Key messages

• Palliative chemotherapy may increase survival in advanced gallbladder cancer (certainty of evidence is low).
• Palliative chemotherapy probably increases adverse effects in advanced gallbladder cancer.
• It is essential to carry out a new systematic review, since methodological errors were identified in the analysis and there is new evidence that has not been included in the previous reviews.

What is the evidence.
See evidence matrix  in Epistemonikos later

We identified two systematic reviews [5], [6] including two studies overall [7], [8], of which one of them was a randomized trial [7].

Finally, this table and the summary, in general, are based on this trial [7] due to the observational study did not increase the certainty of evidence nor did it provide additional relevant information.

What types of patients were included*

Median age of patients was 49 years, and 80.2% were female [7].

Eligibility criteria [7] were**: Patients with a confirmatory biopsy for unresectable or metastatic gallbladder adenocarcinoma, ≥18 year-olds, with a good bone marrow, renal and liver function, >10 g/dL hemoglobin, normal neutrophil counts, > 100,000/uL platelets, <1.8 mg creatinine, liver enzymes (GOT: glutamic-oxalacetic transaminases and GPT: glutamic-pyruvic) <3 times the normal value, or <5 in case of hepatic compromise diffuse, < 3 mg/dL bilirubin, and 0-2 ECOG (Eastern Cooperative Oncology Group).

Patients that had undergone adjuvant chemotherapy or radiotherapy were included if they ended treatments at least 6 months prior to enrollment.

What types of interventions were included*

Interventions included:

• 5- Fluorouracil (FU) 425 mg/m2 and folinic acid 20 mg/m2 intravenous bolus weekly for 30 weeks (FUFA).
• Gemcitabine 900 mg/m2 and oxaliplatin 80 mg/m2 intravenous infusion on day 1 and 8, in 21-day cycles for up to 6 cycles. 

Both schemes were for 6 cycles unless there was disease progression or unacceptable adverse effects (undefined by systematic reviews). 

Both interventions were compared with best supportive care (BSC), which were not defined by systematic reviews.

What types of outcomes 
were measured

• Overall survival
• Progression-free survival
• Response rate
• Disease control rate
• Vomiting
• Sickness
• Severe toxicity

To whom this evidence does and does not apply

• To whom this evidence does and does not applyThis summary applies to adults with histologically confirmed advanced gallbladder cancer (either unresectable or metastatic), good organ function and 0-2 ECOG (Eastern Cooperative Oncology Group).
• This summary does not apply to patients with medical indication of neoadjuvant chemotherapy aiming to reduce tumor size for resection, or to non-adenocarcinomas.
• Best supportive care is not specified in reviews. This topic is currently under discussion, as it can be misused [9]. It is necessary to define a standard of supportive care.

• Given that gallbladder cancer is commonly associated with poor prognosis we chose 1-year survival as a critical outcome for decision-making. The evidence suggests palliative chemotherapy may improve this outcome. Importantly, this study did not use gemcitabine plus cisplatin, the most widely accepted treatment, which is gemcitabine and cisplatin (following publication of the results of the ABC-02 study that compared it to gemcitabine alone).
• Serious adverse effect is another important outcome for making a decision. Unfortunately, this was not adequately reported by the authors. A more comprehensive analysis of the impact of the treatment should include quality of life of patients, however the authors did not report this outcome.
• Progression-free survival and event-free survival are not included in this summary. These are surrogate outcomes and not validated outcomes for gallbladder cancer. This was assessed by two systematic reviews [10], [11] which found a poor correlation with mortality/survival or quality of life.

• Due to the importance of survival in an oncological disease, the risk/benefit balance of this intervention is usually considered favorable due to the great impact on mortality (even presenting a low certainty of the evidence and a poor presentation of the magnitude of serious adverse effects).
• However, in routine clinical practice, it is an individualized decision for each patient, whose key elements for the decision are: the patient's baseline functional status, life expectancy, values, and preferences of the patient and his/her family.It is important to emphasize the limitations of this summary. 
• It is based on systematic reviews, therefore their methodological issues or lack of information might impact the conclusions presented here (garbage in - garbage out). 
• The network meta-analysis [5] used to inform this summary, decided to meta-analyse the randomized trial and observational study together, which, under current methodological parameters, is considered incorrect. Following the GRADE working group guidelines, it would be necessary to analyze trials and observational studies separately, estimating the certainty of each group of studies and presenting the conclusions of the set of evidence with greater certainty of evidence [12]. For this reason, the accuracy of the results might be overestimated. Due to all of the above reasons, it was decided to decrease an additional level of certainty of the evidence. Alternatively, we extracted mortality data directly from the randomized trial (RR 0,78; CI 95% 0.58 to 1.04) and found the same absolute difference, but with a wider confidence interval, reinforcing our decision to downgrade the certainty of evidence.
• For all of the above, it is essential to carry out a new systematic review that overcomes the limitations of its predecessors.

• Due to the uncertainty of benefits, it is difficult to assess the cost/effectiveness of the intervention. This is likely to vary depending on the characteristics of the patient (eg baseline performance status).
• Cost/effectiveness studies are required.

• The opinion of patients/doctors is likely to vary depending on each case. Patients with a good performance status (ECOG) and doctors that prioritize patient survival will likely opt for palliative chemotherapy. In contrast, patients with a poorer functional status and therefore more vulnerable to adverse effects will likely avoid this intervention.

Differences between this summary and other sources

• Both systematic reviews agree with the results displayed on this summary, with the exception of the certainty of the evidence (absence of methodologies such as GRADE or similar).
• National Comprehensive Cancer Network (NCNN) [13] and European Society of Medical Oncology (ESMO) - Multinational Association of Supportive Care in Cancer (MASCC) [14] guidelines propose that systemic chemotherapy increases advanced biliary tract cancer (including gallbladder cancer) patient survival versus best supportive care.

• The conclusions on this summary are likely to change given the certainty of evidence. Regarding serious adverse effects, although this could also change there is greater certainty of evidence.
• An additional study not included in systematic reviews was identified. However, this is an observational study, and therefore unlikely to change the conclusions on this summary [15].
• No systematic reviews or ongoing primary studies were identified on the PROSPERO platform or the WHO International Clinical Trials Registry Platform.