Gallbladder cancer roadmap: from a chance finding at gallstone surgery to a disease with its own trials

Overview

1. 1882-1954historic

   Surgery arrives, and the cancer is found by accident

   Carl Langenbuch performed the first cholecystectomy at the Lazarus Hospital in Berlin in July 1882, an operation for gallstones that would become one of the commonest in the world and the way most gallbladder cancers come to light. In 1954 Glenn and Hays set out the scope of radical surgery for cancers of the extrahepatic biliary tract, the origin of the radical cholecystectomy: gallbladder, liver bed and regional lymph nodes removed together. For the next half century that operation was the whole of treatment.

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   Radical (extended) cholecystectomyIncidental gallbladder cancer (found after cholecystectomy)Surgery & InterventionalGallbladder cancer
2. 1976-2017historic

   Staging by depth, then by side

   Nevin and colleagues staged 66 cases by depth of invasion in 1976 and noted that essentially all had been found incidentally at gallstone surgery; Piehler and Crichlow's 1978 review of 6,222 reported patients described an elderly, mostly female population presenting either as stone disease or as incurable cancer. Depth of invasion became the T category of TNM. In 2015 Shindoh and colleagues showed in 437 patients that T2 tumours on the hepatic side did far worse than those on the peritoneal side (five-year survival 42.6 versus 64.7 percent), and the AJCC eighth edition of 2017 split T2 into T2a and T2b, the one staging change that came from gallbladder cancer's own anatomy.

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3. 2007-2026current

   The incidental cancer pathway: re-resect from T1b, but who, when and how much

   Pawlik and colleagues found residual disease in 46 percent of 115 re-resection specimens in 2007, and the rule that T1b or deeper incidental cancers go back to theatre followed. Ethun's ten-centre analysis (2017) put the best interval at four to eight weeks; a 2026 individual patient data meta-analysis found timing made no measurable difference. The Dutch registry showed only 24 percent of eligible patients were re-resected (2020); the UK CAPBIL study (2026) found 67.7 percent had liver resection across 24 centres. Whether T1b tumours need the second operation at all (Kim 2018: five-year disease-specific survival 93.7 versus 95.5 percent) and whether peritoneal-side T2a tumours need the liver resected are the surgical questions still open.

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4. 2010historic

   A borrowed chemotherapy standard

   ABC-02, a Cancer Research UK trial of 410 patients with advanced biliary tract cancer including gallbladder cancer, showed in 2010 that gemcitabine plus cisplatin lengthened survival from 8.1 to 11.7 months (hazard ratio 0.64). It gave gallbladder cancer its first drug standard and the control arm for every first-line trial since, but the gallbladder subgroup has never had a trial of its own in this setting.

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5. 2017-2021current

   Adjuvant capecitabine and second-line FOLFOX, from UK trials

   BILCAP (reported 2017, published 2019) randomised 447 resected biliary cancers to six months of capecitabine or observation; the intention-to-treat result missed significance (hazard ratio 0.81, p=0.097) yet capecitabine became the adjuvant standard in the UK, Europe and the United States. ABC-06 (2019, published 2021) showed second-line FOLFOX added about a month of median survival and doubled one-year survival (25.9 versus 11.4 percent). NIFTY (2021) added liposomal irinotecan as a Korean option that the German NALIRICC trial later failed to reproduce. The UK CAPBIL surgical cohort (2026) saw no adjuvant benefit in matched analysis, so ACTICCA-1's readout matters.

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6. 2008-2015historic

   Radiotherapy: one single-arm trial and a nomogram

   SWOG S0809 (accrued 2008 to 2014, published 2015) gave 79 patients with resected gallbladder or extrahepatic bile duct cancer gemcitabine-capecitabine then chemoradiation: two-year survival was 65 percent and, unusually, no worse after a positive margin (60 percent) than a clear one (67 percent). With Wang's 2011 SEER-Medicare nomogram it is the basis of the US option of chemoradiation after node-positive or margin-positive resection. No randomised trial followed and UK practice rarely uses it; POLCAGB in Mumbai is testing radiotherapy before surgery in locally advanced disease instead.

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7. 2022-2025current

   Immunotherapy joins chemotherapy

   TOPAZ-1 (2022) added durvalumab to gemcitabine-cisplatin and KEYNOTE-966 (2023) added pembrolizumab; both trials were positive with small median gains and a growing tail of long survivors. The TOPAZ-1 three-year update (2025) reported 36-month survival of 14.6 versus 6.9 percent and extended long-term survivors in 17.0 versus 8.7 percent. Gallbladder cancer was a subgroup in both trials; US and Chilean immunogenomic profiling (2025) shows its immune environment differs by population even where mutations do not.

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8. 2017-2025current

   HER2: the first target where gallbladder cancer leads

   The 2017 Manchester meta-analysis put HER2 overexpression at about 20 percent in extrahepatic biliary cancers against 5 percent in intrahepatic tumours; a 2026 resected series using the trial definition found 9.4 percent of gallbladder cancers positive, often heterogeneous. HERIZON-BTC-01 (2023) gave zanidatamab to 80 HER2-positive patients after chemotherapy with a 41.3 percent confirmed response rate, and the FDA granted accelerated approval in November 2024, the European Commission conditional approval in June 2025, the MHRA approval in February 2026 and NICE a recommendation in May 2026 (TA1153); DESTINY-PanTumor02 gave trastuzumab deruxtecan a tumour-agnostic HER2 3+ route. HERIZON-BTC-302 is testing zanidatamab first line with an estimated primary completion of December 2028. Testing uptake, not drug supply, is now the limiting step.

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9. 2006-2026current

   Prevention where the burden is: Chile, India and typhoid

   Chile's Explicit Health Guarantees programme has guaranteed cholecystectomy for gallstones at ages 35 to 49 since 2006, issuing 284,139 notifications by 2024; mortality has fallen, but it was falling before the programme and uptake does not follow incidence. India carries about a tenth of world cases, concentrated in the Gangetic belt, and Tata Memorial's registry saw 60 percent of 1,950 patients arrive with metastases. Chronic Salmonella Typhi carriage carries a roughly fourfold risk in two meta-analyses. Elsewhere the 2022 European polyp guideline is the only screening-like pathway, and the Kaiser Permanente cohort (2020) found people with polyps no more likely to develop the cancer than people without.

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10. 2026-2030emerging

    What the registry says is coming

    For the first time gallbladder cancer has randomised trials that ask its own questions. OPT-IN (ECOG-ACRIN, phase 2/3, estimated primary completion July 2028) tests chemotherapy before re-resection of incidental cancer; GAIN closed in October 2024 with 68 of 333 planned patients and awaits publication; POLCAGB (Tata Memorial) compares chemoradiation with chemotherapy before surgery in locally advanced disease. ACTICCA-1 (789 patients, estimated primary completion December 2025) and ARTEMIDE-Biliary01 (760, January 2029) will say whether gemcitabine-cisplatin or added immunotherapy beats capecitabine after surgery, and HERIZON-BTC-302 whether HER2-positive patients should get zanidatamab from the start. Residual disease blood tests are prognostic after biliary resection (hazard ratios of 16 and 26 in two 2025 to 2026 cohorts) but no trial yet acts on them.

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11. What sets the pacecurrent

    Under-studied relative to burden

    Gallbladder cancer has been called a rare tumour about which knowledge is scant (2004) and an understudied disease (2025) by successive generations of researchers. The reasons are structural: it is rare where trials are funded and common where they are not; most cases are found incidentally and treated by surgeons rather than oncologists; and it is pooled with bile duct cancer in every drug trial, so its results are subgroups. Whole-exome work across five countries (2026) shows the biology itself differs by population. Separate reporting, a burden-to-funding audit and national incidental cancer pathways are the levers this page proposes; the UK-specific gaps are set out on the UK and NHS page for gallbladder cancer.

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    Gallbladder cancer: lessons from a rare tumourGallbladder cancerGeographic and genetic diversity in gallbladder cancer mutation profiles: insights from a worldwide exome analysisRare and paediatric cancers without marketsFunding follows fashion, not burdenTrials enrol too few, too slowlyA burden-to-funding audit for gallbladder cancer and a dedicated research callReport gallbladder cancer as its own population in every biliary trialA national incidental gallbladder cancer pathway: histology for every gallbladder, referral within two weeks, re-resection by eight

    Papers

    • Gallbladder cancer: lessons from a rare tumour Nature Reviews Cancer, 2004

      Two decades on, the disease is still described as understudied in the 2025 immunogenomics literature; the reasons (rarity in the countries that fund research, incidental diagnosis, pooling with bile duct cancer in trials) have not changed.

    • Gallbladder cancer Nature Reviews Disease Primers, 2022

      The best single starting point for a clinician or researcher new to the disease, written by the groups running the Chilean and Indian cohorts; its list of unmet needs is the skeleton of the ideas section on this page.

    • Geographic and genetic diversity in gallbladder cancer mutation profiles: insights from a worldwide exome analysis EBioMedicine, 2026

      Targeted therapy prevalence estimates from one country may not hold in another, so a UK cohort, with its own ancestry mix, would need its own molecular survey before assuming HER2 or other rates from Asian or Latin American series.

Every era's records, trial outcomes and papers, and every watch item, as JSON.

• How this stays current: scripts/roadmap-watch.ts (npm run roadmap:watch) checks each trial here against ClinicalTrials.gov and searches Europe PMC for new papers on the acronyms since asOf. Anything it prints that this page does not say is an edit to make; then move asOf forward.
• Dates in 'What to watch' are quoted from the registry as read on 2026-09-24 and are not predictions; estimated completion dates move.
• UK and NHS specifics (referral routes, NICE positions, Cancer Drugs Fund status, cholecystectomy histology policy) are held on the UK and NHS page for gallbladder cancer and are not restated here.