Proton and Proton-Photon Hybrid Partial Stereotactic Ablative Boost Radiotherapy (P-SABR) for Unresectable Large Tumors (LARGE-Proton)

A Prospective, Multicenter, Observational Cohort Study of Proton and Proton-Photon Hybrid Partial Stereotactic Ablative Boost Radiotherapy (P-SABR) for Unresectable Large Tumors

This prospective, multicenter, observational cohort study will enroll 60 adults with unresectable larege tumors (longest diameter > 5 cm) who receive one of two treatment modes: (A) proton P-SABR, in which both the proton partial-SABR boost (course 1) and the subsequent proton CFRT (course 2) are delivered at the proton center; or (B) proton-photon hybrid P-SABR, in which course 1 is delivered with protons at the proton center and course 2 CFRT is delivered with photons. The primary objective is to describe, in each cohort, the incidence of treatment-related grade ≥ 3 acute and late adverse events (CTCAE v5.0). Secondary objectives are dosimetric and the 1-year local control rate (RECIST 1.1, in-field). Participants are followed for up to 5 years.

Study Overview

• Status: Not yet recruiting
• Conditions: Solid Tumor; Unresectable Malignant Neoplasm; Bulky Tumor
• Intervention / Treatment: Radiation: Proton P-SABR; Radiation: Proton-Photon Hybrid P-SABR

Detailed Description

BACKGROUND Large tumors (longest diameter > 5 cm) are often unresectable and respond poorly to conventionally fractionated radiotherapy (CFRT) because of their size and hypoxic core, while normal-tissue tolerance prevents delivering stereotactic ablative radiotherapy (SABR) to the whole tumor. Partial stereotactic ablative boost radiotherapy (P-SABR) delivers a SABR boost only to the central part of a large tumor, followed by CFRT to the whole target. Proton beams, with their Bragg-peak dose fall-off, may sharpen this "onion-skin" dose distribution and further increase the biologically effective dose (BED) within the tumor core.

DESIGN This prospective, multicenter, observational cohort study will enroll 60 adults with unresectable bulky tumors (longest diameter > 5 cm) who, as part of routine care, receive one of two treatment modes: (A) proton P-SABR, in which both the proton partial-SABR boost (course 1) and the subsequent proton CFRT (course 2) are delivered at the proton center; or (B) proton-photon hybrid P-SABR, in which course 1 is delivered with protons at the proton center and course 2 CFRT is delivered with photons (IMRT/VMAT) either at the same center or at Peking University First Hospital or one of six photon sub-centers, after central review of the composite plan. Cohort membership follows the patient's own choice and care pathway; the study does not assign treatment or intervene in clinical decisions, and no formal between-cohort hypothesis testing is planned.

OUTCOMES The primary objective is to describe, in each cohort, the incidence of treatment-related grade ≥ 3 acute and late adverse events (CTCAE v5.0). Secondary objectives are dosimetric (percentage of the GTV receiving BED10 ≥ 100 Gy, PTV V95% and V100%, organ-at-risk doses) and the 1-year local control rate (RECIST 1.1, in-field). Participants are followed for up to 5 years.

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Xianshu Gao, MD, PhD; Phone Number: 010-83575239; Email: doctorgaoxs@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adults with histologically or cytologically confirmed, unresectable bulky solid tumors (at least one lesion with longest diameter > 5 cm) who present to the radiation oncology departments of the participating centers, and who elect to receive proton P-SABR (Cohort A) or proton-photon hybrid P-SABR (Cohort B). Eligible patients are enrolled consecutively after written informed consent.

Description

Inclusion Criteria:

• Histologically or cytologically confirmed malignancy
• At least one tumor with a longest diameter > 5 cm
• Not amenable to curative surgical resection, or patient declines surgery, or surgery contraindicated because of medical comorbidities
• Age ≥ 18 years
• ECOG performance status 0-2
• Life expectancy > 3 months
• Written informed consent

Exclusion Criteria:

• Prior radiotherapy to the same site
• Severe cardiopulmonary insufficiency precluding radiotherapy
• Concurrent other active malignancy
• Uncontrolled acute infection or bowel obstruction
• Pregnancy or breastfeeding
• Intracranial lesion
• Tumor directly invading the full thickness of the esophageal, gastric or intestinal wall with active ulceration, fistula or uncontrolled risk of perforation (tumors that only abut or displace a hollow organ without full-thickness invasion are not excluded)
• Uncontrolled active tumor bleeding, or impending pathological fracture requiring orthopedic intervention
• Any other condition that, in the investigator's judgment, makes the patient unsuitable for the study

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cohort A: Proton P-SABR; Participants who receive the entire P-SABR course with protons at Hebei Yizhou Cancer Hospital: course 1, proton partial stereotactic ablative boost (intensity-modulated proton therapy, IMPT); course 2, proton conventionally fractionated radiotherapy (CFRT). Planned enrollment: 30.	Radiation: Proton P-SABR; Course 1 (proton partial-SABR boost, IMPT): CTV 1.8-3 Gy per fraction with a simultaneous boost to the boost volume within the GTV (GTVb) of 8 Gy × 3 fractions; in larger tumors the inner GTVb (GTVb shrunk by 1 cm) is further boosted to 12 Gy × 3 fractions; critical organs at risk < 3 Gy per fraction; robust optimization on the CTV. Course 2 (proton CFRT): CTV 1.8-3 Gy per fraction with robust optimization, to a cumulative PTV dose of 60-70 Gy on the summed plan, with GTVb BED10 ≥ 100 Gy. Proton dose is expressed with a constant RBE of 1.1. Both courses are delivered at Hebei Yizhou Cancer Hospital.; Other Names: Proton partial stereotactic ablative boost radiotherapy; Proton partial-SABR boost followed by proton conventionally fractionated radiotherapy
Cohort B: Proton-Photon Hybrid P-SABR; Participants who receive course 1 (proton partial stereotactic ablative boost, IMPT) at Hebei Yizhou Cancer Hospital, followed by course 2 photon conventionally fractionated radiotherapy (IMRT/VMAT with daily CBCT) delivered either at the same center (pathway A, same-center; planned n = 10) or at Peking University First Hospital or one of six photon sub-centers (pathway B, cross-center; planned n = 20) after central review of the composite plan. Planned enrollment: 30.	Radiation: Proton-Photon Hybrid P-SABR; Course 1 identical to Cohort A: proton partial-SABR boost (IMPT) with GTVb 8 Gy × 3 fractions and inner GTVb 12 Gy × 3 fractions, delivered at Hebei Yizhou Cancer Hospital. Course 2 (photon CFRT): IMRT/VMAT with daily CBCT recommended, PTV 1.8-3 Gy per fraction to a cumulative PTV dose of 60-70 Gy on the summed plan, with GTVb BED10 ≥ 100 Gy, delivered at Hebei Yizhou Cancer Hospital (same-center) or at Peking University First Hospital or a photon sub-center (cross-center). For cross-center participants, DICOM-RT structure, plan and dose files of both courses are reviewed by the central radiotherapy QA committee, which performs deformable registration and dose summation (MIM; proton RBE = 1.1) before course 2 starts. Target interval between courses ≤ 3 working days (maximum 7 working days).; Other Names: Proton-photon hybrid partial stereotactic ablative boost radiotherapy; Proton partial-SABR boost followed by photon conventionally fractionated radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-related adverse events of grade ≥ 3 (CTCAE v5.0)	Up to 5 years after completion of radiotherapy (acute events: from the first fraction of radiotherapy through 90 days after completion; late events: from day 91 after completion through 5 years)	From the first fraction of radiotherapy to the end of the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of the gross tumor volume (GTV) receiving a biologically effective dose (BED10) ≥ 100 Gy	Volume fraction (%) of the GTV receiving BED10 ≥ 100 Gy on the composite (summed) plan, extracted from the treatment planning system (proton dose converted with RBE = 1.1; dose summation in MIM ).	Up to 3 weeks after the first fraction of radiotherapy (when the composite plan of course 1 and course 2 is finalized)
Planning target volume (PTV) coverage: V95% and V100%	Percentage of the PTV receiving ≥ 95% (V95%) and ≥ 100% (V100%) of the prescribed cumulative dose on the composite plan, reported per cohort as mean ± SD.	Up to 3 weeks after the first fraction of radiotherapy (when the composite plan of course 1 and course 2 is finalized)
Doses to organs at risk (OARs)	Dose metrics of organs at risk (e.g., spinal cord maximum dose, esophagus, lung, bowel, brachial plexus) on the composite plan, and the proportion of participants meeting each OAR dose constraint, reported per OAR and per cohort with 95% CI.	Up to 3 weeks after the first fraction of radiotherapy (when the composite plan of course 1 and course 2 is finalized)
1-year local control (LC) rate	Local control is defined as the absence of progressive disease (RECIST 1.1) in in-field lesions; the in-field region is defined by the GTV/CTV/PTV projections exported from the treatment planning system (DICOM-RT) and confirmed by blinded central imaging review. Time to local progression is measured from the first fraction of radiotherapy. The 1-year LC rate and its Greenwood 95% CI are estimated per cohort with the Kaplan-Meier method; no between-cohort test is performed.	12 months after the first fraction of radiotherapy

Collaborators and Investigators

• Sponsor: Peking University First Hospital

Publications and helpful links

General Publications

• Bai Y, Gao XS, Qin SB, Chen JY, Su MM, Liu Q, Qin XB, Ma MW, Zhao B, Gu XB, Xie M, Cui M, Qi X, Li XY. Partial stereotactic ablative boost radiotherapy in bulky non-small cell lung cancer: a retrospective study. Onco Targets Ther. 2018 May 8;11:2571-2579. doi: 10.2147/OTT.S159538. eCollection 2018.
• Bai Y, Gao X, Qin S, Li S, Ma M, Cao X, Lyu F, Chen J, Qi X, Liu S, Gao Y, Li H, Li X, Li X, Ren X, Huang L. Partial Stereotactic Ablative Radiotherapy Boost Before Conventional Radiotherapy (P-SABR) for Large (> 5 cm) Unresectable Stage III Nonsmall Cell Lung Cancer. Thorac Cancer. 2025 Jan;16(2):e15514. doi: 10.1111/1759-7714.15514. Epub 2024 Dec 14.

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: September 3, 2026
• First Submitted That Met QC Criteria: September 9, 2026
• First Posted (Actual): September 14, 2026

Study Record Updates

• Last Update Posted (Actual): September 14, 2026
• Last Update Submitted That Met QC Criteria: September 9, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: bulky tumor; proton therapy; stereotactic ablative radiotherapy; large tumor; spatially fractionated radiotherapy; partial stereotactic ablative boost radiotherapy; P-SABR; proton-photon hybrid radiotherapy; biologically effective dose; conventionally fractionated radiotherapy
• Other Study ID Numbers: LARGE-Proton-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be made publicly available because of Chinese regulations on health data and human genetic resources. De-identified data may be shared with qualified researchers on reasonable request to the principal investigator, subject to ethics committee approval.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No