Total mesorectal excision (TME) is highly effective for early-stage rectal cancer, but is associated with considerable morbidity, which can substantially impair the quality of life (QoL) of patients. For very early tumours (low-risk cT1), local excision (LE) offers the possibility of organ preservation (OP) with reduced morbidity; however, its application is limited to a selected group. For early tumours where upfront LE is not feasible, primary OP with (chemo)radiotherapy as an alternative to TME surgery has been evaluated in the STARTREC phase II/III studies, which reported promising 1-year OP rates.

The STARTREC-3 trial aims to increase the 2-year OP rate from 60% to 80% in early rectal cancer (cT1–3abN0) and from 30% to 60% in early-intermediate rectal cancer (cT1–3abN1, ≤3 mesorectal nodes measuring ≤8 mm) by intensifying neoadjuvant treatment in different study arms.

STARTREC-3 is embedded in the STARTREC master trial protocol, which uses an adaptive platform study design allowing early termination of inferior treatment arms and the addition of novel arms. The multicentre STARTREC-3 trial investigates three parallel, non-comparative treatment strategies for patients with early and early-intermediate rectal adenocarcinoma who prefer OP over primary TME surgery. All arms start with 5x5 Gy radiotherapy, followed by: an endoluminal boost via contact X-ray brachytherapy (arm 1), an external beam radiotherapy (EBRT) boost by MR-guided EBRT (arm 2) or three cycles of capecitabine oxaliplatin systemic treatment chemotherapy (arm 3). Treatment allocation is predefined and centre-dependent. Response evaluations (MRI and endoscopy) are planned at 14–16 weeks and 26 weeks after onset of radiotherapy. The primary endpoint is the proportion of patients with successful OP at 24 months from onset of therapy. Secondary endpoints include toxicity, QoL, functional and oncological outcomes. Data will be analysed separately for early (cN0) and early-intermediate (cN1) disease. The total planned sample size is 210 patients across the three arms. Interim analyses will be performed for each study arm to determine early failures and discontinue ineffective arms.

The trial was approved by the medical ethics committee NedMec of the Netherlands and is registered in the EU Clinical Trials Information System (CTIS). The results will be published in an international peer-reviewed journal.

CTIS EU 2024-514620-17-00

For patients with perihilar cholangiocarcinoma (pCCA), surgical resection remains the sole treatment modality that can potentially result in cure. Unfortunately, the majority of patients present with unresectable tumours or are excluded from surgical treatment due to complications like cholangitis affecting their performance status. In the Netherlands, recommended first-line treatment for patients with unresectable pCCA is palliative chemotherapy with gemcitabine and cisplatin. This regimen yields an estimated median overall survival (OS) of 11.7–15.2 months, highlighting the urgent need for novel treatment options. The STRONG I trial, a phase I study in patients with unresectable pCCA, was completed in 2020. Its aim was to assess the feasibility and toxicity profile of adding stereotactic body radiation therapy (SBRT) to chemotherapy. SBRT, delivered in 15 fractions of 4.0 Gray (Gy), was considered to be feasible and safe, with no dose-limiting toxicity being observed. The 1-year local tumour control rate was 80% and the 1-year OS rate 100%, with maintenance of quality of life (QoL). These results encouraged us to initiate the STRONG II trial, aiming to investigate the efficacy of adding SBRT to chemotherapy in a larger patient cohort.

STRONG II is a single-arm, multicentre phase II study. Patients with non-metastatic unresectable pCCA (T1-4, N0-2) are eligible. A total of 30 patients will be enrolled in six academic centres in the Netherlands and two in Belgium. SBRT will be delivered in 15 fractions of 4.0–4.5 Gy. The primary endpoint is local tumour control, defined by Response Evaluation Criteria in Solid Tumours (RECIST) V.1.1. Secondary endpoints include toxicity, biliary stent-related events, progression-free survival, OS and QoL using the EuroQoL five-dimensional, five-level (EQ-5D-5L) questionnaire, European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30) and the EORTC Biliary Module (QLQ-BIL21). In addition, we will explore the predictive value of the peripheral immunological status (immune-related proteins and serum functional immunological status assay) and its dynamics in determining survival outcomes. For this explorative translational study, two blood samples will be collected, one before the start of chemotherapy and another after completing chemotherapy.

Approval of the study was obtained on 5 June 2024 by the Medical Ethics Review Committee of Erasmus Medical Center Rotterdam, the Netherlands (ID: NL86210.078.24). The anticipated time frame for patient enrolment is July 2024 to December 2027. The main study findings will be published in peer-reviewed medical journals, and presented at national and international conferences.

NCT06493734 (ClinicalTrials.gov).