What is the best course of action for a 73-year-old female with adenocarcinoma of the gallbladder and liver metastases, hyperthyroidism, diabetes, and hypertension, after completing 7 cycles of gemcitabine and cisplatin, and receiving durvalumab?

Management of Advanced Gallbladder Adenocarcinoma After Completing First-Line Therapy

Immediate Recommendation

Continue durvalumab maintenance monotherapy at 1500 mg every 4 weeks until disease progression, unacceptable toxicity, or completion of planned treatment duration. 1, 2

This patient has completed 7 cycles of gemcitabine-cisplatin-durvalumab (GCD), which represents the standard 8-cycle chemotherapy backbone minus one cycle. The current evidence-based approach is to transition to durvalumab maintenance monotherapy rather than stopping all treatment.

Treatment Algorithm Following GCD Induction

If No Disease Progression After Chemotherapy Completion

• Transition to durvalumab maintenance monotherapy 1500 mg IV every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months total treatment duration from initiation 1, 2
• This approach is based on the TOPAZ-1 trial design where durvalumab maintenance following 8 cycles of GCD demonstrated median overall survival of 12.9 months versus 11.3 months with chemotherapy alone (HR 0.76,95% CI 0.64-0.91) 2
• The 24-month overall survival rate with GCD was 23.6% compared to 11.5% with chemotherapy alone, demonstrating sustained long-term benefit 2

Monitoring During Maintenance Therapy

• Perform CT or MRI imaging every 8-12 weeks to assess for disease progression 1
• Monitor for immune-related adverse events including pneumonitis, hepatitis, colitis, endocrinopathies, and dermatologic toxicities 3
• Assess performance status at each visit as declining PS may warrant treatment discontinuation 1

Management of Comorbidities During Immunotherapy

Critical consideration for this patient: The combination of hyperthyroidism on neomercazole, diabetes, and hypertension requires heightened vigilance during durvalumab maintenance:

• Thyroid function monitoring every 4-6 weeks as durvalumab can cause both hypothyroidism and hyperthyroidism; coordinate closely with endocrinology given pre-existing hyperthyroid disease 3
• Blood glucose monitoring as immune checkpoint inhibitors can precipitate type 1 diabetes or diabetic ketoacidosis, particularly concerning in a patient with pre-existing diabetes 3
• Blood pressure monitoring though hypertension is not a common durvalumab adverse event, ensure adequate control given baseline HTN 3

If Disease Progression Occurs

Assess for Conversion to Resectability

Re-evaluate for surgical resection if significant tumor response occurred during first-line therapy 1, 4:

• Obtain multidisciplinary tumor board review with updated cross-sectional imaging 1, 5
• Consider diagnostic laparoscopy if peritoneal disease was initially present, as complete pathological response has been documented with GCD therapy 4
• If converted to resectable disease, proceed with curative-intent surgery followed by consideration of adjuvant therapy 1, 5

Second-Line Systemic Therapy Options

If disease progresses and remains unresectable:

• Molecular profiling is essential before initiating second-line therapy to identify actionable alterations including FGFR2 fusions, IDH1 mutations, HER2 amplification, BRAF mutations, NTRK fusions, and MSI-H/dMMR status 1
• For MSI-H/dMMR tumors: Anti-PD-1 monotherapy (pembrolizumab) is highly effective and FDA/EMA approved 1
• For FGFR2 fusions: Targeted therapy with FGFR inhibitors (pemigatinib, infigratinib, futibatinib) 1
• For IDH1 mutations: Ivosidenib 1
• For HER2 amplification: Trastuzumab-based therapy 1
• For patients without actionable mutations: FOLFOX (5-fluorouracil/leucovorin/oxaliplatin) is a reasonable second-line option 1

Critical Management Pitfalls to Avoid

• Do not discontinue durvalumab prematurely if the patient is tolerating therapy and has stable disease, as the survival benefit extends beyond the chemotherapy phase 2
• Do not delay molecular profiling until after disease progression; obtain tissue or liquid biopsy during maintenance phase to expedite second-line decision-making 1
• Do not overlook immune-related adverse events in the setting of pre-existing autoimmune thyroid disease; maintain low threshold for corticosteroid intervention 3
• Do not assume unresectability is permanent; interval imaging may reveal conversion to resectable disease, particularly given documented cases of complete pathological response with GCD 4

Palliative Care Integration

• Initiate early palliative care consultation regardless of treatment plan, as this improves quality of life and potentially survival in advanced biliary tract cancer 1
• Address biliary obstruction proactively with metal stents if life expectancy exceeds 6 months 5
• Optimize symptom management including pain control, nutritional support, and management of cholestasis-related pruritus 1

Performance Status Considerations

Treatment continuation depends critically on maintained performance status:

• Patients with WHO/ECOG PS 0-1 should continue durvalumab maintenance 1
• Patients whose PS declines to 2 or worse should transition to best supportive care, as survival benefit from continued therapy is not established 1
• Quality of life preservation is paramount and should guide treatment decisions equally with survival endpoints 1