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An International Consensus on the Design of Prospective Clinical–Translational Trials in Spatially Fractionated Radiation Therapy

Open AccessPublished:December 10, 2021DOI:https://doi.org/10.1016/j.adro.2021.100866

      Abstract

      Purpose

      Spatially fractionated radiation therapy (SFRT), which delivers highly nonuniform dose distributions instead of conventionally practiced homogeneous tumor dose, has shown high rates of clinical response with minimal toxicities in large-volume primary or metastatic malignancies. However, prospective multi-institutional clinical trials in SFRT are lacking, and SFRT techniques and dose parameters remain variable. Agreement on dose prescription, technical administration, and clinical and translational design parameters for SFRT trials is essential to enable broad participation and successful accrual to rigorously test the SFRT approach. We aimed to develop a consensus for the design of multi-institutional clinical trials in SFRT, tailored to specific primary tumor sites, to help facilitate development and enhance the feasibility of such trials.

      Methods and Materials

      Primary tumor sites with sufficient pilot experience in SFRT were identified, and fundamental trial design questions were determined. For each tumor site, a comprehensive consensus effort was established through disease-specific expert panels. Clinical trial design criteria included eligibility, SFRT technology and technique, dose and fractionation, target- and normal-tissue dose parameters, systemic therapies, clinical trial endpoints, and translational science considerations. Iterative appropriateness rank voting, expert panel consensus reviews and discussions, and public comment posting were used for consensus development.

      Results

      Clinical trial criteria were developed for head and neck cancer and soft-tissue sarcoma. Final consensus among the 22 trial design categories each (a total of 163 criteria) was high to moderate overall. Uniform patient cohorts of advanced bulky disease, standardization of SFRT technologies and dosimetry and physics parameters, and collection of translational correlates were considered essential to trial design. Final guideline recommendations and the degree of agreement are presented and discussed.

      Conclusions

      This consensus provides design guidelines for the development of prospective multi-institutional clinical trials testing SFRT in advanced head and neck cancer and soft-tissue sarcoma through in-advance harmonization of the fundamental clinical trial design among SFRT experts, potential investigators, and the SFRT community.

      Introduction

      Spatially fractionated radiation therapy (SFRT) is a complex concept of increasing clinical, experimental, and translational interest. Pilot studies have shown low rates of toxicities and unexpectedly high tumor responses to SFRT in bulky metastatic and primary tumors.
      • Mohiuddin M
      • Curtis DL
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      • et al.
      Palliative treatment of advanced cancer using multiple nonconfluent pencil beam radiation. A pilot study.
      • Mohiuddin M
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      • et al.
      High-dose spatially-fractionated radiation (GRID): A new paradigm in the management of advanced cancers.
      • Mohiuddin M
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      • et al.
      Spatially fractionated (GRID) radiation for palliative treatment of advanced cancer.
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      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
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      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
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      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
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      • et al.
      Improved outcome of treating locally advanced lung cancer with the use of Lattice Radiotherapy (LRT): A case report.
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      • et al.
      Spatially fractionated radiation therapy using lattice radiation in far-advanced bulky cervical cancer: A clinical and molecular imaging and outcome study.
      • Mohiuddin M
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      • et al.
      Locally advanced high-grade extremity soft tissue sarcoma: Response with novel approach to neoadjuvant chemoradiation using induction spatially fractionated GRID radiotherapy (SFGRT) (abstract). Meeting abstract presentation at: American Society of Clinical Oncology Annual Meeting, June 2014, Chicago IL.
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      • et al.
      Spatially fractionated grid radiation (SFGRT): A novel approach in the management of recurrent and unresectable soft tissue sarcoma (abstract). Poster presented at: Annual Meeting of the American Society for Radiation Oncology. Chicago, IL, November 2009.
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      Spatially fractionated radiation therapy (SFR) in the palliation of large bulky (>8 cm) melanomas (abstract). Poster presented at: Annual Meeting of the American Society of Radiation Oncology. New Orleans, LA, October 2002.
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      • Shyu S
      • et al.
      Spatially fractionated radiotherapy (GRID) prior to standard neoadjuvant conventionally fractionated radiotherapy for bulky, high-risk soft tissue and osteosarcomas: Feasibility, safety, and promising pathologic response rates.
      • Choi JI
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      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      The observed enhanced tumoricidal effects of SFRT are thought to be related to the vastly inhomogeneous dose distributions.
      • Neuner G
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      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      ,
      • Griffin RJ
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      • et al.
      understanding high-dose, ultra-high dose rate, and spatially fractionated radiation therapy.
      ,
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      Evidence for early stage anti-tumor immunity elicited by spatially fractionated radiotherapy-immunotherapy combinations.
      The inherent advantages of ablative stereotactic radiosurgery or stereotactic radiation therapy like dose “peaks,” dispersed throughout the tumor, combined with interlaced low dose in the “valleys,” suited to preserve the tumor microenvironment and vasculature, are postulated to promote bystander and abscopal effects as potential underlying mechanisms for higher tumor response.
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      Evidence for early stage anti-tumor immunity elicited by spatially fractionated radiotherapy-immunotherapy combinations.
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      Elevated sphingomyelinase activity and ceramide concentration in serum of patients undergoing high dose spatially fractionated radiation treatment: Implications for endothelial apoptosis.
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      The impact of TNF-alpha induction on therapeutic efficacy following high dose spatially fractionated (GRID) radiation.
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      In vivo effects of lattice radiation therapy on local and distant lung cancer: Potential role of immunomodulation.
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      Outcomes of spatially fractionated radiotherapy (GRID) for bulky soft tissue sarcomas in a large animal model.
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      Combined high-dose LATTICE radiation therapy and immune checkpoint blockade for advanced bulky tumors: The concept and a case report.
      Such mechanisms are of particular interest in the current era of immune-modulating agents that are increasingly combined with radiation therapy.
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      • et al.
      Concurrent radiation and immunotherapy: Survey of practice patterns in the United States.
      Multiple single-institution studies have shown high response and local control rates in cohorts treated largely palliatively with GRID and Lattice SFRT.
      • Mohiuddin M
      • Curtis DL
      • Grizos WT
      • et al.
      Palliative treatment of advanced cancer using multiple nonconfluent pencil beam radiation. A pilot study.
      • Mohiuddin M
      • Fujita M
      • Regine WF
      • et al.
      High-dose spatially-fractionated radiation (GRID): A new paradigm in the management of advanced cancers.
      • Mohiuddin M
      • Stevens JH
      • Reiff JE
      • et al.
      Spatially fractionated (GRID) radiation for palliative treatment of advanced cancer.
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      These studies established the initial dose-response relationships and the need for combining SFRT with fractionated conventional radiation therapy.
      • Mohiuddin M
      • Fujita M
      • Regine WF
      • et al.
      High-dose spatially-fractionated radiation (GRID): A new paradigm in the management of advanced cancers.
      ,
      • Mohiuddin M
      • Stevens JH
      • Reiff JE
      • et al.
      Spatially fractionated (GRID) radiation for palliative treatment of advanced cancer.
      More recently, smaller, disease-specific pilot studies in head and neck (H&N),
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      ,
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      ,
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      lung,
      • Amendola BE
      • Perez NC
      • Wu X
      • et al.
      Improved outcome of treating locally advanced lung cancer with the use of Lattice Radiotherapy (LRT): A case report.
      and cervical
      • Amendola BE
      • Perez NC
      • Mayr NA
      • et al.
      Spatially fractionated radiation therapy using lattice radiation in far-advanced bulky cervical cancer: A clinical and molecular imaging and outcome study.
      cancer, sarcoma,
      • Mohiuddin M
      • Memon M
      • Nobah A
      • et al.
      Locally advanced high-grade extremity soft tissue sarcoma: Response with novel approach to neoadjuvant chemoradiation using induction spatially fractionated GRID radiotherapy (SFGRT) (abstract). Meeting abstract presentation at: American Society of Clinical Oncology Annual Meeting, June 2014, Chicago IL.
      ,
      • Mohiuddin M
      • Miller T
      • Ronjon P
      • et al.
      Spatially fractionated grid radiation (SFGRT): A novel approach in the management of recurrent and unresectable soft tissue sarcoma (abstract). Poster presented at: Annual Meeting of the American Society for Radiation Oncology. Chicago, IL, November 2009.
      ,
      • Snider JW
      • Molitoris J
      • Shyu S
      • et al.
      Spatially fractionated radiotherapy (GRID) prior to standard neoadjuvant conventionally fractionated radiotherapy for bulky, high-risk soft tissue and osteosarcomas: Feasibility, safety, and promising pathologic response rates.
      and melanoma
      • Kudrimoti M
      • Regine WF
      • Huhn JL
      • et al.
      Spatially fractionated radiation therapy (SFR) in the palliation of large bulky (>8 cm) melanomas (abstract). Poster presented at: Annual Meeting of the American Society of Radiation Oncology. New Orleans, LA, October 2002.
      have advanced the SFRT concept from palliative treatment to curative-intent therapy of bulky primary tumors and showed similarly promising local control. They have also broadened the SFRT experience from reporting on palliative responses to providing early data on favorable survival outcomes in patients with nonmetastatic cancer
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      • Amendola BE
      • Perez NC
      • Wu X
      • et al.
      Improved outcome of treating locally advanced lung cancer with the use of Lattice Radiotherapy (LRT): A case report.
      • Amendola BE
      • Perez NC
      • Mayr NA
      • et al.
      Spatially fractionated radiation therapy using lattice radiation in far-advanced bulky cervical cancer: A clinical and molecular imaging and outcome study.
      while affording longer follow-up for adverse effect assessment, which corroborates SFRT's overall favorable toxicity profile.
      Thus, SFRT has the potential to broaden radiation therapy options for patients with locally advanced bulky primary, recurrent, and/or metastatic malignancies, for which with current techniques, the deliverable tumor dose is often severely compromised by normal-tissue tolerance limits.
      Based on these hypothesis-generating studies,
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      • Amendola BE
      • Perez NC
      • Wu X
      • et al.
      Improved outcome of treating locally advanced lung cancer with the use of Lattice Radiotherapy (LRT): A case report.
      • Amendola BE
      • Perez NC
      • Mayr NA
      • et al.
      Spatially fractionated radiation therapy using lattice radiation in far-advanced bulky cervical cancer: A clinical and molecular imaging and outcome study.
      • Mohiuddin M
      • Memon M
      • Nobah A
      • et al.
      Locally advanced high-grade extremity soft tissue sarcoma: Response with novel approach to neoadjuvant chemoradiation using induction spatially fractionated GRID radiotherapy (SFGRT) (abstract). Meeting abstract presentation at: American Society of Clinical Oncology Annual Meeting, June 2014, Chicago IL.
      • Mohiuddin M
      • Miller T
      • Ronjon P
      • et al.
      Spatially fractionated grid radiation (SFGRT): A novel approach in the management of recurrent and unresectable soft tissue sarcoma (abstract). Poster presented at: Annual Meeting of the American Society for Radiation Oncology. Chicago, IL, November 2009.
      • Kudrimoti M
      • Regine WF
      • Huhn JL
      • et al.
      Spatially fractionated radiation therapy (SFR) in the palliation of large bulky (>8 cm) melanomas (abstract). Poster presented at: Annual Meeting of the American Society of Radiation Oncology. New Orleans, LA, October 2002.
      • Snider JW
      • Molitoris J
      • Shyu S
      • et al.
      Spatially fractionated radiotherapy (GRID) prior to standard neoadjuvant conventionally fractionated radiotherapy for bulky, high-risk soft tissue and osteosarcomas: Feasibility, safety, and promising pathologic response rates.
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      well-designed prospective clinical trials, preferably multi-institutional studies, are now needed to rigorously study SFRT as a modality. There is also an unmet need to evaluate feasibility of SFRT across institutions and technology platforms and to further elucidate its underlying biologic mechanisms through correlative translational science within the trial design. To our knowledge, no such phase 3 or multi-institutional prospective trials have been conducted in SFRT to date.
      Design of such trials is challenged by SFRT's profound departure from familiar uniform-dose concepts and the requirement of complex biological modeling and nonintuitive dose-prescription metrics. Furthermore, SFRT platforms, techniques, dose and fractionation schemes have been variable. Currently, 2 profoundly different SFRT technologies are in use. GRID therapy,
      • Mohiuddin M
      • Fujita M
      • Regine WF
      • et al.
      High-dose spatially-fractionated radiation (GRID): A new paradigm in the management of advanced cancers.
      ,
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      ,
      • Zhang H
      • Wu X
      • Zhang X
      • et al.
      Photon GRID radiation therapy: A physics and dosimetry white paper from the Radiosurgery Society (RSS) GRID-Lattice-Microbeam-FLASH Radiotherapy Working Group.
      the first SFRT technology, developed using GRID collimators, has since evolved into an multileaf collimator (MLC)-based platform
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      ,
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      ,
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      with a different dose profile. Most recently, Lattice therapy, a 3-dimensional form of SFRT,
      • Amendola BE
      • Perez N
      • Amendola M
      • et al.
      Lattice radiotherapy with RapidArc for treatment of gynecological tumors: Dosimetric and early clinical evaluations.
      • Wu X
      • Ahmed MM
      • Wright J
      • et al.
      On modern technical approaches of three-dimensional high-dose Lattice radiotherapy (LRT).
      • Wu X
      • Perez N
      • Zheng Y
      • et al.
      The technical and clinical implementation of LATTICE radiation therapy (LRT).
      has emerged. These variabilities likely introduce additional inconsistencies that can hamper trial design and interpretation and therefore require thorough assessment, consensus, and standardization for the specific disease site under investigation. The challenge is compounded by a paucity of reviews
      • Griffin RJ
      • Ahmed MM
      • Amendola B
      • et al.
      understanding high-dose, ultra-high dose rate, and spatially fractionated radiation therapy.
      ,
      • Billena C
      • Khan AJ.
      A current review of spatial fractionation: Back to the future?.
      and an absence of meta-analyses to provide guidance to investigators for trial design.
      To address these obstacles toward development of multi-institutional prospective trials in SFRT, we sought to establish an in-advance common understanding and consensus among SFRT experts regarding the major design parameters and feasibility requirements for SFRT trial development, informed by the collective disease-specific clinical experience and by physics and biology expertise. The consensus effort comprised 2 major candidate primary disease sites—H&N cancer and soft-tissue sarcoma (STS)—and focused on the full range of clinical trial design criteria, including eligibility, stratification, endpoints, prescription dose and fractionation, target- and normal-tissue dose parameters, SFRT technology and technique, systemic therapies, patient assessments, and correlative science investigations.

      Methods and Materials

      This consensus effort was conducted as part of the activities of the Radiosurgery Society (RSS) GRID, Lattice, Microbeam and FLASH Radiation Therapy Working Groups that were established, subsequent to an inaugural 2018 RSS–National Cancer Institute Workshop,
      • Griffin RJ
      • Ahmed MM
      • Amendola B
      • et al.
      understanding high-dose, ultra-high dose rate, and spatially fractionated radiation therapy.
      to advance understanding of the biology, physics, and technology, and the clinical applications of these emerging technologies.
      A comprehensive literature search for GRID and Lattice SFRT was performed (Table 1). The literature was systematically reviewed for studies that reported clinical outcomes. Studies were critically appraised for entry criteria, treatment parameters, and outcome reporting; and were tabulated in literature evidence tables (Appendices E1 and E2).
      Table 1Synopsis of the consensus development process
      SequenceProcess description
      1. Initial literature reviewSearch terms: Spatially fractionated radiation therapy, GRID therapy, Lattice therapy, dose fractionation, radiation, neoplasms/radiation therapy, neoplasms/pathology, tumor control

      Databases: PubMed, Web of Science, Cochrane

      Repeat literature search: April 2021
      Tabulation of literature into evidence tables (Appendices 1-2)
      2. Development of initial clinical trial design criteriaDesign criteria: Eligibility/exclusion, pretherapy, on-therapy, and posttherapy patient evaluations (for outcome endpoints), endpoints, stratifications, dose and technical radiation therapy factors, clinical feasibility of correlative of studies, concurrent therapies, and knowledge gaps that may be addressed in a trial
      Performed by expert group of 3 leaders in general SFRT
      3. Voting round 1Anonymous electronic rating of the appropriateness of the proposed trial design criteria:

      21 categories of trial design questions with 1-11 subcriteria, (total of 75 for H&N cancer and 88 for STS): Voting scale 1-9
      Voting scale and categories: Within each voting category, 3 subranks (eg, 7, 8, and 9) signify ranking as lower, intermediate, and higher appropriateness, respectively.


      1 knowledge-gap question

      1 demographic expertise question
      Voters: radiation oncologists, physicists, and biologists with clinical experience in SFRT in the disease site and/or or publications and/or scientific presentations
      4. Vote analysis and statistical modelPrioritization of agreement on the broader appropriateness categories (appropriate, may be appropriate, or not appropriate)
      Voting scale and categories: Within each voting category, 3 subranks (eg, 7, 8, and 9) signify ranking as lower, intermediate, and higher appropriateness, respectively.
      while maintaining the nuancing of the 1-9 scale
      Agreement categories: high, moderate, and low
      Details of vote agreement categories: Agreement on the rating of each clinical trial criterion was categorized as either low, moderate, or high. Low agreement was defined as the percentage of agreement on the broader appropriateness category (appropriate, may be appropriate, and not appropriate) of less than 60%. High agreement was defined as percent agreement > 67% on the appropriateness category AND no disagreement (if any was present) by more than 1 category. Thus, ratings of appropriate and may be appropriate, or may be appropriate and not appropriate for the same clinical trial criterion were allowable under high agreement if at least two-thirds agreed on a single appropriateness category, whereas ratings of both appropriate and not appropriate could not qualify for high agreement, regardless of the overall percentage of agreement. All others were classified as moderate agreement.
      5. Review/discussion of voting results by disease-specific consensus expert panel (“panel”)Panel members: 3 radiation oncologists, 1 physicist, and 1 biologist with SFRT publications or scientific presentations in the specific disease site, physics, or biology, respectively
      Consensus development based on voting statistics, literature and the panel's clinical/scientific experience
      Formal consensus video conference call(s) and consensus communications (email, phone)
      6. Iterative voting round(s)Implemented for trial criteria with persistently low agreement, or new trial criteria identified by the panel
      7. Rereview/discussion of voting resultsAs in step 5 (with or without video conference call)
      8. Draft guideline developmentGuideline draft and review by panel
      9. Public commentsPublic comment posting for 2 weeks per disease site (by RSS)
      10. Repeat literature reviewAs in step 1
      11. Review/discussion of public commentsReview of anonymized public comments, as in steps 5 and 7; guideline revisions as indicated
      12. Final guidelineDevelopment of final guideline by panel
      Voting scale
       Voting rank1 2 34 5 67 8 9
       Voting categoryNot appropriate

      for clinical trial design
      May be appropriate

      for clinical trial design
      Appropriate

      for clinical trial design
       Vote agreementDefinitions
      Details of vote agreement categories: Agreement on the rating of each clinical trial criterion was categorized as either low, moderate, or high. Low agreement was defined as the percentage of agreement on the broader appropriateness category (appropriate, may be appropriate, and not appropriate) of less than 60%. High agreement was defined as percent agreement > 67% on the appropriateness category AND no disagreement (if any was present) by more than 1 category. Thus, ratings of appropriate and may be appropriate, or may be appropriate and not appropriate for the same clinical trial criterion were allowable under high agreement if at least two-thirds agreed on a single appropriateness category, whereas ratings of both appropriate and not appropriate could not qualify for high agreement, regardless of the overall percentage of agreement. All others were classified as moderate agreement.
       HighPercentage agreement ≥67% AND if there is any disagreement, it is by at most 1 voting category
       Moderate60%-67% agreement OR agreement ≥67% but votes in both appropriate and not appropriate vote categories
       LowPercentage agreement <60%
      Abbreviations: H&N = head and neck; RSS = Radiosurgery Society; SFRT = spatially fractionated radiation therapy; STS = soft-tissue sarcoma.
      low asterisk Voting scale and categories:Within each voting category, 3 subranks (eg, 7, 8, and 9) signify ranking as lower, intermediate, and higher appropriateness, respectively.
      Details of vote agreement categories:Agreement on the rating of each clinical trial criterion was categorized as either low, moderate, or high. Low agreement was defined as the percentage of agreement on the broader appropriateness category (appropriate, may be appropriate, and not appropriate) of less than 60%. High agreement was defined as percent agreement > 67% on the appropriateness category AND no disagreement (if any was present) by more than 1 category. Thus, ratings of appropriate and may be appropriate, or may be appropriate and not appropriate for the same clinical trial criterion were allowable under high agreement if at least two-thirds agreed on a single appropriateness category, whereas ratings of both appropriate and not appropriate could not qualify for high agreement, regardless of the overall percentage of agreement. All others were classified as moderate agreement.
      The overall process and rationale of the consensus procedure are described in detail in Table 1. Initial draft criteria for clinical trial design were developed among a group of leading SFRT experts. Design criteria were based on pertinent clinical trial principles according to the categories outlined in Table 2 and then were tailored to the individual primary tumors.
      Table 2Clinical trial design categories
      Design categoriesSubcategories
      Eligible disease sitesPrimary tumor sites
      Eligibility/exclusion criteriaStratificationsDisease stage, tumor size/extent/invasion Histology, molecular markers Prior treatment Patient factors: age, performance status
      Pretreatment evaluationsClinical Imaging Histologic investigations
      Radiation therapy:

      SFRT
      SFRT dose SFRT target volume SFRT OAR constraints SFRT technique
      Radiation therapy:

      Conventional external beam radiation therapy
      cERT dose and fractionation cERT technique cERT OAR constraints
      On-therapy evaluationsClinical Laboratory Imaging Patient-reported outcomes Translational studies (evaluation of clinical feasibility)
      Systemic therapyCytotoxic agents and timing Immunotherapy
      Posttherapy evaluationsClinical Imaging Patient-reported outcomes
      Knowledge gapsClinical Physics Biology/translation science
      Abbreviations: cERT = Conventional external beam radiation therapy; OAR = organ at risk; SFRT = spatially fractionated radiation therapy.
      For each disease site, an anonymous 22-question voting survey with 1 to 11 subcriteria questions and the respective literature evidence tables (Appendices E1 and E2) were distributed to national and international experts with publications, scientific presentations, and/or clinical SFRT practice in the respective disease site (voting round 1). Voting for appropriateness and prioritization of each trial-design criterion was performed on a 1 to 9 scale (Table 1) with additional optional free-text comments.
      For the analysis of voting results, in addition to descriptive statistics quantifying the appropriateness of each design criterion, a statistical model was developed (Table 1) to quantitate the level of agreement among an overall low number of voters to address the challenge of the relatively small number of existing disease-specific SFRT experts.
      A disease-specific consensus expert panel of 3 radiation oncologists, a physicist, and a biologist with scientific SFRT publications and/or presentations was established for each disease site to develop the consensus recommendations and guideline. The aggregated voting round 1 results were circulated among each disease-specific panel, reviewed, and discussed in sequential conference calls and communications, using modified Delphi technique
      • Murphy MK
      • Black NA
      • Lamping DL
      • et al.
      Consensus development methods, and their use in clinical guideline development.
      principles (Table 1). Remaining controversies and/or new trial design considerations were subjected to a second voting round in H&N cancer, followed by iterative panel review and discussions. For STS, only 1 voting round was required. Detailed voting results and panel discussions are presented in the respective consensus tables (Appendices E3 and E4).
      The drafts of the resulting consensus guidelines were posted on the RSS website for public comment. After review of the comments, the panel finalized the guideline as summarized in this article. The detailed guidelines are presented in Appendices E5 and E6.

      Consensus Guideline Recommendations and Discussion

      SFRT Clinical Trial Design Consensus Guideline for H&N Cancer

      The clinical trial design recommendations for H&N cancer were guided by 3 SFRT outcome studies of multiple disease sites containing H&N cancer patients
      • Mohiuddin M
      • Fujita M
      • Regine WF
      • et al.
      High-dose spatially-fractionated radiation (GRID): A new paradigm in the management of advanced cancers.
      • Mohiuddin M
      • Stevens JH
      • Reiff JE
      • et al.
      Spatially fractionated (GRID) radiation for palliative treatment of advanced cancer.
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      and 3 disease-specific series of only H&N cancer
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      ,
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      ,
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      (Appendix E1). These studies showed high local and regional control rates in the neck of 79% to 92% and survival rates of 50% to 79% in patients with far-advanced tumors
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      ,
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      that compared favorably with the regional control rates of 25% to 66% and survival of 30% reported with conventional radiation therapy or radiation therapy and chemotherapy.
      • Mendenhall WM
      • Million RR
      • Cassisi NJ.
      Squamous cell carcinoma of the head and neck treated with radiation therapy: The role of neck dissection for clinically positive neck nodes.
      • Witek ME
      • Wieland AM
      • Chen S
      • et al.
      Outcomes for patients with head and neck squamous cell carcinoma presenting with N3 nodal disease.
      • Goguen LA
      • Posner MR
      • Tishler RB
      • et al.
      Examining the need for neck dissection in the era of chemoradiation therapy for advanced head and neck cancer.
      • Spector ME
      • Chinn SB
      • Bellile E
      • et al.
      Matted nodes as a predictor of distant metastasis in advanced-stage III/IV oropharyngeal squamous cell carcinoma.
      • Vainshtein JM
      • Spector ME
      • Ibrahim M
      • et al.
      Matted nodes: High distant-metastasis risk and a potential indication for intensification of systemic therapy in human papillomavirus-related oropharyngeal cancer.
      These observations provided rationale to test SFRT rigorously in multi-institutional trials of bulky neck disease.

      Eligibility

      The consensus on eligibility and exclusion criteria is summarized in Table 3. Recommendations for eligibility aimed to establish, based on patient characteristics in the pilot studies
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      ,
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      (Appendix E1), a uniform patient cohort of oropharynx, larynx (high consensus), and nasopharynx (moderate consensus) primaries with bulky lymph node involvement. Eligibility should be guided by the lymph node status, not the status (T-stage) of the primary (high consensus), emphasizing that the majority of reported clinical experience with SFRT in H&N cancer is in the treatment of bulky lymph nodes.
      • Mohiuddin M
      • Fujita M
      • Regine WF
      • et al.
      High-dose spatially-fractionated radiation (GRID): A new paradigm in the management of advanced cancers.
      • Mohiuddin M
      • Stevens JH
      • Reiff JE
      • et al.
      Spatially fractionated (GRID) radiation for palliative treatment of advanced cancer.
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      ,
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      Patients with any T-stage oropharynx, larynx, or nasopharynx cancer and N3 nodal stage are eligible (Table 3). Similarly, stage N3 skin primaries may be included (high consensus). Eligible histology includes squamous cell carcinoma, based on the majority of published experience,
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      ,
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      ,
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      both human papillomavirus (HPV) (P16) positive and negative (moderate consensus). Uncommon primaries and uncommon or highly radiosensitive histologies are excluded to minimize confounding variables that may hamper interpretation of outcome results (high consensus).
      Table 3Eligibility, exclusions, and stratifications in H&N cancer SFRT trials
      Eligibility criteria
      Disease sitesOropharynx, hypopharynx, supraglottic larynx, glottic larynx, and nasopharynx primary tumors
      Primary skin cancer with stage N3 lymph node involvement is eligible. There is currently insufficient clinical evidence in favor of specific individual H&N primary sites for inclusion into SFRT trials (high consensus). Uncommon primary sites, such as salivary gland and paranasal sinus tumors, should be excluded because of their different spread pattern, often variable histology, and overall low incidence (high consensus).
      Stage, tumor sizeStage N3 tumors with any T-stage

      Single lymph node or matted nodes with lymph node size totaling >6 cm
      Histology and tumor markersSquamous cell carcinoma, HPV negative or HPV positive
      Prior therapyNo prior therapy
      Recurrent tumors after prior surgery may be eligible if recurrence consists of bulky neck nodes that were not previously irradiated.
      Patient factorsAge >18 y

      No upper age limit if eligible based on performance status
      Exclusion criteria
      Disease sitesSalivary gland tumors, paranasal sinus tumors
      Primary skin cancer with stage N3 lymph node involvement is eligible. There is currently insufficient clinical evidence in favor of specific individual H&N primary sites for inclusion into SFRT trials (high consensus). Uncommon primary sites, such as salivary gland and paranasal sinus tumors, should be excluded because of their different spread pattern, often variable histology, and overall low incidence (high consensus).
      Histology and tumor markersTumors considered radiosensitive, such as lymphoma, multiple myeloma, and leukemic infiltrates
      Tumor stage/extentBoth carotid artery invasion and skin involvement

      Both carotid artery invasion and prior radiation
      Prior therapyRecurrent tumors after prior radiation therapy

      Recurrent tumors after prior surgery
      Recurrent tumors after prior surgery may be eligible if recurrence consists of bulky neck nodes that were not previously irradiated.


      Prior chemotherapy for H&N cancer
      Patient factorsActive scleroderma (systemic sclerosis)
      Stratifications
      T-stage groupingStage T1/2 vs T3/4
      HPV statusHPV negative vs positive
      SFRT technologyGRID vs Lattice
      If Lattice therapy is used in subsequent trials, stratification may include GRID versus Lattice therapy technologies.
      Abbreviations: H&N = head and neck; HPV = human papillomavirus; SFRT = spatially fractionated radiation therapy.
      low asterisk Primary skin cancer with stage N3 lymph node involvement is eligible. There is currently insufficient clinical evidence in favor of specific individual H&N primary sites for inclusion into SFRT trials (high consensus). Uncommon primary sites, such as salivary gland and paranasal sinus tumors, should be excluded because of their different spread pattern, often variable histology, and overall low incidence (high consensus).
      Recurrent tumors after prior surgery may be eligible if recurrence consists of bulky neck nodes that were not previously irradiated.
      If Lattice therapy is used in subsequent trials, stratification may include GRID versus Lattice therapy technologies.
      The panel unanimously recommended exclusion of tumors with both carotid invasion and skin involvement, or both carotid invasion and prior radiation therapy, based on fatal carotid bleeding after SFRT in a patient with carotid invasion and prior radiation,
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      and in a patient with carotid invasion and skin involvement (unpublished).
      Patients with prior radiation therapy (moderate consensus), prior surgery, and/or (induction) chemotherapy (high consensus) are excluded, with the exception of prior surgery with no prior radiation to the target region. A separate clinical trial (to follow an initial trial of patients without previous radiation therapy) is suggested for patients with postradiation recurrences.

      Stratifications

      Stratifications according to T-stage and HPV status are recommended based on their strong influence on outcome. Stratification by SFRT technology—for example, GRID versus Lattice therapy (if Lattice is used in the future)—is recommended because of dosimetric differences (Table 3).

      Endpoints

      Local control and treatment related toxicity are recommended as primary endpoints. The feasibility of delivering SFRT according to the dosimetric and physics specifications
      • Zhang H
      • Wu X
      • Zhang X
      • et al.
      Photon GRID radiation therapy: A physics and dosimetry white paper from the Radiosurgery Society (RSS) GRID-Lattice-Microbeam-FLASH Radiotherapy Working Group.
      (see the section “SFRT: Dose”), disease-specific survival, overall survival, and quality of life (QOL) outcomes represent additional endpoints.

      Radiation therapy

      SFRT: Dose

      Based on the outcome data
      • Mohiuddin M
      • Fujita M
      • Regine WF
      • et al.
      High-dose spatially-fractionated radiation (GRID): A new paradigm in the management of advanced cancers.
      • Mohiuddin M
      • Stevens JH
      • Reiff JE
      • et al.
      Spatially fractionated (GRID) radiation for palliative treatment of advanced cancer.
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      ,
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      (Appendix E1), the preferred SFRT dose is 15 Gy/1 fraction to the bulky lymph node(s). In 2 of the 3 H&N cancer cohorts, 15 Gy/1 fraction was most commonly used and was associated with high local control and low toxicity,
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      ,
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      providing the basis for this recommendation. Although a schedule of 20 Gy/1 fraction was used in 1 cohort
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      and in small proportions of patients in other studies,
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      ,
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      ,
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      20 Gy has been more commonly used in the palliative setting.
      • Mohiuddin M
      • Fujita M
      • Regine WF
      • et al.
      High-dose spatially-fractionated radiation (GRID): A new paradigm in the management of advanced cancers.
      • Mohiuddin M
      • Stevens JH
      • Reiff JE
      • et al.
      Spatially fractionated (GRID) radiation for palliative treatment of advanced cancer.
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      Therefore, and in the absence of a dose response relationship favoring 20 Gy, the panel considered 15 Gy/1 fraction the preferred dosing regimen for an initial SFRT trial (high consensus). The dose at the GTV periphery, which is generally in the range of 3 Gy for a 15-Gy SFRT dose,
      • Zhang H
      • Wang JZ
      • Mayr N
      • et al.
      Fractionated grid therapy in treating cervical cancers: Conventional fractionation or hypofractionation?.
      should be reported.
      Standardization of the GRID dose prescription, defined as the peak dose, is required. In addition, dosimetric and geometric characteristics of the heterogeneous dose distribution, such as dose volume histogram characteristics (D10, D50, D90) and peak-to-peak distance, should be reported according to guidelines further described in the recent GRID physics and dosimetry white paper.
      • Zhang H
      • Wu X
      • Zhang X
      • et al.
      Photon GRID radiation therapy: A physics and dosimetry white paper from the Radiosurgery Society (RSS) GRID-Lattice-Microbeam-FLASH Radiotherapy Working Group.
      Owing to the different SFRT technologies (eg, collimator-based and MLC-based GRID) with different dose distributions,
      • Murphy NL
      • Philip R
      • Wozniak M
      • et al.
      A simple dosimetric approach to spatially fractionated GRID radiation therapy using the multileaf collimator for treatment of breast cancers in the prone position.
      the equivalent uniform dose (EUD) for H&N squamous cell carcinoma (using α/β = 10 Gy) and for normal tissues (generally α/β = 3 Gy) must be determined for any trial regimen. Principles of EUD computation in SFRT, which favor the modified linear quadratic model, and tumor cell sensitivity considerations are described in the recent SFRT physics guideline publications.
      • Zhang H
      • Wu X
      • Zhang X
      • et al.
      Photon GRID radiation therapy: A physics and dosimetry white paper from the Radiosurgery Society (RSS) GRID-Lattice-Microbeam-FLASH Radiotherapy Working Group.
      ,
      • Wu X
      • Perez N
      • Zheng Y
      • et al.
      The technical and clinical implementation of LATTICE radiation therapy (LRT).

      SFRT: Target volume

      The SFRT target should consist of the involved nodal mass (GTV)
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      ,
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      by imaging-based delineation, without an additional margin (high consensus).

      SFRT: Normal organ-at-risk structures

      Based on published data
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      ,
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      and the panel's clinical experience, critical normal organ-at-risk (OAR) structures include the spinal cord, brain stem, and optic chiasm (high consensus). Consideration of the brachial plexus, carotid artery, and mandible as OARs may be appropriate (moderate consensus). The addition of planning organ at risk volume (PRV) margins to the OAR structures can be considered, particularly for the spinal cord and brain stem (moderate consensus).

      SFRT: Technique

      Based on current published data,
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      • Huhn JL
      • Regine WF
      • Valentino JP
      • et al.
      Spatially fractionated GRID radiation treatment of advanced neck disease associated with head and neck cancer.
      • Penagaricano JA
      • Moros EG
      • Ratanatharathorn V
      • et al.
      Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: Initial response rates and toxicity.
      ,
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      GRID technologies are preferred. Collimator-based and MLC-based GRID therapy may be applied within the same trial under the condition that the EUD is comparable. While there was overall support for Lattice therapy as an SFRT technology in the future, to the panel's knowledge, there were no published outcome data on Lattice SFRT in H&N cancer at the time of this writing. Whereas such published experience is expected to emerge, at this time, the panel favored GRID therapy technologies for an initial clinical trial.

      Conventional ERT: Dose and technique

      Conventionally fractionated external beam radiation therapy (cERT) must be given after SFRT, because it has been demonstrated that tumor response is inferior when cERT is omitted.
      • Mohiuddin M
      • Fujita M
      • Regine WF
      • et al.
      High-dose spatially-fractionated radiation (GRID): A new paradigm in the management of advanced cancers.
      ,
      • Mohiuddin M
      • Stevens JH
      • Reiff JE
      • et al.
      Spatially fractionated (GRID) radiation for palliative treatment of advanced cancer.
      The cERT should start within 72 hours of the SFRT fraction.
      For the cERT component of treatment, conventional definitive dose regimens, specific to the H&N disease site, are prescribed. PTV doses are generally in the range of 70 to 72 Gy (2-2.12 Gy/fraction) to the gross tumor, 60 to 63 Gy to the high-risk subclinical target, and 50 to 56 Gy to the low-risk subclinical target (high consensus). Reduction of the definitive cERT dose below standard dose levels is not recommended because a reduced response rate of only 25% was reported with cERT doses of less than 75% of the planned definitive dose.
      • Choi JI
      • Daniels J
      • Cohen D
      • et al.
      Clinical outcomes of spatially fractionated GRID radiotherapy in the treatment of bulky tumors of the head and neck.
      The use of intensity modulated radiation therapy is encouraged (high consensus). A simultaneously integrated boost is acceptable for bulky involvement; however, if used, the dose to the SFRT GTV should be limited to 69.6 Gy.

      Conventional ERT: OAR constraints

      Dose constraints to OARs for the cERT component follow those of standard practice without consideration of the dose contribution from the SFRT (high consensus). The SFRT contributions to OARs must be addressed during the planning of the SFRT component of treatment (see the section “SFRT: Normal organ-at-risk structures”).

      Systemic therapy

      Agents and timing

      Chemotherapy and targeted systemic therapy agents that are typically considered appropriate in conjunction with standard-fractionation radiation therapy for H&N cancer are acceptable for a clinical trial (high consensus). These agents typically include but may not be limited to platinum-based chemotherapies, taxanes, and cetuximab. Chemotherapy can be given concurrently with radiation therapy for the cERT component of treatment. However, systemic therapy should not be given during SFRT (high consensus). Typical schedules that have been used consist of delivering SFRT (without systemic therapy) on a Friday, followed by cERT and concurrent systemic therapy start within 72 hours on the following Monday.

      Immunotherapy

      In the absence of published experience with combinations of SFRT and immunotherapy in H&N cancer, there was no consensus among voters on this combination. The panel favored not to include immunotherapy for an initial trial (moderate consensus) and to test combined therapy in a subsequent trial using guidance from the ablative stereotactic radiation therapy and immunotherapy experience, and future SFRT and immunotherapy experience.

      Evaluations and assessments

      Patient evaluations before, during, and after treatment are recommended according to the standard of care for H&N cancer. These are detailed in Table 4 along with additional trial-specific assessments, specifically QOL assessments, patient-reported outcomes, and imaging. Cone beam computed tomography imaging during treatment can be incorporated into trials to establish criteria for intratreatment response assessment and adaptive therapy that may be required in SFRT.
      • Amendola BE
      • Perez NC
      • Mayr NA
      • et al.
      Spatially fractionated radiation therapy using lattice radiation in far-advanced bulky cervical cancer: A clinical and molecular imaging and outcome study.
      Table 4Pretherapy, on-therapy, and posttherapy assessments in H&N SFRT trials
      AssessmentsEvaluation/testPretherapyOn-therapyPosttherapy
      ClinicalH&N examination
      Weekly.
      Routine follow-up every 3 months in years 1 to 2, and every 4 to 6 months in years 3 to 5.
      Fiberoptic laryngoscopy
      Routine follow-up every 3 months in years 1 to 2, and every 4 to 6 months in years 3 to 5.
      ,‡
      Toxicity assessmentn/a
      Weekly.
      Routine follow-up every 3 months in years 1 to 2, and every 4 to 6 months in years 3 to 5.
      ImagingCT maxillo/facial/neckn/a
      PET/CT, or alternatively (if PET/CT is unavailable), maxillo/facial/neck CT or MRI.
      MRI maxillo/facial/neckn/a
      PET/CT, or alternatively (if PET/CT is unavailable), maxillo/facial/neck CT or MRI.
      CT chest (including liver)n/a
      Swallowing studyn/a
      PET/CTn/a
      PET/CT, or alternatively (if PET/CT is unavailable), maxillo/facial/neck CT or MRI.
      On-board imaging (CBCT)n/a
      CBCT imaging during treatment can be included as response assessment.
      n/a
      LaboratoryCBC
      Blood chemistries
      HistologyHPVn/an/a
      Correlative studiesBlood collection
      Feasible weekly or at prospective time points and dose levels during or after treatment.
      Feasible weekly or at prospective time points and dose levels during or after treatment.
      Urine collection
      Feasible weekly or at prospective time points and dose levels during or after treatment.
      Feasible weekly or at prospective time points and dose levels during or after treatment.
      Tumor biopsy
      Tissue from pretherapy biopsies may be procured for correlative studies.
      Functional/molecular imaging
      Functional imaging can be added to a diagnostic imaging session pretherapy and posttherapy and as additional imaging prospectively scheduled at various time points and dose levels during radiation therapy.
      Functional imaging can be added to a diagnostic imaging session pretherapy and posttherapy and as additional imaging prospectively scheduled at various time points and dose levels during radiation therapy.
      Functional imaging can be added to a diagnostic imaging session pretherapy and posttherapy and as additional imaging prospectively scheduled at various time points and dose levels during radiation therapy.
      Patient-reported outcomesQOL assessment
      Routine follow-up every 3 months in years 1 to 2, and every 4 to 6 months in years 3 to 5.
      Abbreviations:  = recommended;  = recommended if clinically indicated; — = not recommended; CBC = complete blood count; CBCT = cone beam computed tomography; CT = computed tomography; H&N = head and neck; HPV = human papillomavirus; MRI = magnetic resonance imaging; n/a = not applicable; PET = positron emission tomography; QOL = quality of life; SFRT = spatially fractionated radiation therapy.
      low asterisk Weekly.
      Routine follow-up every 3 months in years 1 to 2, and every 4 to 6 months in years 3 to 5.
      § PET/CT, or alternatively (if PET/CT is unavailable), maxillo/facial/neck CT or MRI.
      ǁ CBCT imaging during treatment can be included as response assessment.
      Feasible weekly or at prospective time points and dose levels during or after treatment.
      # Tissue from pretherapy biopsies may be procured for correlative studies.
      low asterisklow asterisk Functional imaging can be added to a diagnostic imaging session pretherapy and posttherapy and as additional imaging prospectively scheduled at various time points and dose levels during radiation therapy.
      The outcome endpoint of local/regional control in the neck is important but can be challenging to definitively characterize because of interinstitutional variability in response assessment and in the use and timing of postradiation neck dissection. Determination of local control should be based on the 3-month posttherapy positron emission tomography/computed tomography (PET/CT), using established response criteria; and on the need for postradiation neck dissection, including pathologic response at the time of neck dissection.
      To enable translational correlative science studies, specimen collection of blood and urine multiple times during radiation therapy should be strongly considered (high consensus). Although pretherapy tumor biopsies are available for correlative studies, tumor tissue sampling during the treatment course was considered not clinically practical or feasible based on the potential clinical risk. If possible and available, advanced functional and molecular imaging techniques such as vascular and metabolic imaging may provide noninvasive and non-tissue-altering approaches to characterize changes in functional tissue properties in response to SFRT during and after treatment.
      • Cooper RA
      • Carrington BM
      • Loncaster JA
      • et al.
      Tumour oxygenation levels correlate with dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the cervix.
      • Egeland TA
      • Simonsen TG
      • Gaustad JV
      • et al.
      Dynamic contrast-enhanced magnetic resonance imaging of tumors: Preclinical validation of parametric images.
      • Padhani AR.
      Dynamic contrast-enhanced MRI in clinical oncology: Current status and future directions.
      • Wang P
      • Popovtzer A
      • Eisbruch A
      • et al.
      An approach to identify, from DCE MRI, significant subvolumes of tumors related to outcomes in advanced head-and-neck cancer.
      Posttherapy patient-reported and QOL outcomes are recommended (high consensus).

      SFRT Clinical Trial Design Consensus Guideline for STS

      As for H&N cancer, trial design recommendations for STS were based on multidisease series that included sarcoma patients and disease-specific series (Appendix E2). This experience comprised 2 studies of largely palliatively treated cohorts that contained sarcoma patients.
      • Mohiuddin M
      • Fujita M
      • Regine WF
      • et al.
      High-dose spatially-fractionated radiation (GRID): A new paradigm in the management of advanced cancers.
      • Mohiuddin M
      • Stevens JH
      • Reiff JE
      • et al.
      Spatially fractionated (GRID) radiation for palliative treatment of advanced cancer.
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      Disease-specific series of definitively treated patients with STS have been presented in abstract form,
      • Mohiuddin M
      • Memon M
      • Nobah A
      • et al.
      Locally advanced high-grade extremity soft tissue sarcoma: Response with novel approach to neoadjuvant chemoradiation using induction spatially fractionated GRID radiotherapy (SFGRT) (abstract). Meeting abstract presentation at: American Society of Clinical Oncology Annual Meeting, June 2014, Chicago IL.
      ,
      • Mohiuddin M
      • Miller T
      • Ronjon P
      • et al.
      Spatially fractionated grid radiation (SFGRT): A novel approach in the management of recurrent and unresectable soft tissue sarcoma (abstract). Poster presented at: Annual Meeting of the American Society for Radiation Oncology. Chicago, IL, November 2009.
      and 1 outcome study
      • Snider JW
      • Molitoris J
      • Shyu S
      • et al.
      Spatially fractionated radiotherapy (GRID) prior to standard neoadjuvant conventionally fractionated radiotherapy for bulky, high-risk soft tissue and osteosarcomas: Feasibility, safety, and promising pathologic response rates.
      was recently published. These studies showed high response rates, local control rates of 85% to 100%,
      • Mohiuddin M
      • Memon M
      • Nobah A
      • et al.
      Locally advanced high-grade extremity soft tissue sarcoma: Response with novel approach to neoadjuvant chemoradiation using induction spatially fractionated GRID radiotherapy (SFGRT) (abstract). Meeting abstract presentation at: American Society of Clinical Oncology Annual Meeting, June 2014, Chicago IL.
      • Mohiuddin M
      • Miller T
      • Ronjon P
      • et al.
      Spatially fractionated grid radiation (SFGRT): A novel approach in the management of recurrent and unresectable soft tissue sarcoma (abstract). Poster presented at: Annual Meeting of the American Society for Radiation Oncology. Chicago, IL, November 2009.
      • Kudrimoti M
      • Regine WF
      • Huhn JL
      • et al.
      Spatially fractionated radiation therapy (SFR) in the palliation of large bulky (>8 cm) melanomas (abstract). Poster presented at: Annual Meeting of the American Society of Radiation Oncology. New Orleans, LA, October 2002.
      • Snider JW
      • Molitoris J
      • Shyu S
      • et al.
      Spatially fractionated radiotherapy (GRID) prior to standard neoadjuvant conventionally fractionated radiotherapy for bulky, high-risk soft tissue and osteosarcomas: Feasibility, safety, and promising pathologic response rates.
      and a limb-sparing rate of 93%
      • Mohiuddin M
      • Memon M
      • Nobah A
      • et al.
      Locally advanced high-grade extremity soft tissue sarcoma: Response with novel approach to neoadjuvant chemoradiation using induction spatially fractionated GRID radiotherapy (SFGRT) (abstract). Meeting abstract presentation at: American Society of Clinical Oncology Annual Meeting, June 2014, Chicago IL.
      in bulky (>8-10 cm) sarcomas, which overall exceeded the outcomes of standard therapy.
      • Eilber FC
      • Rosen G
      • Eckardt J
      • et al.
      Treatment-induced pathologic necrosis: A predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas.
      • DeLaney TF
      • Spiro IJ
      • Suit HD
      • et al.
      Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas.
      • Wang D
      • Zhang Q
      • Eisenberg BL
      • et al.
      Significant reduction of late toxicities in patients with extremity sarcoma treated with image-guided radiation therapy to a reduced target volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial.
      In contrast, with conventional preoperative radiation therapy, few patients with bulky sarcomas attain local control,
      • Kepka L
      • DeLaney TF
      • Suit HD
      • et al.
      Results of radiation therapy for unresected soft-tissue sarcomas.
      and overall outcomes are poor. In high-grade sarcomas, median treatment-induced necrosis is only 50%,
      • Roberge D
      • Skamene T
      • Nahal A
      • et al.
      Radiological and pathological response following pre-operative radiotherapy for soft-tissue sarcoma.
      well below the recognized tumor control and survival predictor of ≥90% necrosis.
      • Eilber FC
      • Rosen G
      • Eckardt J
      • et al.
      Treatment-induced pathologic necrosis: A predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas.
      • DeLaney TF
      • Spiro IJ
      • Suit HD
      • et al.
      Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas.
      • Wang D
      • Zhang Q
      • Eisenberg BL
      • et al.
      Significant reduction of late toxicities in patients with extremity sarcoma treated with image-guided radiation therapy to a reduced target volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial.
      • Kepka L
      • DeLaney TF
      • Suit HD
      • et al.
      Results of radiation therapy for unresected soft-tissue sarcomas.
      • Roberge D
      • Skamene T
      • Nahal A
      • et al.
      Radiological and pathological response following pre-operative radiotherapy for soft-tissue sarcoma.
      • Wang D
      • Harris J
      • Kraybill WG
      • et al.
      Pathologic complete response and survival outcomes in patients with localized soft tissue sarcoma treated with neoadjuvant chemoradiotherapy or radiotherapy: Long-term update of NRG Oncology RTOG 9514 and 0630.
      Collectively, the favorable SFRT pilot results
      • Mohiuddin M
      • Memon M
      • Nobah A
      • et al.
      Locally advanced high-grade extremity soft tissue sarcoma: Response with novel approach to neoadjuvant chemoradiation using induction spatially fractionated GRID radiotherapy (SFGRT) (abstract). Meeting abstract presentation at: American Society of Clinical Oncology Annual Meeting, June 2014, Chicago IL.
      ,
      • Mohiuddin M
      • Miller T
      • Ronjon P
      • et al.
      Spatially fractionated grid radiation (SFGRT): A novel approach in the management of recurrent and unresectable soft tissue sarcoma (abstract). Poster presented at: Annual Meeting of the American Society for Radiation Oncology. Chicago, IL, November 2009.
      ,
      • Snider JW
      • Molitoris J
      • Shyu S
      • et al.
      Spatially fractionated radiotherapy (GRID) prior to standard neoadjuvant conventionally fractionated radiotherapy for bulky, high-risk soft tissue and osteosarcomas: Feasibility, safety, and promising pathologic response rates.
      and the challenge in improving outcomes with other strategies, including more toxic dose escalation
      • Kepka L
      • DeLaney TF
      • Suit HD
      • et al.
      Results of radiation therapy for unresected soft-tissue sarcomas.
      or intensified chemotherapy,
      • Kraybill WG
      • Harris J
      • Spiro IJ
      • et al.
      Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514.
      provide justification for the development of multi-institutional SFRT trials in STS.

      Eligibility

      Eligibility and exclusion criteria are summarized in Table 5. Eligibility recommendations aim to establish a uniform patient cohort of bulky extremity sarcomas, the most common presentation, which also have the most SFRT pilot experience.
      • Mohiuddin M
      • Fujita M
      • Regine WF
      • et al.
      High-dose spatially-fractionated radiation (GRID): A new paradigm in the management of advanced cancers.
      ,
      • Mohiuddin M
      • Stevens JH
      • Reiff JE
      • et al.
      Spatially fractionated (GRID) radiation for palliative treatment of advanced cancer.
      ,
      • Snider JW
      • Molitoris J
      • Shyu S
      • et al.
      Spatially fractionated radiotherapy (GRID) prior to standard neoadjuvant conventionally fractionated radiotherapy for bulky, high-risk soft tissue and osteosarcomas: Feasibility, safety, and promising pathologic response rates.
      This eligibility profile reflects that of the major prior randomized sarcoma trials using conventional radiation therapy.
      • DeLaney TF
      • Spiro IJ
      • Suit HD
      • et al.
      Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas.
      ,
      • Wang D
      • Zhang Q
      • Eisenberg BL
      • et al.
      Significant reduction of late toxicities in patients with extremity sarcoma treated with image-guided radiation therapy to a reduced target volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial.
      ,
      • Wang D
      • Bosch W
      • Roberge D
      • et al.
      RTOG sarcoma radiation oncologists reach consensus on gross tumor volume and clinical target volume on computed tomographic images for preoperative radiotherapy of primary soft tissue sarcoma of extremity in Radiation Therapy Oncology Group studies.
      The panel considered it important to maintain a patient population that is consistent with these trial cohorts to allow comparison of SFRT outcomes with those of conventional radiation therapy.
      Table 5Eligibility, exclusions, and stratifications in sarcoma SFRT trials
      Eligibility criteria
      Disease sitesPatients with primary sarcomas of extremities, to be treated with preoperative radiation therapy
      Less common primary sites, such as head and neck, intraabdominal, or retroperitoneal sites, should be excluded to reduce unnecessary variability (high consensus).
      Stage, tumor sizeUnresectable, stage IB-IIIB, bulky tumors ≥8 cm in largest diameter
      Inclusion of patients with lymph node involvement (which is rare) may be appropriate (high consensus).
      Histology and tumor markersUndifferentiated pleomorphic sarcoma, myxoid liposarcoma, or leiomyosarcoma (high consensus)
      This eligibility profile reflects that of major randomized prior trials in sarcoma with conventional radiation.


      Grade 2-3
      Prior therapyNone except neoadjuvant chemotherapy
      Patient factorsAge >18 y; upper age limit of 85 y may be appropriate (moderate consensus)
      Exclusion criteria
      Disease sitesLess common primary sites, such as head and neck, intra-abdominal, or retroperitoneal sites
      Histology and tumor markersRhabdomyosarcoma; Ewing sarcoma; chondrosarcoma, Kaposi sarcoma, and angiosarcoma; malignant peripheral nerve sheath tumor
      Although some of these histologies have been treated with SFRT, their different natural disease course and rarity was deemed to add confounding variability to an SFRT clinical trial cohort.


      Grade 1
      Tumor stage/extentTumors <8 cm in largest diameter
      Prior therapyRecurrent tumors after prior radiation

      Recurrent tumors after prior surgery

      Recurrent tumors after prior chemotherapy
      Patient factorsScleroderma (systemic sclerosis)
      Exclusion because of high risk of toxicities, particularly in skin and subcutaneous tissues (high consensus).
      Stratifications
      Tumor bulkLargest dimension ≤12cm vs >12 cm
      Neoadjuvant chemotherapyNeoadjuvant chemotherapy vs none
      Abbreviation: SFRT = spatially fractionated radiation therapy.
      low asterisk Less common primary sites, such as head and neck, intraabdominal, or retroperitoneal sites, should be excluded to reduce unnecessary variability (high consensus).
      Inclusion of patients with lymph node involvement (which is rare) may be appropriate (high consensus).
      This eligibility profile reflects that of major randomized prior trials in sarcoma with conventional radiation.
      § Although some of these histologies have been treated with SFRT, their different natural disease course and rarity was deemed to add confounding variability to an SFRT clinical trial cohort.
      Exclusion because of high risk of toxicities, particularly in skin and subcutaneous tissues (high consensus).
      Patients with stage IB-IIIB, grade 2 to 3, bulky ≥8 cm STS, who are planned to be treated with preoperative radiation therapy (high consensus), are eligible. Both neoadjuvant chemotherapy and no chemotherapy are permitted, reflecting the current practice pattern in STS. Prior resection, prior radiation therapy, and scleroderma (associated with higher risk of toxicities, particularly in subcutaneous and skin regions) are exclusion criteria (high consensus).

      Stratifications

      Tumor bulk, using the largest imaging-based tumor diameter of <12 cm versus ≥12 cm, and use of neoadjuvant chemotherapy versus no chemotherapy (see the section “Concurrent systemic therapy: Agents and timing”), should be stratified (Table 5). Owing to the redundancy in molecular pathways, molecular marker-based subclassification or stratification is not recommended for an initial trial in this rare disease.

      Endpoints

      The feasibility of delivering SFRT according to the dosimetric and physics specifications
      • Zhang H
      • Wu X
      • Zhang X
      • et al.
      Photon GRID radiation therapy: A physics and dosimetry white paper from the Radiosurgery Society (RSS) GRID-Lattice-Microbeam-FLASH Radiotherapy Working Group.
      (see the section “SFRT: Dose”), primary tumor response (by imaging and pathologic response), and resectability are suitable primary endpoints. Local recurrence-free, metastasis-free, overall survival, and QOL outcomes present additional endpoints.

      Radiation therapy

      SFRT: Dose

      A dose range of 15 to 18 Gy in 1 fraction is an appropriate dosing regimen for clinical trials (high consensus), with the higher dose favored. The EUD of the SFRT regimen must be determined for sarcoma and for the normal tissues as described for H&N cancer.

      SFRT: Target volume

      The SFRT target volume, based on clinical experience,
      • Mohiuddin M
      • Memon M
      • Nobah A
      • et al.
      Locally advanced high-grade extremity soft tissue sarcoma: Response with novel approach to neoadjuvant chemoradiation using induction spatially fractionated GRID radiotherapy (SFGRT) (abstract). Meeting abstract presentation at: American Society of Clinical Oncology Annual Meeting, June 2014, Chicago IL.
      ,
      • Mohiuddin M
      • Miller T
      • Ronjon P
      • et al.
      Spatially fractionated grid radiation (SFGRT): A novel approach in the management of recurrent and unresectable soft tissue sarcoma (abstract). Poster presented at: Annual Meeting of the American Society for Radiation Oncology. Chicago, IL, November 2009.
      ,
      • Snider JW
      • Molitoris J
      • Shyu S
      • et al.
      Spatially fractionated radiotherapy (GRID) prior to standard neoadjuvant conventionally fractionated radiotherapy for bulky, high-risk soft tissue and osteosarcomas: Feasibility, safety, and promising pathologic response rates.
      is the GTV of the primary tumor without an additional margin.

      SFRT: OAR constraints

      Consideration should be given to excluding sensitive neural structures such as the brachial plexus from the SFRT volume and beam path (high consensus). Exclusion of OARs with a 1-cm margin, usually through secondary collimation with MLC blocking, are expected to achieve a negligible SFRT dose. It is also recognized that this may not be possible if these OARs are involved with a tumor. The skin surface dose from SFRT should be limited to <150% of the prescribed SFRT dose based on the STS brachytherapy experience.
      • Emory CL
      • Montgomery CO
      • Potter BK
      • et al.
      Early complications of high-dose-rate brachytherapy in soft tissue sarcoma: A comparison with traditional external-beam radiotherapy.

      SFRT: Technique

      For an initial clinical trial, GRID therapy is the technology of choice, because all currently published clinical experience is in GRID therapy
      • Mohiuddin M
      • Fujita M
      • Regine WF
      • et al.
      High-dose spatially-fractionated radiation (GRID): A new paradigm in the management of advanced cancers.
      ,
      • Mohiuddin M
      • Stevens JH
      • Reiff JE
      • et al.
      Spatially fractionated (GRID) radiation for palliative treatment of advanced cancer.
      ,
      • Mohiuddin M
      • Memon M
      • Nobah A
      • et al.
      Locally advanced high-grade extremity soft tissue sarcoma: Response with novel approach to neoadjuvant chemoradiation using induction spatially fractionated GRID radiotherapy (SFGRT) (abstract). Meeting abstract presentation at: American Society of Clinical Oncology Annual Meeting, June 2014, Chicago IL.
      ,
      • Mohiuddin M
      • Miller T
      • Ronjon P
      • et al.
      Spatially fractionated grid radiation (SFGRT): A novel approach in the management of recurrent and unresectable soft tissue sarcoma (abstract). Poster presented at: Annual Meeting of the American Society for Radiation Oncology. Chicago, IL, November 2009.
      ,
      • Snider JW
      • Molitoris J
      • Shyu S
      • et al.
      Spatially fractionated radiotherapy (GRID) prior to standard neoadjuvant conventionally fractionated radiotherapy for bulky, high-risk soft tissue and osteosarcomas: Feasibility, safety, and promising pathologic response rates.
      (high consensus). Although published data with Lattice in STS are currently lacking, Lattice therapy may be appropriate in subsequent trials.

      Conventional ERT: Dose and technique

      The cERT dose, following the SFRT fraction, is 50 to 50.4 Gy / 25 to 28 fractions to the PTV (high consensus) per RTOG trial regimens,
      • Wang D
      • Zhang Q
      • Eisenberg BL
      • et al.
      Significant reduction of late toxicities in patients with extremity sarcoma treated with image-guided radiation therapy to a reduced target volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial.
      ,
      • Wang D
      • Bosch W
      • Roberge D
      • et al.
      RTOG sarcoma radiation oncologists reach consensus on gross tumor volume and clinical target volume on computed tomographic images for preoperative radiotherapy of primary soft tissue sarcoma of extremity in Radiation Therapy Oncology Group studies.
      using intensity modulated radiation therapy or a 3-dimensional conformal technique.
      • Wang D
      • Zhang Q
      • Eisenberg BL
      • et al.
      Significant reduction of late toxicities in patients with extremity sarcoma treated with image-guided radiation therapy to a reduced target volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial.
      ,
      • Wang D
      • Bosch W
      • Roberge D
      • et al.
      RTOG sarcoma radiation oncologists reach consensus on gross tumor volume and clinical target volume on computed tomographic images for preoperative radiotherapy of primary soft tissue sarcoma of extremity in Radiation Therapy Oncology Group studies.
      As in standard-of-care radiation therapy, treatment to the entire extremity circumference must be avoided (high consensus).
      Most commonly, the cERT course begins 1 to 2 days after SFRT
      • Neuner G
      • Mohiuddin MM
      • Vander Walde N
      • et al.
      High-dose spatially fractionated GRID radiation therapy (SFGRT): A comparison of treatment outcomes with Cerrobend vs. MLC SFGRT.
      and should start ideally within 3 days of the SFRT fraction. The interval between SFRT and cERT should be documented to elucidate any potential effects on outcome.

      Conventional ERT: OAR constraints

      Conventional dose constraints to critical normal tissues are applied. The dose contribution from the SFRT is not counted toward the dose constraints (moderate consensus). For concerns regarding normal-tissue doses, the OAR dose should be reduced up front when planning the SFRT by adjusting field size and shape (see the section “SFRT: OAR constraints”).

      Systemic therapy

      Agents and timing

      Neoadjuvant chemotherapy (prior to radiation therapy) and adjuvant chemotherapy after radiation therapy completion are acceptable. Agents considered acceptable in standard-of-care practice are allowable in clinical trials (high consensus).
      Concurrent chemotherapy, delivered during the radiation therapy course, is not considered permissible in an initial clinical trial (high consensus). Concurrent chemotherapy is inconsistently and not widely used in current practice, providing a rationale for its omission, along with the potential to introduce confounding variables for the interpretation of tumor control and toxicity outcomes.

      Immunotherapy

      Immunotherapy was not considered to be recommended in an initial clinical trial (high consensus) but can be studied in subsequent trials or as a lead-in study as more combined STS radiation therapy and immunotherapy data emerge.

      Evaluations and assessments

      Evaluations are presented in Table 6. Pretherapy standard workup includes magnetic resonance imaging or CT of the extremity and chest, abdomen, and pelvis CT or PET/CT for metastatic workup.
      Table 6Pretherapy, on-therapy, and posttherapy assessments in sarcoma SFRT trials
      AssessmentsEvaluation/testPretherapyOn-therapyPostradiation therapy/preoperativeSurgical/ histologicAfter completion of all therapy
      ClinicalClinical examination
      Weekly.
      Four to 8 weeks after radiation therapy completion.
      n/a
      Routine follow-up every 3 to 4 months in years 1 to 2, every 6 months in years 3 to 5, then yearly.
      Toxicity assessmentn/a
      Weekly.
      Four to 8 weeks after radiation therapy completion.
      n/a
      Routine follow-up every 3 to 4 months in years 1 to 2, every 6 months in years 3 to 5, then yearly.
      ImagingMRI (extremity)n/a
      Magnetic resonance imaging preferred, using Response Evaluation Criteria in Solid Tumors and quantitative assessment of tumor necrosis.
      n/a
      Magnetic resonance imaging preferred, using Response Evaluation Criteria in Solid Tumors and quantitative assessment of tumor necrosis.
      CT (extremity)n/a
      Magnetic resonance imaging preferred, using Response Evaluation Criteria in Solid Tumors and quantitative assessment of tumor necrosis.
      n/a
      Magnetic resonance imaging preferred, using Response Evaluation Criteria in Solid Tumors and quantitative assessment of tumor necrosis.
      CT Chest/abdomen/pelvis CTn/an/an/a√ǁ
      PET/CTn/an/an/a√ǁ
      LaboratoryCBCn/an/a
      Blood chemistriesn/an/a
      HistologyTumor necrosisn/an/an/a
      Tumor necrosis of at least 90%.
      n/a
      Correlative studiesBlood collection
      Feasible weekly or at prospective time points and dose levels during and after treatment.
      n/a
      Urine collection
      Feasible weekly or at prospective time points and dose levels during and after treatment.
      n/a
      Tumor biopsy/specimen
      Tissue from pretherapy biopsies and postradiation specimens (from the definitive resection) may be procured for correlative studies.
      Tissue from pretherapy biopsies and postradiation specimens (from the definitive resection) may be procured for correlative studies.
      n/a
      Patient-reported outcomesQOL assessment
      Four to 8 weeks after radiation therapy completion.
      n/a
      Abbreviations:  = recommended; ǁ = recommended if clinically indicated; — = not recommended; CBC = complete blood count; CT = computed tomography; MRI = magnetic resonance imaging; n/a = not applicable; PET = positron emission tomography; QOL = quality of life; SFRT = spatially fractionated radiation therapy.
      low asterisk Weekly.
      Four to 8 weeks after radiation therapy completion.
      Routine follow-up every 3 to 4 months in years 1 to 2, every 6 months in years 3 to 5, then yearly.
      § Magnetic resonance imaging preferred, using Response Evaluation Criteria in Solid Tumors and quantitative assessment of tumor necrosis.
      Tumor necrosis of at least 90%.
      # Feasible weekly or at prospective time points and dose levels during and after treatment.
      low asterisklow asterisk Tissue from pretherapy biopsies and postradiation specimens (from the definitive resection) may be procured for correlative studies.
      On-treatment evaluations should consist of a standard weekly response, toxicity, QOL assessments, and patient-reported outcomes. Specimen collection of blood and urine multiple times during radiation therapy for translational correlative studies are feasible and strongly recommended (high consensus). Tumor biopsies during the treatment course are considered not clinically feasible (high consensus). Uniquely in the preoperative radiation therapy setting, the surgical specimen after radiation therapy provides an important potential resource for the prospective study of post-SFRT molecular markers in both tumor and normal tissue.
      After radiation therapy, preoperative response assessment is recommended, preferably with magnetic resonance imaging, using the Response Evaluation Criteria in Solid Tumors, quantitative imaging assessment of tumor necrosis (>90% necrosis), and standard clinical examination (high consensus) at 4 to 8 weeks after radiation therapy. Evaluations should be performed in conjunction with QOL assessments and patient-reported outcomes (high consensus).

      Surgical evaluation, pathologic response

      Pathologic tumor response, as routinely assessed in standard of care, provides an important outcome assessment for SFRT response in STS clinical trials. Assessment of negative-margin resectability, R0 versus R1 resection, and pathologic criteria of tumor response including quantitative histologic assessment of necrosis of >90%
      • Eilber FC
      • Rosen G
      • Eckardt J
      • et al.
      Treatment-induced pathologic necrosis: A predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas.
      is required (high consensus).

      Posttherapy evaluations (after completion of all therapy)

      History and clinical examination are indispensable for the assessment of function and toxicity outcomes. Clinical examination and imaging surveillance schedules should follow the standard of care (Table 6) and be combined with patient-reported outcomes and QOL assessments in the routine posttherapy evaluations.

      Conclusion

      The pilot experience that has defined SFRT dose and techniques and shown promising tumor control, toxicity outcomes, and early survival outcomes, has reached an inflection point that enables the development of multi-institutional SFRT trials in definitively treated bulky primary tumors.
      SFRT for both STS and H&N cancer share common properties of high ablative stereotactic radiation therapy dosing, generally excluding OARs; and are administered in close time proximity before conventional radiation therapy or radiation therapy and chemotherapy.
      Standardization of the novel, nonconventional physics and dosimetric parameters with inherent dose and response modeling of the heterogeneous dose to tumor and normal structures is essential for the feasibility of SFRT trials and for their success in generating meaningful results. The inclusion of well-conducted translational science into clinical trial design is critically important to investigate in clinical patients the preclinically observed biological mechanisms and potential immunologic phenomena of SFRT.
      • Johnsrud AJ
      • Jenkins SV
      • Jamshidi-Parsian A
      • et al.
      Evidence for early stage anti-tumor immunity elicited by spatially fractionated radiotherapy-immunotherapy combinations.
      • Sathishkumar S
      • Boyanovsky B
      • Karakashian AA
      • et al.
      Elevated sphingomyelinase activity and ceramide concentration in serum of patients undergoing high dose spatially fractionated radiation treatment: Implications for endothelial apoptosis.
      • Sathishkumar S
      • Dey S
      • Meigooni AS
      • et al.
      The impact of TNF-alpha induction on therapeutic efficacy following high dose spatially fractionated (GRID) radiation.
      • Kanagavelu S
      • Gupta S
      • Wu X
      • et al.
      In vivo effects of lattice radiation therapy on local and distant lung cancer: Potential role of immunomodulation.
      • Nolan MW
      • Gieger TL
      • Karakashian AA
      • et al.
      Outcomes of spatially fractionated radiotherapy (GRID) for bulky soft tissue sarcomas in a large animal model.
      • Jiang L
      • Li X
      • Zhang J
      • et al.
      Combined high-dose LATTICE radiation therapy and immune checkpoint blockade for advanced bulky tumors: The concept and a case report.
      To accomplish this, “liquid biopsy” concepts, leveraged through serial blood and urine collections and synchronized prospectively with the treatment course, may advance our understanding of the underpinnings of SFRT response. The challenge of the inability to procure tumor tissue during the radiation therapy course to interrogate molecular markers may be alleviated by prospective functional and molecular imaging. Finally, physicians’ and physicists’ education was a knowledge gap identified during this consensus effort and is hoped to be addressed by these guidelines.
      This development of guidelines for clinical trial design is a novel concept to establish broad consensus (through ample a priori communication and vetting) among the respective scientific and clinical communities, well ahead of clinical trial design and development. We have adapted existing consensus process models that have been in use for clinical care guidelines, which are generally based on ample published data and large numbers of experts. We applied and further developed these concepts for the requirements of consensus development in the different domain of clinical trial design, which has to build on much sparser, less mature pilot data and fewer experts, but nonetheless requires agreement among the broader community to facilitate trial success. Intense engagement and consensus building among clinical, physics, and biology expertise enabled identification of current knowledge gaps and development of design strategies to address them in clinically feasible trials.
      The trial design recommendations presented herein are based on the current status of knowledge in SFRT and the developed common understanding among SFRT experts and community. Although they may provide guidance for clinical trial design and embedded translational studies, new data, longer-term outcome results, and larger patient cohorts may further refine, adapt, or modify these initial concepts. Ultimately, these consensus recommendations should be individualized by the respective investigators and their teams pursuing clinical trials in SFRT.

      Acknowledgments

      The authors are deeply grateful to the Radiosurgery Society (RSS) for their collaboration in this research, without which this work would not have been possible. Specifically we thank the RSS Research Committee for reviewing our study proposal, and the RSS for creating a forum for clinical trial design consensus on their website and facilitating the public comment posting for this consensus guideline effort.

      Appendix. Supplementary materials

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