approach is limited, and local therapy such as EBRT with a brachytherapy boost may be considered. Given the gallbladder's proximity to radiation-sensitive organs, such as the liver and small bowel, administering a brachytherapy boost may be the most effective method to escalate the dose enough for local control. Intraluminal brachytherapy (ILBT) has been used alongside chemotherapy and external beam radiation therapy (EBRT).

Results from a study found that patients who underwent ILBT for cholangiocarcinoma had an increase in median survival compared to those who did not receive any radiation (11 months vs 4 months, P < 0.00001). Another retrospective review showed that ILBT increased patency in malignant biliary tract obstruction (10 months vs 4-6 months) and provided better local control and complete and partial response rates. An increase has also been observed in the weighted mean overall survival, with 11.8 months compared to 10.5 months. The Mayo Clinic protocol for brachytherapy administration for cholangiocarcinoma is presented below and may also be used for gallbladder cancer.

The easiest way to deliver brachytherapy for gallbladder malignancies is via the transhepatic and transduodenal techniques. Both methods limit the radioactive isotopes to the obstruction. The locations of the stenoses are visualized with CT, magnetic resonance imaging, or other imaging, such as ultrasound.

The Mayo Clinic protocol for perihilar cholangiocarcinoma preceding liver transplantation is as follows:

• EBRT and chemotherapy: Patients receive a targeted dose of 45 Gy twice daily for 3 weeks and continuous 5-FU administration at 225 mg/m2/day.
• Brachytherapy: ILBT is then given endoluminally using iridium-192, targeting a dose of 16 Gy across 4 fractions over 2 days. If brachytherapy is not feasible, an additional EBRT boost of 1000 to 1500 cGy may be provided.
• Prolonged chemotherapy: After these treatments, oral capecitabine at 2000 mg/m²/day is given in 2 divided doses for 2 out of every 3 weeks until transplantation.
• Pretransplantation staging: Before potential liver transplantation, an abdominal exploration is performed to confirm the disease has not spread beyond local regions; suspicious lymph nodes are removed.
• Liver transplant: A cava-sparing approach is used, and postoperative care includes various immunosuppressants.[22]

Brachytherapy implantation may require catheter placement via endoscopic retrograde cholangiopancreatography. In this procedure, an 8.5- or 10-Fr, 250 cm long nasobiliary catheter is inserted into the bile duct, extending more than 1 cm beyond the malignant structure. This catheter ideally curves gently through the stomach without excess looping, as it is important to reduce friction and facilitate the extension of the HDR afterloader's source wire into the bile duct. For some patients, dual catheter placement into both the right and left biliary systems is performed, and a stent may accompany the nasobiliary catheter to stabilize and prevent migration.[23] Iridium-192 is the preferred radioactive source.

The external end of the catheter is rerouted transnasally, with its position verified radiographically to avoid internal looping. The catheter is then secured using a nasogastric strip and adhesive. A dummy wire enhances catheter rigidity, and a specialized marker wire helps distinguish paths in dual catheter scenarios.

After placement, the setup is confirmed via imaging, and adjustments are made to ensure efficient treatment delivery. Pretreatment simulation involves using a CT scanner to verify the catheter path and adjust the setup if the dummy wire stalls, ensuring low friction and proper reach of the afterloader. This simulation is accomplished before the treatment to plan the dose, maximizing the therapeutic effect while minimizing exposure to nontarget tissues such as the duodenum. The targets are then contoured, and the dwell position and dwell times are determined with the goal of complete volumetric coverage. The total dose and technique depend on whether the brachytherapy is administered following EBRT, given alone, and the goals of care.

In bile duct cancer brachytherapy, the clinical target volume (CTV) margin is established at 1 cm around the stenosis. A planning target volume is created by adding a margin around the CTV to account for setup variability. EBRT delivers 30 to 40 Gy in 2-Gy fractions, targeting the tumor and regional lymph nodes. High-dose-rate brachytherapy follows, with 15 to 20 Gy delivered directly to the PTV over 2 to 3 sessions. Pulsed-dose-rate brachytherapy may involve 20 Gy per course or up to 40 to 50 Gy in 2 to 3 courses for intensive treatment scenarios. Palliative treatment options range from 20 to 40 Gy in 1 or 2 courses (see Image. Brachytherapy and Radiation Techniques).[24]

Complications

Brachytherapy for gallbladder cancer carries certain risks due to its invasive nature. Acute adverse events include nausea and elevated transaminase levels, which are generally mild. However, severe complications can arise, such as cholangitis, gastrointestinal and biliary bleeding, and duodenal stenosis. Dose constraints ensure that nearby organs like the stomach and duodenum receive less than 55 Gy to minimize the risk of severe complications. Doses above 55 Gy increase the risk of severe gastrointestinal issues in approximately one-third of patients. Long-term complications may include strictures and chronic inflammation at the treatment site.

Clinical Significance

Brachytherapy shows promise as a treatment option for gallbladder cancer. This intervention is particularly relevant for cases where surgery is not feasible, shifting the treatment focus from cure to disease control and symptom palliation. By delivering targeted radiation via catheter-based techniques, brachytherapy offers an alternative that may improve survival and control over the disease, as demonstrated in other biliary tract cancers. In gallbladder malignancies, the transhepatic and transduodenal delivery methods isolate radioactive isotopes to the obstructed area, minimizing exposure to surrounding organs. Data suggest that brachytherapy could be a valuable addition to the therapeutic arsenal against gallbladder cancer, particularly in locally advanced or metastatic cases, providing a means to extend survival and improve quality of life when traditional therapies may fall short.[25]

Enhancing Healthcare Team Outcomes

Brachytherapy for gallbladder cancer requires a comprehensive and collaborative approach among healthcare professionals to optimize patient outcomes. Various specialists, including radiation oncologists, medical physicists, interventional radiologists, surgical oncologists, radiation therapists, and specialized nursing staff, are needed to provide effective and compassionate care to patients. Each member of the interprofessional team brings unique skills and knowledge essential for the effective planning, delivery, and follow-up care required by brachytherapy.

Radiation oncologists oversee the treatment, ensuring the correct dose and placement of radioactive sources. Medical physicists are responsible for planning the radiation dose and ensuring the accuracy and safety of the treatment. Interventional radiologists perform the catheter placement using imaging, and surgical oncologists may be involved in cases where surgical resection is part of the treatment plan. Radiation therapists assist in delivering the treatment, and specialized nursing staff provide patient care before, during, and after the procedure.

Effective interprofessional communication is important to ensure clear information exchange and collaborative decision-making. Regular team meetings and case discussions allow for the sharing of insights and coordination of care plans. This communication ensures that each team member is aware of their responsibilities and can contribute effectively. For example, during pretreatment simulations, medical physicists and radiation oncologists work together to verify the catheter path and adjust the setup. This collaboration ensures low friction and proper reach of the afterloader.