Comparing Radiotherapy Dose Strategies for Symptom Relief in Large Solid Tumors

Purpose and study design

SCALE-LRT (Symptom-Control Assessment of LATTICE Escalation) is a prospective, multicenter, open-label, parallel-group, randomized phase IIb superiority trial in adults with symptomatic bulky solid tumors. It tests whether three-dimensional LATTICE spatially fractionated radiotherapy improves patient-reported symptom relief compared separately with homogeneous radiotherapy of 20 gray (Gy) in five fractions and 25 Gy in five fractions. LATTICE creates selected high-dose regions inside the tumor while maintaining a lower dose across the surrounding treatment volume.

The radiotherapy strategy is assigned through central randomization. One index lesion and one symptom attributable to that lesion are selected before randomization. The index lesion and exact symptom wording cannot change after allocation.

Participants are randomized in a 1:1:1 ratio. Allocation uses Pocock-Simon minimization with a random component, balancing participating center, pain versus non-pain target symptom, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 versus 2-3, and gross tumor volume (GTV) of 100 to less than 500 versus at least 500 cubic centimeters. Allocation is concealed until assignment. Participants and treating teams are not masked. Standardized symptom collection and allocation-masked imaging review are used where specified and feasible; the trial is not uniformly assessor-blinded.

Treatment strategies

Arm A receives homogeneous external-beam photon radiotherapy of 20 Gy in five 4-Gy fractions to the protocol-defined low-dose planning target volume, without an intentional intratumoral boost.

Arm B receives homogeneous external-beam photon radiotherapy of 25 Gy in five 5-Gy fractions to the same type of planning target volume, without an intentional intratumoral boost.

Arm C receives 20 Gy in five 4-Gy fractions to the low-dose planning target volume with a simultaneous integrated boost to a total of 66.7 Gy in five 13.34-Gy fractions in protocol-defined intratumoral high-dose regions. The boost is delivered during the same five fractions, not as an additional fraction or an additional 66.7 Gy. The high-dose regions use complete 1.5-centimeter spheres in a locked three-dimensional geometric pattern. At least three complete, protocol-conforming high-dose regions must be feasible. Individual high-dose regions may not be moved on the basis of positron emission tomography uptake or another biological imaging signal in the main randomized intervention.

All arms use intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT), protocol immobilization and motion management, and volumetric image-guided radiotherapy (IGRT) before each fraction. Hard organ-at-risk (OAR) constraints take precedence over target coverage. Eligibility requires documented clinical and technical feasibility of all three allocations before randomization; it does not require optimization of three complete treatment-ready plans. The assigned arm cannot be replaced because another regimen is operationally preferred.

Treatment is given once daily on five consecutive working days, ordinarily Monday to Friday. The first fraction should start within seven calendar days of randomization. Planned completion is within seven calendar days of the first fraction; completion within a maximum of ten calendar days is permitted only after a documented medical, public-holiday or technical interruption. Twice-daily or compensatory double fractions are prohibited. Protocol safety holds and replanning may be used when clinically required.

Primary symptom assessment

The participant chooses the symptom they most want treatment to improve after clinical attribution to the index lesion. Severity is measured on a numeric rating scale (NRS) from 0 to 10. Baseline severity must be at least 4. The symptom category, wording and recall period are fixed before allocation.

The primary endpoint is target-symptom response in the week-8 window, days 49-63 after the final fraction. Response requires a valid in-window NRS showing an improvement of at least 2 points from baseline, with the participant alive and free of index-lesion rescue through the fixed day-63 cutoff. Death or rescue on or before day 63 is nonresponse, regardless of an earlier improved score. Rescue means unplanned local treatment of the index lesion because of inadequate symptom control, progression, a complication or imminent risk. Escalation of supportive medicines alone is not rescue for the general target-symptom endpoint. A participant who is alive and rescue-free through day 63 but lacks a valid in-window score is missing for the primary estimand, rather than automatically a nonresponder.

If treatment is delayed, not initiated or not completed, the main patient-reported outcome schedule remains tied to the planned final-fraction date recorded at randomization. Actual treatment dates are retained and prespecified sensitivity analyses address the actual last fraction. Non-initiation, interruption or crossover does not remove a randomized participant from the intention-to-treat analysis.

Follow-up and complementary assessments

Symptoms, medicines and rescue treatment are recorded at baseline, the end of radiotherapy, day 7 and weeks 2, 4, 8 and 12. Complementary assessments include quality of life, physical function, patient global impression of change, patient-reported symptomatic adverse events (AEs), clinician-graded AEs, treatment completion, tumor response, clinically relevant local failure, overall survival, progression-free survival, healthcare use and days alive out of hospital. Protocol imaging is planned at week 12, with later imaging at months 6 and 12 when clinically appropriate and feasible. Follow-up continues for at least 12 months after randomization where survival permits, with record-based or direct follow-up to 24 months when possible.

Days alive and out of hospital are a nonconfirmatory secondary endpoint measured in all randomized participants as allocated over the fixed 90-calendar-day interval [randomization date, randomization date plus 90 days), namely days 0-89. Each day alive without an inpatient overnight contributes one day. All-cause planned and unplanned inpatient stays count; outpatient radiotherapy and same-day emergency care without admission are not inpatient stays. The day of death and subsequent days contribute zero. Dead and inpatient time are not subtracted twice; unknown status remains missing. Treatment delays, noninitiation, discontinuation, rescue and subsequent therapy do not reset this interval. Mortality and hospitalization components are reported separately. Detailed healthcare-utilization counts are exploratory, from randomization through this interval and, where available, month 12.

Consensus pain response using pain scores and oral morphine-equivalent dose is a nonconfirmatory secondary endpoint only in the subgroup whose target symptom was frozen as pain before randomization. The algorithm originates in bone-metastasis trials; its use for other sites is an adaptation. Custom volumetric-response categories are exploratory and mutually exclusive: complete disappearance (delta volume equals minus 100%); major reduction (minus 100% < delta volume <= minus 65%); moderate reduction (minus 65% < delta volume <= minus 30%); stable volume (minus 30% < delta volume < plus 30%); and increase (delta volume >= plus 30%). They do not replace RECIST or continuous volume-change analyses.

In-person assessments are preferred. Trained staff may collect protocol-authorized patient-reported, healthcare-use and survival information by telephone if a participant cannot or will not attend. Telephone contact does not substitute for physical examination, clinician-graded adverse-event assessment, laboratory testing or imaging.

Concomitant treatment and safety

Best supportive care is permitted in every arm and is not withheld to preserve an endpoint. Other necessary cancer treatments are managed under prespecified timing, interaction and documentation rules. Cytotoxic chemotherapy and antiangiogenic treatment must not overlap with protocol radiotherapy and ordinarily require at least a five-day interval before the first and after the final fraction, with longer intervals or documented prospective approval when applicable. Continuation of immunotherapy, endocrine treatment or targeted treatment requires participant-specific review. Unplanned rescue treatment is provided when clinically needed and is recorded.

Adverse events are collected from consent, with baseline and pre-radiotherapy events recorded separately. Acute events are new or worsened events with onset from the first actual fraction through 90 days after the actual final fraction; the intolerance/morbidity composite uses the same interval. Late events have onset after that cutoff. For permanent early discontinuation, the actual last fraction is used once course termination is confirmed. Actual dates, dose, fractions and observation duration are retained. Nonstarters remain in randomized SAE/death reporting and are labeled unexposed; all-treated and all-randomized safety summaries are distinct, and as-treated comparisons are not interpreted as pure randomized treatment effects. The planned final-fraction rule for patient-reported assessment scheduling remains unchanged.

The first 15 participants randomized to Arm C form an embedded safety and technical-implementation cohort. Cohort membership is fixed by randomization order, including nonstarters, and participants are not silently replaced by treated participants or completers. Plans receive prospective technical review. Safety days 30 and 90 are 30 and 90 days after the actual final fraction of the assigned course. For a documented definitive nonstarter, review maturity uses the planned final-fraction date recorded at randomization, with the participant explicitly labeled unexposed. All further randomization is paused when the fifteenth cohort participant reaches the defined safety day 30. Resumption requires mature day-30 safety data or an earlier clinically documented definitive outcome for all first 15 participants, plus documented Sponsor and Principal-Investigator authorization. A second review occurs when all 15 reach the defined safety day 90 or have an earlier definitive outcome. Loss to follow-up is not maturity or a definitive outcome. Additional Arm-C allocations before the pause do not replace this cohort; available additional exposure data are reviewed. Prespecified urgent triggers are unchanged, including at least 3 of the first 15 with qualifying treatment-related grade-3-or-higher nonhematologic events by their defined safety day 30. The Sponsor and Principal Investigator may expand the safety cohort if exposure is insufficient. Tumor lysis syndrome risk assessment and risk-adapted laboratory surveillance apply across all arms.

Planned sample and analysis

The initial target is 426 randomized participants, 142 per arm. A single blinded reassessment based only on pooled primary-outcome missingness may increase the total to a maximum of 480 without examining treatment effects. The primary analysis follows randomized assignment. The two confirmatory comparisons are Arm C versus Arm A and Arm C versus Arm B, with a two-sided Dunnett adjustment controlling family-wise type-I error at 0.05. Each comparison can support its own conclusion; superiority to both controls requires both adjusted comparisons to be positive. Arm B versus Arm A is a secondary, estimation-oriented comparison, not an equivalence test. Missing week-8 scores in participants alive and rescue-free are handled using multiple imputation, with prespecified sensitivity analyses. No formal comparative interim efficacy or futility analysis is planned.

Ancillary research

Biologically guided vertex placement and optional biomarker studies require a separately approved prospective substudy and appropriate consent.

Additional prespecified exploratory analyses and operational assessments

The following hypothesis-generating analyses and operational assessments are prespecified in the protocol. They do not replace the primary and secondary outcome measures or create additional confirmatory comparisons. Longitudinal symptom analyses include area-under-the-score-curve summaries at the registered symptom assessment times.

Dosimetry and clinical outcomes: Exploratory associations of spatial dose geometry, vertex number and vertex-to-gross-tumor-volume fraction, high-dose-target dose, dose-volume metrics, peak-to-valley dose ratio, conformity, dose gradient, dose spill, organ-at-risk proximity and delivered-dose reconstruction with symptom response, imaging cytoreduction and treatment-related morbidity. Each dosimetric exposure and clinical outcome is analyzed separately. Analyses are hypothesis-generating and do not infer a biological mechanism or a causal treatment effect from uncontrolled correlations. Planning and treatment dosimetry are related to clinical outcomes assessed through month 12.

Treatment-effect heterogeneity: Exploratory treatment-by-subgroup interaction analyses for maximum diameter (7 to less than 10, 10 to less than 15, or at least 15 cm), gross tumor volume (100 to less than 250, 250 to less than 500, or at least 500 cubic centimeters), anatomical site, histology/radiosensitivity class, pain versus non-pain target symptom, Eastern Cooperative Oncology Group performance status, baseline symptom score, previous nonoverlapping radiotherapy, systemic-treatment class/timing and treatment completion. Continuous size models supplement categories. Interaction estimates and confidence intervals are reported, rather than comparing significance within subgroups. These analyses may be underpowered. These analyses use the week-8 primary response and the separately specified time-to-event endpoints over their registered follow-up horizons.

Variation in treatment-related AEs and morbidity: Exploratory safety analyses according to anatomical site, gross tumor volume, organ-at-risk proximity or invasion, motion-management class, number of high-dose vertices, renal function and tumor-lysis-syndrome risk category. Outcomes include clinician-graded AEs and the separately registered morbidity composite; grades, attribution and event types remain separate. Analyses characterize safety variation and are not confirmatory efficacy tests. The assessment period extends from the first actual radiotherapy fraction through month 12; acute onset is from the first actual fraction through 90 days after the actual final fraction, with late onset thereafter.

Trial feasibility and outcome ascertainment: Pooled, arm-masked descriptive assessment of screening, recruitment, technical eligibility, time to treatment, completion, deviations, patient-reported outcome availability/timing, telephone use and reasons for missing data. Screening and randomized denominators are kept distinct. The first-year milestone uses the first 60 consecutive randomized participants without post-randomization selection and requires mature week-12 windows or earlier determinable outcomes. This assessment does not test comparative efficacy or report arm-specific primary response. An optional pooled, allocation-masked operational review may occur after approximately six months. An optional first-year feasibility analysis uses the first 60 consecutive randomized participants only after all have completed their week-12 windows or have an earlier documented event determining the relevant feasibility status. If fewer than 60 have mature follow-up at 12 months, a pooled descriptive recruitment update may be used internally; a clinical feasibility manuscript is not required. Comparative efficacy and arm-specific primary response are not examined or disclosed in these reviews.

Treatment delivery and site experience: Exploratory treatment-delivery summaries including treatment time, imaging/setup corrections, adaptive replanning, protocol deviations, patient-specific quality-assurance results and changes with site experience. Each technical metric is retained separately; this analysis does not create a combined technical-success score. Data cover planning through completion of radiotherapy, in treated participants.

Missing information and assessment mode: Exploratory analysis of missing patient-reported outcomes and in-person versus authorized telephone assessment. Reasons for missingness are coded, and exact assessment timing and mode are retained. Planned analyses include multiple imputation, inverse-probability weighting, pattern-mixture models and tipping-point sensitivity analyses. Known death or rescue failures remain distinct from an alive, rescue-free participant with a genuinely missing report. These analyses evaluate robustness and do not replace the primary responder estimand. These analyses concern information collected from baseline through week 12 after the final radiotherapy fraction, using the protocol-prespecified planned-date rule when treatment is delayed, not initiated or incomplete.

Conditional imaging research: Conditional ancillary analyses of baseline imaging heterogeneity, necrosis, spatial peak/valley response and early imaging change. Analyses are conducted only when acquisition and processing are prospectively harmonized in a separate locked ancillary plan. Imaging-derived features and their associations with clinical outcomes are hypothesis-generating; no biological mechanism is inferred from uncontrolled correlations. The protocol identifies baseline through month 12 as the potential observation period; specific measurements will require the separate prospective plan before the ancillary analyses can be implemented.

Conditional translational research: Conditional translational analyses of circulating biomarkers, immune signals or tissue. Samples and analyses are permitted only under separately approved consent and laboratory manuals. Biomarker findings and associations with clinical outcomes are exploratory, and no biological mechanism is inferred from uncontrolled correlations. Each biomarker is analyzed according to the prospectively approved ancillary plan rather than combined into an unprespecified score. The protocol identifies baseline through month 12 as the potential observation period; specific measurements will require the separately approved consent and laboratory manuals before this work can be implemented.