Gallbladder Cancer Treatment & Management

Although complete surgical resection is the only therapy to afford a chance of cure for gallbladder cancer, en bloc resections of the gallbladder and portal lymph nodes carry a high morbidity and mortality (similar to bile duct carcinoma). Adequate surgical margins may be difficult to achieve.

The role of adjuvant radiation therapy is to control microscopic residual deposits of carcinoma in the tumor bed and regional lymph nodes. ^[27] The rationale for radiation therapy with or without concurrent chemotherapy in patients with unresectable disease is to provide palliation of symptoms. Rarely, it may increase survival.

The role of radiotherapy for carcinoma of the gallbladder is unclear because the available literature is derived from small, single-institutional experiences over many years, with a variety of treatment methods used. Complicating this is the fact that only approximately 25% of patients with carcinoma of the gallbladder can undergo curative surgery.

Even large institutions do not accrue more than single-digit numbers of patients per year, and many are not on protocol. Available reports contain small numbers of patients with incomplete reporting of technical treatment data, histological grading, and tumor extent. The literature is strongly biased by patient selection, and interpretation of the reports is difficult. Given these difficulties, the data support the following statements:

Radiotherapy has been delivered in a variety of situations, including after curative resections with close or positive microscopic margins, gross macroscopic residual disease, and palliative debulking with bypass.

Significant increases in survival rates have been reported after curative surgery is attempted and only microscopic residual disease remains. Survival in these patients after surgery alone ranges from 6-7 months and can be prolonged to longer than 12 months with adjuvant external beam radiotherapy. This excludes patients with T1 or stage I disease confined to the mucosa of the gallbladder, whose survival rates are extremely high and who are at very low risk for lymph node metastases.

All patients with tumors beyond the mucosa are candidates for external beam radiotherapy. Patients with curative resection and AJCC stages T2-T4 who have had complete resection who receive radiation have a mean survival of over 16 months. This compares with less than 6 months mean survival with surgery alone.

Combination chemotherapy with gemcitabine plus cisplatin is the standard first-line chemotherapy regimen for patients with advanced biliary tract cancer. ^[28] The multicenter, phase III randomized ABC-02 study, which included 149 patients with gallbladder cancer, established gemcitabine plus cisplatin as the standard of care in this setting. In ABC-02, the median overall survival was 11.7 months for those receiving gemcitabine plus cisplatin compared with 8.1 months for those receiving gemcitabine alone; progression-free survival was 8 months in the group receiving gemcitabine plus cisplatin compared with 5 months in those receiving only gemcitabine. ^[29]

Simiarly, a randomized, controlled, single-institution study in 81 patients with unresectable gallbladder cancer by Sharma et al found that gemcitabine plus oxaliplatin provided statistically superior rates of overall response, median overall survival, and progression-free survival, compared with best supportive care or 5-fluorouracil plus folinic acid. ^[30]

However, the TOPAZ-1 trial demonstrated that the addition of the programmed death–ligand 1 (PD-L1) inhibitor durvalumab to the gemcitabine/cisplatin regimen improved  In the trial—a double-blind, placebo-controlled, phase 3 study in 685 patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease—24-month overall survival was 24.9% (95% CI, 17.9 to 32.5) in the durvalumab group, versus 10.4% (95% CI, 4.7 to 18.8) in the placebo group. The hazard ratio for progression-free survival (PFS) with durvalumab was 0.75. Objective response rates were 26.7% with durvalumab and 18.7% with placebo. ^[3] Real-world experience has largely confirmed the TOPAZ-1 results. ^[31] Current National Comprehensive Cancer Network guidelines recommend durvalumab/gemcitabine/cisplatin as the preferred regimen for unresectable and metastatic disease. ^[25]

For the most part, randomized studies of the addition of biological therapies (EGFR or VEGF inhibitors) to treatment for gallbladder cancer have failed to show an improvement in survival. ^[28] For example, the BINGO trial concluded that the addition of cetuximab did not seem to enhance the activity of gemcitabine and oxaliplatin in patients with advanced biliary cancer. ^[32] However, an open-label, single-arm, phase II trial found that treatment with nab-paclitaxel plus gemcitabine-cisplatin prolonged median progression-free survival and overall survival versus the rates reported for historical controls. ^[33]

For patients with gallbladder cancer that progresses despite treatment with cisplatin and gemcitabine, the phase III ABC-06 study demonstrated a role for second-line therapy with FOLFOX (folinic acid, fluorouracil, and oxaliplatin). In ABC-06, median overall survival with FOLFOX plus active symptom control versus symptom control only was 6.2 versus 5.3 months, respectively (adjusted hazard ratio 0.69 [95% CI 0.50–0.97]; P=0.031). FOLFOX had an acceptable toxicity profile. ^[28]

Because some patients are not able to receive platinum-based chemotherapy, Iqbal et al explored gemcitabine plus capecitabine as a possible treatment option in a phase II study of 57 patients with advanced or metastatic biliary cancer. This study included both patients with cholangiocarcinoma (67%) and patients with gallbladder cancer (33%). No complete responses were seen. Of the 52 patients who were able to continue the study, a confirmed partial response was seen in 7 patients, and an unconfirmed partial response was seen in 6 patients. Stable disease was seen in 12 patients. Six-month overall survival was 55%, and median survival was 7 months. Of the 51 patients available for toxicity assessment, 6 had grade 4 toxicities. The study concluded that the combination of gemcitabine and capecitabine was well tolerated. ^[34]

Targeted therapy for gallbladder canceris is an area of active investigation. ^{[35, 4]} For patients with unresectable or metastatic disease, current National Comprehensive Cancer Network guidelines recommend entrectinib or larotrectinib for NTRK gene fusion–positive tumors and pembrolizumab for tumors with high microsatellite instability or deficient mismatch repair. ^[25]

Selected patients with initially unresectable disease may be considered for surgical resection after response to chemotherapy. This is based on a retrospective study showing markedly improved survival in a small number of patients who received gemcitabine and cisplatin followed by surgery. ^[36] More trials are needed to evaluate this benefit.

Patients with a good performance status should be considered for treatment with the regimens described in this section, or for participation in a clinical trial. Patients with a poor performance status may be best treated with supportive care.

Complete surgical resection is the only therapy to offer a chance of cure in this disease. Unfortunately, only a minority of patients present with early-stage disease and are, therefore, considered for curative resection.

Optimistically, 5 year survival rates for gallbladder cancer have increased 5-12% up to 38%. This increase is felt to be related to a trend in standardizing aggressive approaches to locally confined disease. ^[37] Studies evaluating the significance of tumor involvement of the liver in early T-stage tumors and lymph node metastases on outcomes suggest that a need to standardize minimum requirements for adequate surgical resection and pathological examination of gallbladder cancer resections. ^[38]

Patients who present with a gallbladder mass or jaundice are evaluated preoperatively for resectability, including chest imaging, abdominal/ pelvic CT scan, or MRI and possibly a staging laparoscopy. Nodal metastases outside of the regional area (ie, porta hepatis, gastrohepatic ligament, retroduodenal area) are not resectable. If the tumor is resectable, the patient should undergo a cholecystectomy, hepatic resection, and regional lymphadenectomy (see the image below).

The necessary extent of hepatic resection is currently undefined. However, approximately 25% of T2 tumors have liver involvement. Liver involvement is a prognostic indicator of worse outcome. ^[38] Bile duct excision may also be necessary, especially if jaundice is present. The operative morbidity and mortality rate increases with the complexity of the operative procedure.

Gallbladder cancer is sometimes an incidental pathology finding after a cholecystectomy is performed for reasons other than cancer. If the tumor is carcinoma in situ (Tis) or only invades the lamina propria (T1a) and the margins of resection are negative, then postoperative observation alone is acceptable. If the tumor is T1b or greater or the margins of resection are positive and if no metastatic disease is present on evaluation (CT or MRI scan and chest radiograph), then a second surgical resection is required. This additional surgery should include partial hepatic resection and regional lymphadenectomy (porta hepatis, gastrohepatic ligament, and retroduodenal lymph nodes). A bile duct resection may also be necessary, depending on tumor size and location.

If the original surgery was performed via a laparoscopic approach, then the port sites should also be resected to avoid tumor seeding. However, several studies have found that port site resection does not improve survival in patients with incidentally discovered gallbladder cancer. ^[39]

Because of the high incidence of gallbladder cancer in a calcified (porcelain) gallbladder, patients with this finding should be strongly considered for an open cholecystectomy, even if they are asymptomatic. Avoid a laparoscopic cholecystectomy in this setting to avoid the risk of peritoneal seeding if, indeed, gallbladder cancer is present.

Lymph node evaluation is a critical component of radical resections for gallbladder cancer and has been shown to improve survival in a retrospective trial. ^[40] Although no consensus has been reached on the minimum number of lymph nodes required for evaluation for accurate staging, one study demonstrated that resection and histologic evaluation of at least 6 lymph nodes improves risk stratification. ^[38] This underscores the importance of a thorough lymphadenectomy of the porta hepatis and complete review of the pathological specimens in patients with gallbladder cancer. ^[38]

The surgical role in treatment of unresectable disease is usually limited to biopsy of the tumor for diagnosis and possible biliary decompression procedures.

A radiation oncologist and medical oncologist should be part of the multidisciplinary team participating in the treatment of patients with gallbladder cancer.