What Comes First — Neoadjuvant Chemotherapy or Re-Resection for Patients with Incidental Gallbladder Cancer?

William Jarnagin MSK

Dr. William Jarnagin

At Memorial Sloan Kettering Cancer Center, more than half of patients with gallbladder cancer are diagnosed incidentally following elective cholecystectomy for assumed benign disease. The traditional treatment approach for these patients is re-resection to achieve a cure.

Gallbladder cancer is characterized by unfavorable tumor biology and frequent distant recurrence, the most common cause of surgical failure. We should only re-resect patients who are most likely to benefit from the surgery.

On the other hand, if we can identify high-risk patients who likely have micrometastases at diagnosis, and treat them with neoadjuvant chemotherapy before re-resection, we could theoretically improve outcomes. But a poor response to neoadjuvant chemotherapy risks local progression to unresectability, and the toxicities of chemotherapy can reduce functional status, which impairs surgical candidacy.

This paradox means that we must weigh the risks and benefits carefully when choosing the optimal treatment sequence. In a review paper published recently in Updates in Surgery, we outline the current evidence and the judgment we use at MSK to select the best treatment sequence for patients with incidental gallbladder cancer. (1)

Rationale and Considerations for Selecting Re-Resection First

The standard approach for treating patients with incidental gallbladder cancer is re-resection. In our experience at MSK, all comers who had re-resection had a disease-specific survival (DSS) of 43 months. (2) Several other multicenter and single-institution studies have also found a survival advantage with re-resection. (3), (4), (5), (6)

The rationale is to remove gross and/or microscopic residual disease left after the initial cholecystectomy, which is present in 45 to 60 percent of re-resection specimens. (7), (8), (9) Re-resection is associated with significantly improved five-year overall survival (OS) of 41 percent compared to only 15 percent for nonoperative management. (10)

These results have been achieved despite the fact that an initial cholecystectomy may disseminate cancer cells, potentially negating the benefit of re-resection and a particular concern in gallbladder cancer given its predisposition to peritoneal seeding. (11), (12) In an MSK study of 135 patients with incidental gallbladder cancer, 61 percent of patients with residual disease had a disease-free survival of 11 months and a disease-specific survival of 25 months, compared to 93 months and not reached (meaning the study has not yet reached the point where half of the participants are deceased) for patients without residual disease. (13)

However, an incidental diagnosis does not preclude re-resection to aim for a cure. We have observed similar outcomes for incidental gallbladder cancer patients and primarily resected patients when matched for disease stage. (2), (14) The five-year OS rate for patients who undergo re-resection ranges from 35 to 42 percent, (2), (14), (15) and more than 60 percent for those with T2 disease. (2), (16), (17) The rationale may be that patients with incidental gallbladder cancer are more likely to undergo resection for a curative goal since they present with earlier-stage disease and a lower involvement of other structures.

Rationale and Criteria for Selecting Neoadjuvant Chemotherapy

Positive results with two other gastrointestinal malignancies, gastric cancer and pancreatic cancer, inform and justify a neoadjuvant approach for patients with gallbladder cancer who have a particularly high risk for early disease recurrence. (18), (19), (20)

A deeper look at the data for patients with gallbladder cancer reveals that a significant fraction have poor tumor biology, early and frequent distant disease recurrence, followed by death. Gallbladder cancer recurrence occurs early with a median time to recurrence of 11 months and within two years for 88 percent of patients. (21), (22) The earlier the recurrence, the more irrelevant the surgery becomes for improving overall prognosis.

Early and distant recurrence likely indicates that metastatic disease was present and undetectable by imaging at the time of initial diagnosis - a logical basis for treating these patients with neoadjuvant chemotherapy first. The rationale is to immediately treat micrometastases, optimize patient selection for surgery, allow time to assess tumor response to chemotherapy that may guide future treatment decisions, and downstage the primary tumor.

Early and distant recurrence likely indicates that metastatic disease was present and undetectable by imaging at the time of initial diagnosis - a logical basis for treating these patients with neoadjuvant chemotherapy first.
William R. Jarnagin Chief, Hepatobiliary Service; Leslie Blumgart Chair in Surgery

In addition to tumor biology, two important criteria must be met for the neoadjuvant approach to be successful: (1) we need to be able to identify those patients at high risk of distant recurrence who are most likely to benefit from neoadjuvant chemotherapy, minimizing toxic side effects in those who would benefit more from upfront re-resection; and, (2) we need effective chemotherapy for both local and micrometastatic disease.

Identifying High-Risk Patients

Multiple characteristics identify high-risk patients, including two that are associated with prognostic factors within the American Joint Committee on Cancer (AJCC) staging system: advanced T stage and node-positive disease. (2), (23), (24), (25) Note that disease in regional nodes along the cystic duct, common bile duct, hepatic artery, and portal vein are most associated with poor prognosis, whereas disease in nodes along the visceral vessels (periaortic, pericaval, superior mesenteric artery, and celiac artery) is classified as M1. (26)

As of the 8th edition of the AJCC staging criteria, T2 gallbladder cancers are now stratified by their location on the hepatic or the peritoneal side, (26) based on results from an international study that found an independent association for hepatic-side tumor location and OS of 43 percent compared to 65 percent for peritoneal-side tumor location following curative-intent resection for T2 stage cancer. (27) By contrast, T1 tumors are associated with good outcomes regardless of location (five-year OS of 85 to 90 percent), and T3 tumors with poor outcomes (five-year OS of 25 to 29 percent). (1)

Other clinical factors that predict patient survival include histologic grade of differentiation (well, moderate, or poor), (13), (23), (22), (25) lymphovascular invasion, (13) total lymph node count of six or more, (24) CBD involvement, (23) jaundice, (2) and bile spillage at index cholecystectomy. (28)

Effective Chemotherapy as a Prerequisite for Neoadjuvant Therapy

Notably, there is no level I evidence supporting a neoadjuvant therapy approach for managing incidental gallbladder cancer, so conclusions can only be drawn from adjuvant, locally advanced, and metastatic settings. (1)

The evidence most closely resembling the neoadjuvant setting is our retrospective series at MSK that assessed chemotherapy response in 74 patients, including 25 with incidental gallbladder cancer, with either locally advanced or presumed node-positive disease. Patients were treated primarily with gemcitabine-based chemotherapy (57 percent with a gem/platinum doublet). At two months, systemic therapy showed some efficacy with a 26 percent response rate and a 78 percent disease control rate, with 30 percent proceeding to exploration, and just over 7 percent achieving an R0 resection. However, the risk for progression was real for 23 percent (17 patients), and five of the 12 patients who proceeded to exploration were found unresectable. (29)

Extrapolation of current evidence from the micrometastatic setting is made on thin ground. The best comparison is two randomized controlled trials in the adjuvant setting: Both trials were negative and contained a mix of biliary tract cancers, and a minority were gallbladder cancer. (30), (31)

Future Research to Validate the Neoadjuvant Approach

A new phase III randomized controlled trial to validate the neoadjuvant chemotherapy approach is in the planning stages. The international trial will take place at multiple sites, including MSK, and will compare neoadjuvant chemotherapy with upfront surgery to hopefully provide robust evidence on the ideal treatment sequence. It will examine the therapeutic benefit of four cycles of preoperative gemcitabine/cisplatin for patients who proceed to re-resection followed by six months of postoperative capecitabine. The control group receiving upfront surgery will receive capecitabine only. The primary endpoint is three-year OS. The trial is not yet recruiting.

While the treatments in this trial align with current practice — doublet therapy for metastatic disease and monotherapy in the adjuvant setting — the conclusions from this trial may require scrutiny given that more active chemotherapy could be used in the neoadjuvant group.

Another clinical trial, NCT03673072, opened in Germany in March 2019, is seeking to recruit 300 participants with incidental gallbladder carcinoma and biliary tract cancer. Participants will be randomized to receive either gemcitabine plus cisplatin (three cycles preoperatively and three cycles postoperatively) plus radical resection, or surgery directly followed by investigator’s choice of adjuvant chemotherapy. The primary measure is OS with a planned follow-up period of six years.

The MSK Approach to Treatment Selection

For patients with incidental gallbladder cancer following cholecystectomy for presumed biliary colic, we start by evaluating cross-sectional imaging. Next, we examine the cholecystectomy specimen for T stage, presence of positive lymph nodes, and poor differentiation. Positive margins either along the cystic duct or at the gallbladder, an infiltrating liver mass, or clinically positive nodes, indicate the presence of residual disease.

Patients with evidence of T3, node-positive, poor differentiation, or residual disease are candidates for neoadjuvant chemotherapy. In theory, this approach immediately treats any micrometastatic disease in high-risk patients and identifies patients who are most likely to progress quickly to distant disease and therefore, will not benefit from surgery.

For patients without these disease characteristics, we pursue re-resection first, in accordance with the weight of the published evidence supporting re-resection as the most effective approach for managing incidental gallbladder cancer.

At MSK, our team of multidisciplinary gallbladder cancer experts develops individualized treatment plans for each patient, taking into account the nature of their disease and the most up-to-date evidence.

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Dr. Jarnagin reports no conflicts of interest.

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