Technical Note: A step‐by‐step guide to Temporally Feathered Radiation Therapy planning for head and neck cancer

Abstract Purpose Prior in silico simulations propose that Temporally Feathered Radiation Therapy (TFRT) may reduce toxicity related to head and neck radiation therapy. In this study we demonstrate a step‐by‐step guide to TFRT planning with modern treatment planning systems. Methods One patient with oropharyngeal cancer planned for definitive radiation therapy using intensity‐modulated radiation therapy (IMRT) techniques was replanned using the TFRT technique. Five organs at risk (OAR) were identified to be feathered. A “base plan” was first created based on desired planning target volumes (PTV) coverage, plan conformality, and OAR constraints. The base plan was then re‐optimized by modifying planning objectives, to generate five subplans. All beams from each subplan were imported onto one trial to create the composite TFRT plan. The composite TFRT plan was directly compared with the non‐TFRT IMRT plan. During plan assessment, the composite TFRT was first evaluated followed by each subplan to meet preset compliance criteria. Results The following organs were feathered: oral cavity, right submandibular gland, left submandibular gland, supraglottis, and OAR Pharynx. Prescription dose PTV coverage (>95%) was met in each subplan and the composite TFRT plan. Expected small variations in dose were observed among the plans. The percent variation between the high fractional dose and average low fractional dose was 29%, 28%, 24%, 19%, and 10% for the oral cavity, right submandibular, left submandibular, supraglottis, and OAR pharynx nonoverlapping with the PTV. Conclusions Temporally Feathered Radiation Therapy planning is possible with modern treatment planning systems. Modest dosimetric changes are observed with TFRT planning compared with non‐TFRT IMRT planning. We await the results of the current prospective trial to seeking to demonstrate the feasibility of TFRT in the modern clinical workflow (NCT03768856). Further studies will be required to demonstrate the potential benefit of TFRT over non‐TFRT IMRT Planning.


| INTRODUCTION
Head and neck squamous cell carcinomas are now primarily treated with definitive, nonsurgical, organ sparing approaches with radiotherapy. Since the advent of intensity-modulated radiation therapy (IMRT), acute and late toxicities of radiotherapy have declined dramatically but still remain prevalent. In a recent study of patients receiving definitive radiotherapy with or without chemotherapy for oropharyngeal cancer, 42% of patients experienced acute grade 3 or greater toxicity. 1 In effort to reduce toxicity, Temporally Feathered Radiation Therapy (TFRT) has been introduced as a novel planning technique. Prior in silico simulations of TFRT have demonstrated potential for reduced normal tissue toxicity compared with non-TFRT IMRT technique. 2 In non-TFRT IMRT planning, a daily fractional dose is delivered to the target and surrounding organs at risk (OAR) with each fraction of radiotherapy. In contrast, TFRT planning varies the dose delivered to the surrounding OARs, while keeping the dose to the target unchanged (i.e., the target volume should be covered by > 95% of the prescribed dose). TFRT plans are composed of five isocurative (same tumor dose) subplans, each of which are delivered once per week as illustrated in Fig. 1. In each subplan, one OAR is deprioritized and therefore receives a higher fractional dose (d H ). By pushing dose into the deprioritized organ, the other OARs of interest will receive a lower fractional dose (d L ). Resultantly, each feathered OAR will receive a slightly higher fractional dose once weekly, followed by slightly lower fractional doses the remaining four fractions. Previously it has been hypothesized that if a single fraction of d H is delivered to an OAR once weekly and four fractions of d L on the remaining days, normal tissues may exhibit increased recovery despite higher total doses delivered to the OAR. This increase in normal tissue recover may reduce clinical toxicity. 2 This technique seeks to optimize normal tissue recovery through the nonlinear temporal nature of healing.
In this study, we describe the step-by-step planning process by which temporally feathered radiation therapy plans are generated and assessed. We will also provide a dosimetric analysis of the TFRT plan referenced against a non-TFRT IMRT plan.

| MATERIALS AND METHODS
One patient with squamous cell carcinoma of the oropharynx planned for definitive radiation therapy (with concurrent chemotherapy) using IMRT techniques was replanned using the TFRT technique. The prescription dose was 70 Gy/ 35 fractions to the highdose planning target volumes (PTV) and 56 Gy/ 35 fx to the lowdose PTV using simultaneous integrated boost technique. The TFRT technique was evaluated for technical feasibility and was also compared dosimetrically to the non-TFRT IMRT plan.

2.A | Simulation and target volume definition
The patient was immobilized with a 5-point mask (Orfit, Belgium) and a customized cushion. A bite block covered with dental wax was used to create separation between the tongue and the hard palate.
Intravenous contrast was administered. The treatment planning CT was obtained in 3 mm slices using Philips CT Big Bore simulator.
The physician was responsible for delineating the gross tumor volumes (GTV), clinical target volumes (CTV), and PTV. To delineate the tumor volumes, diagnostic images were coregistered with the treatment planning CT. The PTV margin was 2.5 mm. All organs at risk (OARs) were also delineated by the treating physician.

2.B | FRT plan generation
All treatment plans were generated using Pinnacle 3 treatment planning software (version 9.10, Philips Healthcare, Fitchburg, WI, USA).
Before TFRT planning, the treating physician and a physicist identified five OARs to be feathered based on proximity to the target. These OARs may have included but were not limited to the oral cavity, each submandibular gland, each parotid gland, OAR pharynx, supraglottis, larynx, and esophagus. Five isocurative subplans (same tumor dose) were generated in which one OAR was deprioritized during planning. In an index subplan, the deprioritized organ receives The "base plan" which is later manipulated to create each subplan is generated through the following steps. First, a limited set of structures which include the PTVs and ring structures are fed into the optimizer. Then, optimization rounds were completed adding 3-5 normal structure objectives (not including the feathers OARs) into the optimizer. With each optimization round, the PTV coverage, plan conformality, and OAR constraints were evaluated. Lastly, additional planning structures were created manually to reduce hot and cold spots within the PTV volumes, push dose away from midline structures, remove low-dose spillage, and shape the isodose lines.
To generate a TFRT subplan, the base plan was re-optimized with planning objectives for the four prioritized OARs (i.e., those receiving d L ). No planning objectives were added to the optimizer for the deprioritized OAR (i.e., the OAR receiving d H in that particular subplan). Five subplans were generated from each base plan. The five subplans were used to create the composite TFRT plan. Each subplan contributed one fifth of the total dose.

2.C | TFRT plan assessment
Plan assessment and approval were performed by the physician following a meticulous protocol. First the composite TFRT plan was reviewed, then each subplan was individually reviewed. Both the composite plan and each TFRT subplan met the criteria detailed in the supplementary material. Normal tissue constraints were adapted from RTOG 1016 (NCT01302834). As per institutional protocol, a "scorecard" was generated for the composite plan and filed in Mosaiq indicating that safety metrics were met.

2.D | Quality assurance
Standard quality assurance procedures were followed per AAPM TG-218. 3 Each subplan was quality assured separately. The patientspecific QA for each TFRT subplan was generated and recorded.
Both the physicist and the attending physician reviewed and signed the QA document.

3.A | TFRT plan overview
The following organs were feathered: oral cavity, right submandibular gland, left submandibular gland, supraglottis, and OAR Pharynx

3.B | PTV coverage
Greater than 95% of each PTV was covered by the prescription dose in each subplan and the composite TFRT plan. Table 1 demonstrates the dosimetric constraints and data from the composite TFRT plan compared with the previously planned non-TFRT IMRT plan. OAR Dosimetric Differences.

| DISCUSSION
In this study, one patient previously treated for head and neck cancers was replanned using the temporally feathered radiation therapy technique. A step-by-step guide is detailed for radiation planning.
Additionally, dosimetric data from the TFRT plan were compared against the previously planned IMRT plan. In this study, all feathered organs were considered "parallel organs" and as such we used the simplified measure of dose, mean doses, as adapted from RTOG 1016. Each subplan and the F I G . 2. Planning flowchart to develop five TFRT subplans and the final composite plan. First, planning structures such as normal tissue rings, OAR-PTV, mid-line structures, etc., were created. A good "base" plan, which does not push on the five TFRT feathering target OARs, was generated before making the five TFRT subplans. Then, planning goals for OARs B-E were added to the planning objectives. Further optimizations were run to create subplan A from the base plan. Subplan B, C, D, and E were created by copying the previous subplan and optimizing after modifying prioritized and deprioritized OARs. Further improvements were made to each subplan to meet the planning criteria. At the end, a composite plan was made by importing all the beams from the subplans into one trial. The fraction number of each prescription was changed to 7, for a total of 35 fractions for the composite plan composite TFRT were required to meet the compliance criteria and dose constraints set forth by the physician. There are ongoing efforts to define the best metrics to evaluate TFRT plans. In comparing a composite TFRT plan to a non-TFRT IMRT plan, it was understood that though the dose to the organs at risk in the composite TFRT plan may have been greater than that of the non-TFRT IMRT plan, it was previously hypothesized that the normal tissue complication probability may be less in the composite TFRT plan. 2 This is owing to the assumed increased repair allowed in with the TFRT technique. Although once weekly a greater fractional dose was delivered to the deprioritized organ, the fractional dose was always less than 2 Gy per fraction. Therefore, we do not anticipate increased late toxicity. Notably, in this study we chose to feather five OARs for logistical reasons, however, this technique of planning can be implemented for any number of feathered organs.
Theoretically with TFRT, the five organs at risk (OAR) chosen to be feathered would receive a higher total dose. TFRT hypothesizes that despite receiving higher total doses, the feathered OARs would accumulate less toxicity due to improved time for normal tissue recovery. 2 When TFRT subplans were generated clinically, not all Here, we present a step-by-step guide to TFRT planning using modern treatment planning systems. The currently open-phase I fea-sibility trial (NCT03768856) seeks to evaluate feasibility implementing Temporally Feathered Radiation Therapy in the modern clinical workflow prospectively. As part of this study, the time required for treatment planning, plan evaluation, quality assurance, and delivery will be recorded.

ACKNOWLEDG MENTS
We would like to thank the dosimetrists, physicists, and therapists who have spent considerable time bringing TFRT to fruition.

CONFLI CTS OF INTEREST
The author has no conflict of interests to disclose.