SUPR-3D: A randomized phase iii trial comparing simple unplanned palliative radiotherapy versus 3d conformal radiotherapy for patients with bone metastases: study protocol

Background Bone metastases in the lower spine and pelvis are effectively palliated with radiotherapy (RT), though this can come with side effects such as radiation induced nausea and vomiting (RINV). We hypothesize that high rates of RINV occur in part because of the widespread use of inexpensive simple unplanned palliative radiotherapy (SUPR), over more complex and resource intensive 3D conformal RT, such as volumetric modulated arc therapy (VMAT). Methods This is a randomized, multi-centre phase III trial of SUPR versus VMAT. We will accrue 250 patients to assess the difference in patient-reported RINV. This study is powered to detect a difference in quality of life between patients treated with VMAT vs. SUPR. Discussion This trial will determine if VMAT reduces early toxicity compared to SUPR and may provide justification for this more resource-intensive and costly form of RT. Trial registration Clinicaltrials.gov identifier: NCT03694015. Date of registration: October 3, 2018.


Background
Bone metastases are the most common site of distant metastases in oncologic patients. There is a high incidence of bone metastases in the pelvis and lower spine, often causing pain which can significantly impact a patient's quality of life [1]. Palliative radiotherapy (RT) is an effective treatment for bone metastases, resulting in significant pain reduction in the majority of patients [2]. It is also effective in preserving function and maintaining skeletal integrity, while minimizing the occurrence of adverse skeletal related events [3]. In many centres, bone metastases are treated using a Simple Unplanned Palliative Radiation (SUPR) technique using static fields. This technique requires minimal contouring and dosimetric calculations, and less stringent dosimetric quality review, making this a time-and cost-effective treatment technique.
SUPR is associated with irradiation of normal tissue within the treatment field since the entire portal is exposed to the prescribed dose. While fatigue, pain flare, and erythema in the irradiated area are relatively common adverse effects associated with treating bone metastases, sitespecific toxicity can also occur, including esophagitis, nausea, or diarrhea when dose is delivered to the gastrointestinal tract. The majority of patients treated with SUPR to the pelvis and lower spine suffer from radiation induced nausea and vomiting (RINV) due to incidental bowel irradiation [4]. This potentially greatly affects quality of life in these patients, for whom quality of life is the cornerstone of treatment. By using more complex 3D conformal RT like volumetric modulated arc therapy (VMAT), the dose to the intestines can be decreased whilst still treating the bone metastases to an effective dose, possibly reducing early and late toxicity after palliative RT. [5][6][7] In SUPR, radiation dose is delivered using one or two static radiation fields with a fixed shape. In contrast, VMAT delivers the radiation dose in a continuous rotation of the radiation source, allowing treatment from a 360°beam angle with continuous modulation of the beam shape and intensity. This results in a highly conformal dose distribution with improved target coverage, while better sparing normal tissue [5] (Fig. 1). However, VMAT includes more complex planning and quality assurance (QA) processes compared to SUPR [8]. This can be expensive and time-consuming, which can have a significant impact on departmental resources and wait time for patients [9]. Therefore, it is important to demonstrate that VMAT results in a reduction of RINV to justify increased costs and longer waiting times for patients.
The current standard of care in many Canadian and European centres for palliative patients with bone metastases is SUPR. To the best of our knowledge, there is no level I evidence supporting the use of VMAT for palliative patients with bone metastases. The goal of this study is to investigate whether the use of VMAT in these patients is warranted. We hypothesize that VMAT will reduce RINV in palliative patients treated for bone metastases in the lower spine and pelvic regions as compared to patients treated with SUPR.

Methods/design
This is a randomized, multi-centre phase III trial where 250 participants will be randomized between SUPR or 3D conformal palliative RT using VMAT. The study has been approved by the University of British Columbia Research Ethics Board in compliance with the Helsinki Declaration.

Objectives
The primary objective is to compare patient-reported Quality of Life related to RINV between standard palliative radiotherapy and VMAT. Secondarily, we will assess rate of complete control of RINV, compare patient reported toxicity, and evaluate pain response. However, we hypothesize that there will be no difference in pain response between the two arms, because they are receiving the same dose.

Study design
This study is a multicentre randomized trial. Participating centres will be tertiary, academic hospitals or radiotherapy treatment centres in Canada. Patients will be randomized in a 1:1 ratio between Arm 1 or Arm 2 with stratification for prescribed dose.

Entry procedures
All randomizations will be done using a computergenerated randomization scheme. All eligible patients enrolled in the study by the participating treatment centre will be assigned a study number, which must be used on all documentation.
The following information will be required Trial Code Name of investigator under whose name the patient will be randomized Informed consent, version date, date signed by patient, name of person conducting consent discussion and date signed by the person who conducted the consent form discussion Confirmation that the patient meets the eligibility requirements Stratification factors

Randomization
Simple randomization with stratification for 8 Gray (Gy) single fraction vs. 20 Gy in 5 fractions will be used to randomly assign patients to either Arm 1 or Arm 2 in a 1:1 ratio (Fig. 2) using a computer-generated randomization scheme. Randomization will be performed on patientlevel, meaning that if a patient is treated for multiple bone metastases in the same course, all will receive the same treatment technique. The randomization sequence is known only to the statistician and uploaded into a restricted-access database (REDCap) housed on secure hospital servers at BC Cancer. Upon enrollment of a patient, the database will be accessed by the trial coordinator to obtain the next intervention in the random sequence, which will then be assigned to the patient.

Intervention
Patients randomized to the intervention group will be treated with palliative radiotherapy using a VMAT technique.

Inclusion criteria
Age 18 or older Able to provide informed consent Clinical diagnosis of cancer with bone metastases (biopsy of treated bone metastases not required) Currently being managed with palliative intent RT to 1-3 bone metastases, at least one of which must (at least) partly lie within T11-L5 or pelvis. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-3 Patient has been determined to potentially benefit from 8 Gy or 20 Gy Radiation Oncologist (RO) is comfortable prescribing 8 Gy in 1 fraction or 20 Gy in 5 fractions RT for bone metastases Pregnancy test for women of child-bearing potential Patient is able (i.e. sufficiently fluent) and willing to complete the patient-reported outcomes questionnaires in English. The baseline assessment must be completed within required timelines, prior to randomization. Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up. For simplicity of planning, expected Gross Tumor Volume (GTV) should be less than 20 cm based on radiological or clinical evidence. Patient must be prescribed a 5HT-3 receptor antagonist (e.g. Ondansetron) as antiemetic prophylaxis prior to RT start.

Radiation treatment planning for VMAT Contouring
GTV: based on available imaging (GTV may be based on Computed Tomography (CT) simulation scan alone; no special imaging is required) and is expected to be between 1.5 cm and 20 cm clinically.
In case of only bone involvement: no margin outside the bone In case of bone and soft tissue involvement: no margin outside the bone, only adapt CTV margin in soft tissue to organs. No CTV adaptation in i.e. muscle. CTV may be optional and if used can encompasses whole vertebral body as per RO's discretion Planning AAA or other type-2 / model-based calculation framework Heterogeneity corrections applied Maximum calculation grid size = 2.5 mm Planning VMAT flash is permitted but not required Jaw-tracking is permitted but not required A normal tissue constraint should be used to control conformity to at least the 65% isodose level For the VMAT arm, up to two arcs are permitted

Suggested constraints
Recommended OAR constraints are given in Table 1 below, which are based on QUANTEC, adapted to the specific dose per fraction of the two schedules using EQd2. The decision to include or adjust these constraints is at the discretion of the RO.

Plan review and QA
No pre-treatment dosimetric review is required if both the required and RO-specified OAR constraints are met. Otherwise, the plan must be reviewed by the RO prior to treatment. Document any further plan modification secondary to subsequent local QA procedures as a minor protocol violation. Physics and dosimetry checks are to be performed as per local standard-of-care.

Verification imaging
(Image Guided Radiotherapy (IGRT): Minimum IGRT is daily 2D kV matching. Cone-beam CT (CBCT) is not required but may be used at the discretion of the treating radiation oncologist.

Nausea prophylaxis
All patients will receive a 5HT-3 receptor antagonist (e.g. Ondansetron) as anti-emetic prophylaxis prior to RT start. Dexamethasone may also be given for nausea prevention, though is not mandated.

Quality assurance
Dosimetric compliance with protocol constraints will be evaluated by the planning dosimetrist(s). Plan review by the radiation oncologist is not required for both arms. The radiation oncologist might review the plan but no plan modification at that point is permitted.
For VMAT, patient-specific QA should be performed per standard processes. Institutional QA rounds may also evaluate the radiation plans.

Data safety monitoring committee
There is no independent data safety monitoring committee (DSMC) for this study. The DMSC will be made up of the study co-investigators. The DSMC will meet twice annually after study initiation to review toxicity outcomes. If any grade 3-5 toxicity is reported, the DSMC will review the case notes to determine if such toxicity is related to treatment. If the DSMC deems that toxicity rates are excessive (> 25% grade 3 toxicity, or > 10% grade 4 or > 3% grade 5 toxicity), then the DSMC can, at its discretion, recommend cessation of the trial, dose adjustment, or exclusion of certain treatment sites that are deemed as high-risk for complications.

Subject discontinuation/withdrawal
Subjects may voluntarily discontinue participation in the study at any time. If a subject is removed from the study, the clinical and laboratory evaluations that would have been performed at the end of the study should be obtained. If a subject is removed because of an adverse event, they should remain under medical observation as long as deemed appropriate by the treating physician.

Follow-up schedule
See Table 2 for follow-up schedule.

Physician/registered nurse (RN)/other reported outcomes
HCP-reported baseline and follow-up Outcome ECOG status Medication use Toxicity (CTCAE v5.0) Pain Fatigue

Treatment response evaluation FLIE
Scores on all individual questions will be weighted equally, reversed if required and summed to create an overall FLIE score between 18 and 126. Scores will then be normalized with a range from 0 to 108 for ease of interpretation on figures in the manuscript. A low score is favorable, reflecting less nausea and vomiting.

RINV
Complete control: no increased episodes of nausea or vomiting with no increased use of anti-emetic medication from baseline. Partial control: 1-2 increased episodes of nausea or vomiting with no increased use of anti-emetic medication from baseline. Uncontrolled response: 3 or more increased episodes of nausea or vomiting, or increased use of anti-emetic medication from baseline.
Overall control: includes complete and partial control.

Pain
Complete response: pain score of 0 at treated site with no increase in analgesic intake (stable or reducing analgesics in daily oral morphine equivalent dose (OMED). Partial response: pain reduction of 2 or more at the treated site on a scale of 0 to 10 without analgesic increase, or analgesic reduction of 25% or more from baseline without an increase in pain. Pain progression: Increase in pain score of 2 or more above baseline at the treated site with stable OMED, or an increase of 25% or more in OMED from baseline with the pain score stable or 1 point above baseline.
Indeterminate response: Any response that is not captured by the complete response, partial response or pain progression definitions [10].

Statistical analysis Sample size
The primary outcome is Functional Living Index -Emesis (FLIE) score compared between the two arms at day 5 post start of RT. Based on previous literature, we expect both arms to have a relatively normal (i.e. score of 0) FLIE score at baselines. We expect patients in the SUPR arm to have a mean FLIE score of 18, 5 days post start of RT. [11] We anticipate that VMAT will have a much lower RINV impact (i.e. less decline in FLIE) and for the purpose of this study will hypothesize that the FLIE will be approximately 10.
Sample size was calculated with these FLIE scores. With alpha Type I error set at 0.05 and power set at 0.9, with a dropout rate of 30%, we calculated a conservative sample size of 250 patients.
Our most important secondary outcome (primary efficacy outcome) is RINV which occurs in 60% of patients who receive RT to the lower spine and pelvis [4,11]. Using the sample size of 250 patients (see above), this study has a power of 0.8 to detect a 25% difference in RINV (from 60 to 35%, see Table 3.) with alpha Type I error set at 0.05 and a dropout rate of 20%. As outlined in the table below, if RINV difference is lower or higher, our power will be lower and higher, respectively.

Analysis plan
Patients will be analyzed in the groups to which they are assigned (intention-to-treat). De-identified data (except for study number and initials, see confidentiality below) will be transmitted from participating centres via RED-Cap to be collected centrally where it will be stored on secure hospital servers at BC Cancer. Source documents will also be uploaded. Research coordinators (clinical trials staff) will perform data checks throughout the trial period and will call participating centres or visit as necessary. Patients in both arms will receive the same radiation dose. Therefore we do not expect a difference in toxicity or other safety concerns. Thus, we will not conduct an interim-analysis and there will be no stopping rules. All outcomes based on means will be analysed using the students t-test. All proportions will be analysed using chi-square test.

Confidentiality
The names and personal information of study participants will be held in strict confidence. All study records (case report forms, safety reports, correspondence, etc.) will only identify the subject by initials and the assigned study identification number. The investigator will maintain a confidential subject identification list (Master List) during the course of the study. Access to confidential information (i.e., source documents and patient records) is only permitted for direct subject management and for those involved in monitoring the conduct of the study (i.e., Sponsors, CRO's, representatives of the IRB/REB, and regulatory agencies). The subject's name will not be used in any public report of the study.

Data sharing statement
Deidentified participant data from this trial will not be shared publicly, however, the full protocol will be published along with the primary analysis of the outcomes.

Protocol amendments and trial publication
Any modifications to the trial protocol must be approved and enacted by the principal investigator. Protocol amendments will communicated to all participating centres, investigators, IRBs, and trial registries by the principal investigator. Any communication or publication of trial results will be led by the principal investigator, and is expected to occur within 1 year of the primary analysis. Trial results will remain embargoed until conference presentation of an abstract or until information release is authorized. Authorship of the trial abstract and ultimately the full manuscript will be decided by the principal investigator at the time of submission. Professional writers will not be used for either abstract or manuscript preparation.

Discussion
This study has been designed to compare early toxicity between two radiation treatment techniques currently used for palliative treatment of bone metastases, with vastly different resources required to implement. The primary potential advantage of VMAT over SUPR is the conformality of radiation dose to the target, and avoidance of normal tissue, such as bowel. Theoretically, this should lead to less RINV in the population eligible for this trial, though we believe this should be assessed in randomized trials before widespread adoption of this expensive and resource intensive technique is more widely adopted. Many radiation centres world-wide have already implemented the use of more advanced radiation techniques like VMAT for palliative patients. This trial has the potential of proving no difference between SUPR and VMAT which might lead to the need for revisions of local treatment protocols. If the outcome in both arms is equal, centres might want to decrease the use of VMAT for palliative patients with advantages regarding planning time and costs. However, even if the outcomes in this trial are similar for both arms, VMAT might still be warranted in certain scenarios. There are many reasons to choose one technique over the other. The decision on which treatment technique will be used has to be made on an individual patient level, where possible in a shared decision-making setting. We hypothesize that with this trial, we are able to provide evidence that can improve this decision-making process.