Table 4:

Practical process-level considerations and queries in design and reporting of adaptive clinical trials and observational adaptive regimens.

Process	Clinical consideration	Query formulation	Sub-queries/examples	Suggested guidance document(s)
Adaptive regimen prescription/ intent documentation	A priori definition of clinical plan intent	-What is the physician- defined clinical intent of the adaptive regimen?	What conceptual approach underlies the adaptive trial/regimen (viz Table 1)? -Define, if possible the expected magnitude of clinical benefit in terms of locoregional control or toxicity reduction. Examples: - “Reduce by 15% Grade 3 acute symptoms due to inadvertent elective risk PTV overdosage in the presence of >10% weight loss.” - “Improve local control probability by 15% via an isotoxic dose escalation of residual PET-derived high-risk regions on mid-therapy imaaina.”	(35),(36, 37) (44, 81),
Adaptive regimen prescription/ intent documentation	A priori definition of dosimetric aims of adaptive regimen.	What is the intended dosimetric intent of the adaptive regimen?	Examples: - “Shrinkage of CTV/PTV as tumor regression occurs through weekly offline adaptation, while ensuring >95% coverage of weekly PTVadapted”. - “Ensure parotid V15 overdosage of less than 5% deviation from pretherapy prescription via weight loss and deformation is prevented by mid-treatment verification.” - “Replan patient if systematic setup error exceeds a pre-specified tolerance of >3mm.”	(35),(36, 37) (44, 81),
Pre-therapy imaging/simulation	Annotation of worklow for initial planning image acquisition, as well as subsidiary images utilized for therapy planning.	What immobilization strategy/devices were implemented at simulation?	Was this method standardized for all patients in regimen/trial?	(81,82)
Pre-therapy imaging/simulation		Was additional imaging (PET/MR/CT) used for pre-therapy treatm ent planning?	If so, have all images utilized been archived and registered with the simulation DICOM dataset?	(44)
Target delineation/OAR initial segmentation	Specification, in a reproducible manner, of segmentation process for initial planning.	Were TVs/OARs segmented manually?	If so, using what quality assurance procedures(83), guidelines(84–86) and nomenclature (41) in the TPS?	(84–88) (41)
Target delineation/OAR initial segmentation		Were any TVs/OARs segmented by automated/semi- automated processes?	-If so, using what software/version/approach? -Are automated/semi-automated ROIs annotated to differentiate manual vs automated(18, 21,22, 89–93) vs. assisted(17, 24) segmentation?	(84–88) (41)
Initial dose prescription/evaluation	Reporting utilized parameters of interest for planning, as well as the reference model for potential dose modification.	What were pre-therapy dose-constraints implemented for TVs/OARS?	If using a reference constraint(s) (e.g. QUANTEC(94–100) or other extant models(3, 71, 101–109), note prior reference/model.	(45, 99, 110)
Initial dose prescription/evaluation		If constraints were based on a biological model, which one(s)?		(45, 99, 110)
Serial on-treatment imaging	Explicit exposition of implemented processes for image acquisition and image-guided translational/set-up error modification.	Is reimaging performed online (e.g. CBCT, CT-on- rails, MRI-LinAc), or offline (inter-fraction CT resimulation)?	-What is the frequency of on- treatment re-imaging? -Are all on-treatment images archived?	(44) (42) (43)
		Are additional offline image-data implemented (e.g. contrast CT, PET, diagnostic MRI), and if so, how utilized?	Is the method of offline-images (e.g. PET-guided dose- painting (76, 78–80, 111–115)) clearly defined? Are all utilized offline-images archived with co-registration to closest interval online volumetric images?
		Are serial on-treatment translational corrections applied using IGRT in the presence/absence of simultaneous image- registration?	-If so, are translational shifts performed relative to ROI(s), isocenter, or fiducial(s)? -Are all image-based shifts recorded and archived with matched IGRT image dataset?
Replanning/ Plan adaptation	Overt description of the methodologlc approach to planned/delivered dose calculation, as well as associated ROI/segmentation and related dose-constraint monitoring.	Is the replanning strategy online (i.e. while patient is on treatment device) or offline (occurring between treatment fractions)?	-What is the frequency/interval of adaptive replanning(116–118)? -What software/version/algorithm is utilized for replanning/adaptation?	(44)
		What if any, are the replanning criteria/action level specified (e.g. % underdosage of target, overdose of an OAR)?	-Are replanning criteria fixed interval, reactive (e.g. once a dose constraint has been exceeded/unmet) or proactive (triggered by a projected dose or dose trajectory model)? -If so, specify action level.	(44)
		Are non-dosimetric surrogate criteria (e.g. systematic set-up error, morphometric alteration, ROI superimposition on daily IGRT) used as a trigger for replanning?	If so, specify action level.
		Are ROIs for adaptation (re)segmented manually, semi-automated, or fully DIR-propagated?	-Are all propagated and manually generated ROIs archived with daily images after IGRT/replanning review? -Is faculty/st aff approval required for relevant ROIs, and if so, are these annotated and timestamped?
		Is serial manual review of criteria/action level performed (i.e. does a human “check the DVH”) or is automated triggering performed?	-Are all generated/reviewed DVHs (or analogous metrics(119)) archived? -If faculty/staff approval is performed, are relevant DVHs annotated and timestamped?	(41)
Uncertainty margination	Estimation of the relative daily uncertainty accounted for by margin expansion, and disclosure of site- specific rationale/measurements used to calculate/justify utilized margins.	-Are isotropic margins implemented? If so, provide an IGRT-system specific population estim ator. -For anisotropic approaches, describe the margin calculation approach.	Are deformable phantoms(33, 120–125), digital phantoms(126–128), or other QA methods employed to generate trial/regimen-specific margins, or are standard institutional margins employed?	(35, 44, 129)
		Are margins population- derived, or patient specific?
		How do margination strategies account (if at all) for registration uncertainty?
Image Registration/ Dose accumulation assessment	Coherent and understandable explication of serial image/dose relational processes, allowing clear representation of how serially derived image and dose data are analyzed and assessed during treatment, as well as the manner by which the completed therapy course image and dose alterations are summarized.	By what method is image- registration performed: rigid, or deformable?	-If deformable, using what approach (e.g. biomechanical atlas-based, B-spline, DEMONS) and via what software/version?Describe performance metrics for software selection, if available(32, 33). -To what reference data are images used for evaluation/replanning coregistered (e.g. planning simulation, previous daily on-line imaging, or offline imaging)? -Are all DVFs archived? -Are DVFs annotated so that it is readily determined whether they were actually utilized for treatment, or as a function of post hoc plan summation?	(44, 130)
Image Registration/ Dose accumulation assessment		By what approach is dose- summation performed (e.g. iterative dose- accumulation, or superimposition of delivered dose)?	-What software/version/algorithm is used for initial and replanning dose calculation(34)? -Describe utilized dose delivery quality assurance methods (e.g. pre-therapy phantom dosimetry(33, 120–125), EPID- dosimetry(131)) and frequency relative to imaging/plan adaptation. -Is accumulated dose iteratively recorded, archived and summarized? Are final accumulated dose and backprojected dose archived/summarized(31)?	(44, 130)
Data description/ dissemination	Collation of all relevant and informative data elements of the adaptive trial/regimen into a coherent and FAIR-compliant format for reporting of clinical, technical, and dosimetric observations/outcomes and data sharing.	Have relevant clinical outcome data been recorded using an established ontology/nomenclature(48–50)?	Example: If locoregional control is an endpoint, are failure events mapped to delivered/accumulated dose and acquired pre-therapy imaging(132–136) using an accepted methodology/nomenclature(137, 138)? Are the data described, not just in free text format, but using a recognized informatics ontology(48–50)?	(46)
		Has relevant patient- and cohort-specific plan intent/TPS/IGRT/adaptive replanning/archival system data been collated into a single repository that meet FAIR criteria(47, 139)?	If so, are all data compatible with DICOM-RT linked (e.g. via DVF) to a common reference geometry and FAIR-compliant (i.e. machine searchable) image, ROI, and DVH nomenclature? When possible, are clinical data embedded within the DICOM-standard(140, 141)?	(41,44, 47, 49, 50, 139)
		After trial/protocol completion and/or publication, can archived trial/adaptive protocol data be shared, either directly, or via distributed learning systems, to allow learning from extant data(64, 65, 142, 143)?		(41,44, 47, 49, 50, 139)