Key messages

•  Resective surgery compared to palliative care may increase survival rate in patients with advanced gallbladder cancer (low certainty of evidence).

What is the evidence.
See evidence matrix  in Epistemonikos later

Only one systematic review [3] was found, which included three primary studies [4], [5], [6], none of them a randomized trial.

What types of patients were included*

All primary studies included adult patients with advanced gallbladder cancer.
Average participant age ranged from 64 to 68 years.
All studies included patients in stages IVA and IVB, according to the American Joint Committee on Cancer (AJCC) classification scale.
In one of the studies 78% of patients were classified IVB and 22% IVA [4]. In another study [5], 88% were IVB and 12% IVA. In the last study, 55% of patients were IVA and 45% IVB [6].

What types of interventions were included*

All primary studies assessed surgical treatment in comparison to any type of palliative non-surgical treatment. One study [4] assessed resective surgery, palliative chemotherapy and best available supportive care (biliary duct prosthesis, external biliary drain and radiotherapy). Another study [5] evaluated resective surgery and palliative care (chemotherapy and radiotherapy). The last study [6] compared surgical treatment to chemotherapy and other palliative treatments.

What types of outcomes
were measured

All studies and the review reported survival as main outcome.
Average follow-up was 10.6 years, with a range of seven to 16 years. Only one of them reported the number of patients with R0 borders after surgery.

To whom this evidence does and does not apply

• The results presented are applicable to patients with advanced gallbladder cancer, in which conventional therapy with curative intention has been ruled out. All three included studies consider patient with gallbladder adenocarcinoma in stages IVA and IVB of the American Joint Committee on Cancer (AJCC). In absence of direct evidence, it seems reasonable to extrapolate these conclusions to other stages considered incurable such as IIIA or IIIB. It is important to mention that the studies did not report functionality of patients prior to surgery, which should be considered when interpreting the results.
• The results are not applicable to patients presenting with gallbladder cancer in early stages, in which treatment with curative intent is an option, being cholecystectomy or hepatic wedge in accordance with staging. Similarly, these results are not applicable to with other histological types or to incidental diagnosis of gallbladder cancer after cholecystectomy, which are usually eligible for curative treatment.

• The outcome included by the systematic review and reported as main outcome by the primary studies is overall survival. The authors of this summary agree this outcome corresponds to the critical outcome for decision making 
  Additionally, the authors agree that it is necessary to consider other outcomes at the time of making decisions, such as quality of life after either intervention and adverse effects associated with them. These are not reported by the systematic review.
  The authors agree that in cases of poor prognosis histology, such as advanced gallbladder cancer, one-year survival rate usually is more relevant for decision-making, however, the studies report the outcomes differently, two of them dichotomously [4], [5] and one as extra months of survival [6].

• In relation to the comparison between resective surgery and non-surgical palliative care in patients with advanced gallbladder cancer, there is a substantial lack of information. Furthermore, the analysis of the little data available is troublesome given the impossibility of conducting a meta-analysis. Considering the former, and the high risk of bias of the studies presented in this review, the quality of the evidence is considered to be low in accordance with GRADE working group criteria.
• Considering that surgical treatment may have better results regarding survival rate in patients with advanced gallbladder cancer, it is necessary to evaluate risks and complications associated with surgery, considering the patient's underlying conditions and the accessibility to existing alternative treatments. In any case, the authors agree that any decision and evaluation must be made in conjunction with the patient.

• The systematic review analysed does not report costs associated to the surgical treatment versus non-surgical palliative care in advanced stage gallbladder cancer.
  Given the current uncertainty about the survival benefit, and the lack of data on other relevant outcomes, it is not possible to estimate the balance between costs and benefits.

• The generalized clinical opinion about gallbladder cancer treatment is frequently biased by the ominous prognosis of this disease, which is greater in advanced stages, where prognosis is poor regardless of the treatment strategy. Whether there are clinically significant benefits associated with resective surgery despite not achieving negative margins (R0) is a matter of unresolved controversy, therefore, most clinicians choose to dismiss the possibility of surgical treatment when curative intention is not possible, especially considering the risks and complications of surgery in the fragile condition of most patients. This approach might disregard the potential benefits on survival for patients with residual disease after surgery.
  In relation to the opinion of patients at the moment of choosing between treatments, there should be great variability depending on the underlying values and preferences. Notwithstanding, it is common to find patients agreeing with the surgical option after a clear explanation about the aim of the surgery, in terms of survival and quality of life, particularly among younger patients.
  There is a special group of patients whom, given their baseline condition, cannot opt ​​for surgical treatment. In this group, palliative treatment plays a fundamental role in their care.

Differences between this summary and other sources

• In general, the results presented in this summary, agree with those presented in the systematic review [3]. However, given the lack of information regarding other critical outcomes, new primary studies and systematic reviews are needed.
  We found three guidelines regarding treatment of advanced gallbladder cancer. The first [7] reached a similar conclusion, recommending that all TNM classified cancers in stage T2 or over should be treated with extended cholecystectomy including hepatic wedge or segmentectomy of segments IVB/V, associated or not to lymph node dissection or resection of bile duct, based on a low-certainty evidence. On the other hand, the other two guidelines [8], [9], state that in cases where curative treatment is not an option or resectability has not been evaluated, surgical treatment is not recommended and palliative care based on chemotherapy and/or radiotherapy is preferred.

• The results in relation to survival presented in this summary are likely to change with future, evidence, considering the limited certainty of the existing evidence.
• We found three primary studies relevant for this question [10], [11], [12], which were not included in any systematic review. All of them evaluated survival in patients with gallbladder cancer. One [10] evaluated surgery with curative intent compared to other non-surgical palliative therapies. Other [11] cytoreductive surgery associated with radiotherapy in relation to palliative chemotherapy. The last one [12] compared non-surgical palliative treatment and aborted surgery.
• We did not identify ongoing trials or systematic reviews in the International Clinical Trials Registry Platform of the World Health Organization, or the PROSPERO database respectively.