Adjuvant Phase III Randomized Trial of Capecitabine plus Temozolomide Versus Surveillance in R0‑resected Stage I‑III Pancreatic Neuroendocrine Tumors (ADJUPANET)

In patients with R0‑resected stage I‑III Pancreatic neuroendocrine tumors at intermediate to high risk of recurrence, the primary objective is to evaluate the effect of six cycles of capecitabine–temozolomide followed by active surveillance versus active surveillance alone on disease‑free survival, providing a direct measure of adjuvant therapeutic benefit. Secondary objectives include comparison of the two strategies with respect to overall survival and disease‑specific survival; assessment of treatment safety according to NCI‑CTCAE v6.0; description of recurrence patterns and timing; evaluation of health‑related quality of life using EORTC QLQ‑C30, QLQ‑GINET21 and EQ‑5D‑5L instruments; comparison of trial outcomes with an observational cohort of eligible patients who declined randomisation; and pooled analysis of the randomized and observational cohorts to examine primary and secondary endpoints across the combined population.

The trial enrolled adult patients (age ≥ 18 years) of both sexes who had undergone R0 resection of stage I–III Pancreatic NeuroEndocrine Tumors and were classified as intermediate to high risk of recurrence based on Ki‑67 index, tumor size, nodal status, and histologic features. Participants were required to have an ECOG performance status of 0–1, adequate bone‑marrow reserve, and no evidence of distant metastasis on postoperative imaging. Inclusion criteria mandated the absence of prior systemic therapy, availability of tumor tissue for WHO classification and MGMT assessment, and compliance with effective contraception measures. General health status was otherwise unrestricted, and no specific dietary or physical‑activity requirements were stipulated. The sponsor did not provide information on the total number of participants enrolled in the study.

The study is a randomized, controlled phase III trial evaluating six cycles of oral capecitabine (1500 mg/m² per day) combined with temozolomide (200 mg/m² per day) followed by active surveillance versus active surveillance alone in patients with Pancreatic NeuroEndocrine Tumors that have been completely resected (R0) and are at intermediate to high risk of recurrence. Eligible participants undergo a screening visit to confirm pathology, postoperative imaging, ECOG status, and laboratory criteria, after which they are randomized 1:1 to the chemotherapy arm or the observation arm. The chemotherapy arm receives six 28‑day cycles of the study drugs, with clinic visits at the start of each cycle for drug dispensing, safety assessment, and laboratory tests; toxicity is graded using NCI‑CTCAE v6.0 at baseline and monthly during the first year. All participants attend follow‑up visits every three months for the first year to collect disease status, imaging, and quality‑of‑life questionnaires, then annually thereafter until the end‑of‑study visit, which occurs at the study’s conclusion (estimated recruitment 2026‑07‑25 to 2036‑01‑25). The total duration of individual involvement ranges from approximately 18 months for patients completing chemotherapy to up to 10 years of surveillance, depending on the time of enrollment. Early termination may occur if a participant experiences disease recurrence, unacceptable toxicity, withdraws consent, or is lost to follow‑up; such cases are censored in the disease‑free survival analysis according to the treatment‑policy strategy.

The experimental arm utilizes oral Capecitabine film‑coated tablets (500 mg, 300 mg, and 150 mg strengths) administered at a dose of 1500 mg/m² per treatment cycle. The medication is taken by mouth according to the protocol‑specified schedule for six consecutive cycles of combination chemotherapy.

Oral temozolomide hard capsules (250 mg, 200 mg, 180 mg, 140 mg, 20 mg, and 5 mg strengths) are provided as the second component of the combination regimen. Each capsule is dosed to achieve a total of 200 mg/m² per cycle and is administered orally for the same six‑cycle treatment period.

The comparator arm consists of active surveillance without administration of systemic chemotherapy. Participants in this group receive routine clinical follow‑up and imaging assessments in accordance with the study schedule.

All investigational drugs are dispensed in labeled containers, and dosing is calculated based on body surface area. Compliance is monitored through patient‑maintained medication diaries, pill counts at each study visit, and verification of administration times recorded in the electronic case report form.

The primary efficacy parameter is Disease‑free survival, defined as the interval from randomization to the first documented recurrence of pancreatic neuroendocrine tumor or death from any cause. Participants without an event at the data‑cutoff date are censored at the date of their last evaluable follow‑up. The treatment‑policy strategy is applied, whereby intercurrent events such as treatment discontinuation or subsequent anticancer therapy are ignored in the analysis.

Secondary efficacy assessments include:

• Specific survival: time from randomization to death attributable to disease progression, treatment toxicity, or uncontrolled secretory syndrome, with censoring at the last known alive date.
• Overall survival: time from randomization to death from any cause, censored similarly.
• Toxicity evaluation using the National Cancer Institute Common Terminology Criteria for Adverse Events version 6.0 (NCI CTCAE v6.0) performed at baseline, monthly during the first year, and annually thereafter.
• Time and pattern of recurrence: interval from randomization to detection of recurrence (local, distant, or synchronous) and competing‑risk analysis of local recurrence, distant recurrence, and death without recurrence.
• Quality of life: assessment with the EORTC QLQ‑C30, the NET‑specific EORTC QLQ‑GINET21, and the EQ‑5D‑5L questionnaires. Scores are collected at baseline, every three months during the first year, and annually for the duration of the study.

Data collection follows a predefined schedule: baseline assessments occur prior to randomization; efficacy endpoints are captured through routine clinical visits and imaging as per standard of care, with specific timepoints for patient‑reported outcomes and toxicity monitoring as described above. All efficacy data are analyzed using appropriate time‑to‑event statistical methods, including Kaplan‑Meier estimation for survival endpoints and Fine‑and‑Gray competing‑risk models for recurrence patterns.