Clinical trial for patients with incidentally discovered T2 or T3 gallbladder cancer: OPT-IN/EA2197

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract, with 90 percent of patients having unresectable or metastatic disease at diagnosis.¹ The often advanced nature of the disease at presentation contributes to a five-year overall survival (OS) rate of less than 5 percent.² Globally, approximately 30 percent of all patients with GBC are diagnosed incidentally following cholecystectomy, with the proportion approaching 60 percent in the U.S.^3,4

At present, the standard of care for patients with incidentally discovered T1b to T3 GBC (AJCC Cancer Staging Manual, 8th edition) is resection of the segment IVB/V hepatic parenchyma, along with a portal lymphadenectomy with a retrieval goal of at least six lymph nodes for complete staging.^5-8 Residual disease is found in upward of 60 percent of patients, with more than 70 percent having either regional nodal or distant disease.⁹ Recurrence at one year has been estimated to be as high as 40 percent for patients found to have residual disease in the re-resection specimen (see Figure 1).⁹ The possibility of radiographically occult disease makes it difficult to accurately preoperatively select patients for re-resection given the limitations of radiographic imaging in detecting peritoneal carcinomatosis.¹⁰

Systemic chemotherapy for GBC

The role of adjuvant therapy has been suggested in the BILCAP (Capecitabine compared with Observation in Resected Biliary Tract Cancer) trial.¹¹ This trial randomized patients with resected biliary tract cancers, including cholangiocarcinoma and GBC (18 percent of trial patients had GBC), to receive eight cycles of adjuvant capecitabine compared with observation alone. A per-protocol analysis demonstrated a 53-month OS in patients treated with capecitabine versus 36 months in the observation arm (p = 0.02) after a built-in sensitivity analysis.¹¹

FIGURE 1. RECURRENCE-FREE SURVIVAL OF PATIENTS WITH INCIDENTALLY DISCOVERED GBC FOUND TO HAVE RESIDUAL DISEASE AT THE TIME OF RE-RESECTION

This trial has been criticized based on the statistically negative intention-to-treat analysis (OS capecitabine: 51.1 months versus observation: 36.4 months; HR 0.81, p = 0.09). Although recurrence-free survival (RFS) was not the primary endpoint, the intention-to-treat analysis of RFS did reach clinical and statistical significance (RFS for capecitabine arm: 24.2 months versus observation: 17.5 months; HR 0.75, p = 0.03). Because less than 20 percent of patients enrolled in the trial had GBC, the BILCAP trial was statistically underpowered to make a specific recommendation regarding the benefit of adjuvant capecitabine in this subgroup of patients. Nonetheless, adjuvant capecitabine remains an accepted standard of care for patients with resected GBC.

In 2010, the Advanced Biliary Cancer-02 trial randomized patients with advanced biliary tract cancers (36 percent GBC) to receive either cisplatin plus gemcitabine or gemcitabine alone for up to six months.12 Median OS was 11.7 months in the cisplatin-gemcitabine arm compared with 8.1 months in patients treated with gemcitabine alone (HR 0.64; 95 percent confidence interval [CI], 0.52 to 0.80; p<0.001). To date, the data from the ABC-02 trial remain the standard of care for patients with advanced biliary tract cancers including GBC.

Many oncologists will recommend adjuvant treatment with gemcitabine plus cisplatin rather than capecitabine alone because of presumed better efficacy, particularly in high-risk subgroups such as patients with lymph node-positive disease. This approach is being investigated in the Adjuvant Chemotherapy With Gemcitabine and Cisplatin Compared to Standard of Care After Curative Intent Resection of Biliary Tract Cancer (ACTICCA-1) trial (ClinicalTrials.gov identifier: NCT02170090), which is comparing adjuvant gemcitabine plus cisplatin to capecitabine monotherapy. The ACTICCA-1 trial is a multi-center international randomized phase 3 effort, which is estimated to complete accrual in 2023.

Given the high risk of residual disease found at re-resection for patients with incidentally diagnosed T2 and T3 GBC, interest has been growing in the role of neoadjuvant treatment for these patients. The OPT-IN trial (EA2197; ClinicalTrials.gov identifier: NCT04559139) has recently been activated to compare perioperative (neoadjuvant) gemcitabine plus cisplatin with postoperative (adjuvant) treatment with the same regimen.

FIGURE 2. OPT-IN EA2197 TRIAL SCHEMA

OPT-IN for patients with T2 or T3 incidentally discovered GBC

The OPT-IN trial was developed to address the high recurrence rates seen in patients with presumably localized disease after re-resection of incidentally diagnosed GBC (see Figure 2). This trial is sponsored by Eastern Cooperative Oncology Group (ECOG-ACRIN Cancer Research Group) and is being conducted as a collaborative effort through the National Clinical Trials Network (NCTN). Patients must have undergone initial cholecystectomy with incidentally discovered T2 or T3 GBC within 12 weeks before randomization. Patients will be randomized to either upfront re-resection followed by six months of adjuvant gemcitabine plus cisplatin or to three months of preoperative gemcitabine plus cisplatin followed by restaging and re-resection followed by three months of postoperative gemcitabine plus cisplatin. The primary endpoint is OS, with an accrual goal of 186 patients.

The trial was recently activated through the NCTN and can be opened at any institution through the National Cancer Institute’s cancer cooperative group mechanism. Importantly, this will be the first randomized trial designed specifically for patients with incidentally discovered GBC and will help to establish the standard of care for patients with this challenging disease.

The OPT-IN principal investigator is Shishir Maithel, MD, FACS, professor of surgery, division of surgical oncology, department of surgery, Emory University School of Medicine; scientific director, Emory Liver and Pancreas Center; director, Katz Foundation Research Program in Surgical Oncology, Atlanta, GA.

For more information on the OPT-IN trial, contact Dr. Maithel at smaithe@emory.edu.

References

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