Local Ablation Plus Systemic Therapy for Metachronous Liver and/or Lung Oligometastases From Nasopharyngeal Carcinoma

Metachronous metastasis is defined as distant metastasis detected at least 6 months after curative treatment of the primary nasopharyngeal tumor. Eligible participants are randomized 1:1 to local ablation plus systemic therapy or systemic therapy alone.

Ablation is performed under CT guidance by two interventional radiologists; multiple lesions are treated in up to 3 sessions 3-4 weeks apart, and complete ablation is assessed by contrast-enhanced CT or PET/CT 3-4 weeks after ablation.

Systemic therapy in both arms consists of gemcitabine 1000 mg/m2 on days 1 and 8 plus cisplatin 80 mg/m2 on day 1 with a PD-1 inhibitor on day 1 every 3 weeks for 6 cycles, followed by PD-1 inhibitor maintenance every 3 weeks for up to 2 years. Tumor response is assessed per RECIST 1.1 every 8 weeks. Adverse events are graded per NCI CTCAE v5.0.

The sample size of 138 (69 per arm) provides 80% power at a two-sided alpha of 0.05 to detect an improvement in objective response rate from 70% to 90%, allowing for 10% dropout.

Inclusion criteria

• Written informed consent to participate in the trial
• Age 18 to 75 years, any sex
• Histologically or cytologically confirmed nasopharyngeal carcinoma, with clinically diagnosed liver and/or lung metastases
• Primary nasopharyngeal tumor cured after curative treatment, with no lymph node metastasis and no metastases outside the liver and lung (metachronous metastasis: distant metastasis detected at least 6 months after curative treatment of the primary tumor)
• No more than 5 liver and/or lung metastases, each 3 cm or smaller in diameter
• Liver and/or lung metastases amenable to ablation
• ECOG performance status 0 or 1
• Adequate hematologic and organ function: absolute neutrophil count ≥1.5×10^9/L; hemoglobin ≥70 g/L; platelet count ≥50×10^9/L; white blood cell count ≥3.0×10^9/L; serum albumin ≥28 g/L; total bilirubin ≤3.0 mg/dL; AST and ALT ≤5×ULN; serum creatinine ≤1.5×ULN; INR ≤2.3 (without anticoagulant therapy)
• No prior systemic therapy for metastatic disease (e.g., gemcitabine plus cisplatin chemotherapy or PD-1 inhibitor)

Exclusion criteria

• History of hypersensitivity or intolerance to any study drug
• Severe hepatic insufficiency, pulmonary fibrosis, or pulmonary hypertension
• Poorly controlled infectious or radiation-induced inflammation around the lesion, skin infection at the puncture site, systemic infection, or fever >38.5 °C
• Estimated life expectancy less than 3 months
• Poorly controlled malignant pleural effusion
• Clinically significant bleeding within 30 days before study entry
• Uncorrectable coagulopathy or marked hematologic abnormality with evident bleeding tendency
• Severe hepatic, renal, cardiac, pulmonary, or cerebral dysfunction; severe anemia, dehydration, or nutritional/metabolic disturbance that cannot be corrected in the short term; left ventricular ejection fraction <45%
• History of congenital long QT syndrome, or corrected QT interval >480 ms (Fridericia)
• Psychiatric disorder in an active episode
• Poorly controlled hypertension: systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg
• Urine protein ≥1 g/24 h (participants with ≥1+ proteinuria on dipstick must have 24-hour urine protein measured); prior organ transplantation
• Anticoagulant and/or antiplatelet therapy (except novel oral anticoagulants such as dabigatran and rivaroxaban) not discontinued for more than 5-7 days before ablation
• Other malignancy within the previous 3 years or concurrently
• Prior gemcitabine plus cisplatin chemotherapy or PD-1 inhibitor therapy
• Any other condition that, in the investigator's judgment, makes the patient unsuitable for the trial