Key PointsQuestion听
How does rectal spacing with hyaluronic acid affect acute grade 2 or higher gastrointestinal toxic effects before hypofractionated radiation therapy?
Findings听
In this multicenter randomized clinical trial of 260 patients with prostate cancer, 201 patients were randomized to the presence or absence of the spacer before receiving hypofractionated radiation therapy. The spacer was associated with a 2.9% rate of acute grade 2 or higher gastrointestinal toxic effects compared with 13.8% for the control group.
Meaning听
The trial results suggest that hyaluronic acid rectal spacer should be considered for patients who are receiving hypofractionated radiation therapy.
Importance听
Hypofractionated radiation therapy (RT) for prostate cancer has been associated with greater acute grade 2 gastrointestinal (GI) toxic effects compared with conventionally fractionated RT.
Objective听
To evaluate whether a hyaluronic acid rectal spacer could (1) improve rectal dosimetry and (2) affect acute grade 2 or higher GI toxic effects for hypofractionated RT.
Design, Setting, and Participants听
This randomized clinical trial was conducted from March 2020 to June 2021 among 12 centers within the US, Australia, and Spain, with a 6-month follow-up. Adult patients with biopsy-proven, T1 to T2 prostate cancer with a Gleason score 7 or less and prostate-specific antigen level of 20 ng/mL or less (to convert to 渭g/L, multiply by 1) were blinded to the treatment arms. Of the 260 consented patients, 201 patients (77.3%) were randomized (2:1) to the presence or absence of the spacer. Patients were stratified by intended 4-month androgen deprivation therapy use and erectile quality.
Main Outcomes and Measures听
For the primary outcome, we hypothesized that more than 70% of patients in the spacer group would achieve a 25% or greater reduction in the rectal volume receiving 54 Gy (V54). For the secondary outcome, we hypothesized that the spacer group would have noninferior acute (within 3 months) grade 2 or higher GI toxic effects compared with the control group, with a margin of 10%.
Results听
Of the 201 randomized patients, 8 (4.0%) were Asian, 26 (12.9%) Black, 42 (20.9%) Hispanic or Latino, and 153 (76.1%) White; the mean (SD) age for the spacer group was 68.6 (7.2) years and 68.4 (7.3) years for the control group. For the primary outcome, 131 of 133 (98.5%; 95% CI, 94.7%-99.8%) patients in the spacer group experienced a 25% or greater reduction in rectum V54, which was greater than the minimally acceptable 70% (P鈥�<鈥�.001). The mean (SD) reduction was 85.0% (20.9%). For the secondary outcome, 4 of 136 patients (2.9%) in the spacer group and 9 of 65 patients (13.8%) in the control group experienced acute grade 2 or higher GI toxic effects (difference, 鈭�10.9%; 95% 1-sided upper confidence limit, 鈭�3.5; P鈥�=鈥�.01).
Conclusions and Relevance听
The trial results suggest that rectal spacing with hyaluronic acid improved rectal dosimetry and reduced acute grade 2 or higher GI toxic effects. Rectal spacing should potentially be considered for minimizing the risk of acute grade 2 or higher toxic effects for hypofractionated RT.
Trial Registration听
ClinicalTrials.gov Identifier:
The use of hypofractionated radiation therapy (HFRT) for treating prostate cancer has substantially increased in recent years. Use rates ranging from 50% to 85% have been reported at centers in the US, Australia, and England between 2018 and 2020.1-4 Hypofractionated radiation therapy is more convenient and cost-effective5 than conventionally fractionated RT (CFRT), given that HFRT can be completed in 4 to 6 weeks rather than 8 to 9 weeks. Furthermore, numerous randomized studies have reported that HFRT exhibits similar biochemical control as CFRT for low-risk and intermediate-risk prostate cancer.6-11 However, a recent meta-analysis reported that HFRT was associated with a 9.1% greater absolute risk of acute grade 2 or higher gastrointestinal (GI) toxic effects compared with CFRT.12
Rectal spacers have been associated with reduced risk of acute GI toxic effects for HFRT. By creating distance between the prostate and rectum, spacers can reduce the rectal volume receiving a high radiation dose.13 In a single-arm phase 2 study of 36 patients who received a hyaluronic acid (HA) spacer followed by HFRT (62 Gy in 30 fractions with image-guided intensity-modulated RT [IG-IMRT]), only 1 patient experienced an acute grade 2 GI toxic effect (eg, proctitis).14 Previously, a randomized clinical trial reported that a polyethylene glycol hydrogel rectal spacer (Boston Scientific) before CFRT (79.2 Gy in 44 fractions with IG-IMRT) reduced rectal dose15 and improved late grade 1 or higher GI toxic effects and bowel quality-of-life (QOL).16 However, to our knowledge, there have not been any previously reported randomized clinical trials involving rectal spacers for HFRT.
The purpose of this study was to report end points of a randomized clinical trial evaluating an HA spacer (Palette Life Sciences) for HFRT (60 Gy in 20 fractions with IG-IMRT). Hyaluronic acid spacers are clearly visible with transrectal ultrasonography (TRUS) and allow for customizable spacing given the absence of a time limit for injection. For the primary end point, we hypothesized that more than 70% of patients would achieve a 25% or greater reduction in the rectal volume receiving 54 Gy. For the secondary end point, we hypothesized that patients randomized to the rectal spacer would have noninferior acute grade 2 or higher GI toxic effects compared with patients without the rectal spacer.
This was a prospective, randomized, single (patient)鈥揵linded multicenter clinical trial. Patients were enrolled at 12 trial sites within the US, Australia, and Spain (eTable 1 in Supplement 1). This trial was conducted with an investigational device exception (IDE), which was approved by the US Food and Drug Administration and a postmarketing study (PMS). The trial encompassing both IDE and PMS was approved by institutional review boards/ethical committees at each site (Supplement 2, Supplement 3, and Supplement 4).
The inclusion criteria comprised adult patients (age 鈮�18 years) with biopsy-proven prostate cancer within the previous 9 months who had a clinical stage of T1 to T2, Gleason score of 7 or less, and a prostate-specific antigen level of 20 ng/mL or less (to convert to 渭g/L, multiply by 1). Exclusion criteria included allergy to HA, prostate volume less than 15 cc or greater than 90 cc, transurethral resection of the prostate within the past year, inflammatory bowel disease requiring treatment with steroids, lupus, scleroderma, active bleeding disorder, or bilateral hip implants. On April 10, 2020, the protocol was amended to allow for 4 months of treatment with androgen deprivation therapy (ADT) that was initiated 1 to 2 months before fiducial marker placement. All patients provided written informed consent for IDE and the PMS before randomization.
Randomization and Masking
Initially, investigators enrolled patients onto the training portion of this study. This portion comprised injecting 1 to 3 patients with HA with the guidance of a proctor. The proctor critiqued the injection process and imaging of the space created. Investigators then proceeded to the randomized portion.
For the randomized portion, patients were randomly assigned to receive either HA spacer plus fiducial markers followed by HFRT (spacer group) or fiducial markers only followed by HFRT (control group) in a 2:1 ratio. Randomization was performed according to a separate, central computer-generated block schedule. Stratification factors included site groups (3 geographic regions), intended ADT use (yes vs no), and erectile quality (good vs poor). Poor erectile quality was defined as 鈥渘one at all鈥� or 鈥渘ot firm enough for any sexual activity鈥� responses to the Expanded Prostate Cancer Index Composite (EPIC)鈥�26 sexual function question: 鈥淗ow would you describe the usual quality of your erections during the past 4 weeks?鈥�17
Patients were blinded to treatment assignment. Masking was maintained during the injection procedure, as all patients underwent implant with fiducial markers. Additionally, all patients were assessed similarly postinjection.
All patients underwent a baseline history and physical examination. Patients randomized to the spacer group underwent baseline computed tomography (CT)/magnetic resonance imaging (MRI) scans. Within 14 days, patients had fiducial markers and the Non-Animal Stabilized HA spacer (Barrigel; Palette Life Sciences) inserted with TRUS via a transperineal approach. The spacer (9-12 cc) was injected between the Denonvilliers fascia and the anterior rectal wall. The type of anesthesia (local or conscious sedation) was selected at the discretion of the physician. Aseptic technique was observed, and antibiotic prophylaxis was administered before any manipulation. Patients randomized to the control group only had fiducial markers placed with TRUS guidance. Between 3 and 10 days after the procedure, all patients underwent CT/MRI scans for radiation treatment planning with a comfortably full bladder and empty rectum.
For all CT/MR scans, the treating investigator delineated the following structures: clinical target volume (CTV: prostate plus proximal 1 cm of the seminal vesicles, measured cephalo-caudal from the seminal vesicle origin), planning target volume (PTV: 5-10 mm per institutional definition, except 5 mm posteriorly around the CTV), the rectum (rectosigmoid flexure or bottom of sacroiliac joints to the inferior extent of the ischial tuberosities), the bladder (dome to the base), the penile bulb (bulbous spongiosum of the penis immediately inferior to the urogential diaphragm), and femoral heads (contoured to the level of the ischial tuberosity).
A dosimetrist created a radiation plan using IMRT or volumetric-modulated arc therapy. For CT/MRI scans without a spacer present, the dosimetrist was masked as to whether a patient would ultimately receive a spacer (spacer group) or not (control group). The PTV prescription dose was 60 Gy in 20 fractions. At least 99% of the CTV and 98% of the PTV were to be covered by the 100% isodose line (60 Gy). The maximum dose to the CTV or PTV was not to exceed 10% of the prescription dose. Dose constraints for organs at risk were as follows: rectum (V57鈥�<鈥�15%, V53鈥�<鈥�20%, V49鈥�<鈥�25%, V45鈥�<鈥�35%, and V38鈥�<鈥�50%), bladder (V60鈥�<鈥�10%, V48.6鈥�<鈥�25%, and V40.8鈥�<鈥�50%), penile bulb (V57鈥�<鈥�10% and V40.8鈥�<鈥�50%), and femoral heads (V34鈥�<鈥�5%).
All CT/MRI images, contours, and treatment plans were forwarded to an independent core laboratory (D.A.L. and A.U.K.) for measuring the spacer volume and prostate-rectum distance at midgland, as well as evaluating contours and treatment plans. For both groups, plans that did not meet contour or prescribed dose-volume histogram (DVH) constraints were returned to the center for replanning. This was necessary to ensure consistent contouring and planning parameters across this multi-institutional study. Replans were requested for 22% of scans in the control group and 23% of baseline scans (before spacer placement) in the spacer group.
Treatment with RT commenced within 30 days after fiducial marker/spacer placement. During RT, patients were evaluated weekly by the physician. Patients were assessed for toxic effects per the Common Terminology Criteria for Adverse Events, version 5.0, during RT, and at 3 and 6 months after fiducial marker/spacer placement. All adverse events (AEs) were adjudicated by an independent committee masked to treatment randomization. Adverse events were assessed regarding severity and relatedness to a device. As this trial was conducted in 2020 and 2021, virtual office visits were allowed during follow-up visits due to COVID-19.
Patients completed the EPIC-26 QOL questionnaire at baseline, 3 months, and 6 months.17 Patients also underwent a repeated MRI at 3 months for the core laboratory to measure changes in spacer volume and prostate-rectum distance measurements.
Patients receiving ADT had to initiate treatment within 30 to 60 days before fiducial marker placement and continue treatment for 4 months. Allowable forms of ADT included injectable gonadotropin-releasing hormone agonists (eg, leuprolide, leuprorelin, triptorelin) with bicalutamide, as well as injectable gonadotropin-releasing hormone antagonist (degarelix).
The primary effectiveness outcome was the percentage of patients who achieved at least a 25% reduction in rectal volume receiving 54 Gy (V54) after placement of the HA spacer compared with the baseline rectal V54 before spacer placement. This was based on the primary effectiveness end point for the polyethylene glycol pivotal trial.15 The secondary outcome was the percentage of patients experiencing grade 2 or greater GI toxic effects per the Common Terminology Criteria for Adverse Events, version 5.0, within the first 3 months. Other prespecified end points included evaluating the proportion of patients with a minimal clinically important decline (MCID: 5 points for bowel, 6 points for urinary, 11 points for sexual, and 5 points for hormonal) in EPIC-26 scores between baseline and 3 months.18 All outcomes were centrally assessed.
The sample size for the trial was based on the primary end point of the PMS study, which will evaluate whether the proportion of spacer participants with an MCID in EPIC-26 bowel QOL at 36 months would be significantly less than that for control participants. Assuming proportions of 0.19 for the spacer and 0.40 for control group and a 2:1 spacer group: control group ratio, the sample size required for a 1-sided Pearson 蠂2 test at an 伪 of .025 and a power of 80% was 159 participants. The sample size was adjusted to 201 to account for 20% attrition. Using this sample size, the available power for testing the primary hypothesis and key secondary hypothesis was greater than 90%.
The primary hypothesis tested whether the percentage of patients achieving the primary effectiveness outcome (鈮�25% reduction in rectum V54) was greater than a minimally acceptable success rate of 70%. This end point was evaluated with the binomial exact test, with 1-sided significance defined as P鈥�&濒迟;鈥�.03.
The secondary safety hypothesis tested whether the percentage of patients in the spacer group with 1 or more acute grade 2 or higher toxic effects was noninferior to the percentage of patients in the control group with 1 or more acute grade 2 or higher toxic effects, assuming a 10% noninferiority margin. The 10% noninferiority margin was based on the 9.1% difference in acute grade 2 or higher GI toxic effects between HFRT and CFRT in a recent meta-analysis.12 This end point was evaluated with a Fisher exact test, with significance defined as P鈥�&濒迟;鈥�.05.
Additional secondary end points included comparing the proportions of patients who achieved MCID for EPIC-26 bowel QOL (5 points), urinary QOL (6 points), sexual QOL (11 points), and hormonal QOL (5 points) at 3 months. End points were analyzed in this sequence with the Pearson 蠂2 test. All other end points were considered exploratory. Analysis was done by intention to treat. All calculations were conducted using SAS, version 9.4 (SAS Institute).
From March 30, 2020, through June 29, 2021, 260 patients were assessed for eligibility, and 201 patients (77.3%) were randomized (136 [67.7%] to the spacer group and 65 [32.3%] to the control group). The Consolidated Standards of Reporting Trials diagram is shown in the Figure. Baseline demographic characteristics are shown in Table 1. Notably, 63 of 201 patients (31.3%) received ADT. For the spacer group, a mean (SD) of 11.2 (1.7) mL of HA spacer was injected (eFigure in Supplement 1). The injection procedure from needle insertion to removal took a mean (SD) of 13.7 (7.8) minutes. A total of 92.7% of investigators rated the device鈥檚 ease of use as easy or very easy on a 4-point scale (eTable 2 in Supplement 1). There were no peri-procedural AEs reported.
Postinjection, the mean (SD) volume of the injected spacer, as well as the mean (SD) prostate-rectum separation, were 10.9 (2.1) mL and 12.9 (3.5) mm, respectively. Although the spacer volume at 3 months decreased to a mean (SD) of 8.8 (1.8) mL, the mean (SD) prostate-rectum separation remained at 12.6 (3.5) mm.
The primary end point was assessable in 133 patients (3 patients had missing baseline scans). Of these, 131 (98.5%; 95% CI, 94.7%-99.8%) patients experienced at least a 25% reduction in rectum V54, which was significantly higher than the minimally acceptable rate of 70% (P鈥�<鈥�.001). The mean (SD) reduction was 85.0% (20.9%). Of the 2 patients who did not achieve the primary end point, 1 patient had received ADT. As shown in Table 2, the spacer showed numerical reductions in all protocol rectal DVH metrics. Bladder and penile bulb DVH metrics are presented in eTables 3 and 4 in Supplement 1. Compared with the control group, the postimplant spacer group had numerically lower rectal DVH metrics (eTable 5 in Supplement 1). As shown in Table 3, 4 of 136 patients (2.9%) in the spacer group experienced acute (within 3 months) grade 2 or higher GI toxic effects (1 proctitis, 1 constipation, 1 diarrhea, and 1 hemorrhoids). Only 1 patient had received ADT. The acute grade 3 GI event was attributed to severe diarrhea (loose stools >10 times/day over his baseline 2-3 times/day) requiring suspension of RT at 9 fractions. Radiologist review of preinjection MRI (B.S.) showed rectal wall edema and extensive diverticular disease, with good placement of the HA spacer and no rectal wall infiltration. Results of CT of the pelvis and sigmoidoscopy were unremarkable. The patient continued treatment with RT after 37 days but discontinued treatment at 17 fractions due to recurrence of severe diarrhea. His symptoms have since resolved to baseline. No AEs were attributed to the device.
Nine of 65 patients (13.8%) in the control group experienced acute grade 2 or higher toxic effects (4 proctitis, 3 diarrhea, 2 hemorrhoids, and 1 rectal hemorrhage), with 1 patient experiencing 2 events. Three patients had received ADT. All acute grade 2 or higher GI toxic effects resolved at 6 months. Regarding the secondary end point, the patients randomized to the spacer demonstrated noninferior acute grade 2 or higher GI toxic effects compared with patients without rectal spacer (difference, 鈭�10.9%; 95% 1-sided upper confidence limit, 鈭�3.5; P鈥�=鈥�.01). As the upper confidence limit was less than 0, the spacer demonstrated superior acute grade 2 or higher GI toxic effects.19
Table 4 shows the percentage of patients who achieved an MCID in EPIC-26 QOL at 3 months and 6 months. A numerically smaller percentage of patients in the spacer group (35 [26.5%]) had an MCID in bowel function at 3 months compared with 23 (37.7%) in the control group (P鈥�=鈥�.13).
To our knowledge, this is the first randomized clinical trial evaluating the clinical efficacy of a rectal spacer for HFRT. This trial achieved the primary end point, in that more than 70% of patients in the spacer group achieved a 25% or greater reduction in rectal V54. This trial also achieved the secondary end point, in that the spacer group had reduced acute grade 2 or higher GI toxic effects (2.9%) compared with the control group (13.8%). Given that HFRT has been associated with greater acute grade 2 or higher GI toxic effects than CFRT,7,12 rectal spacing may address a clinically important need for the large volume of patients receiving this effective and convenient treatment.2
The acute grade 2 or higher GI toxic effect rates observed in this study are consistent with prior literature. For the spacer group, the 2.9% rate of acute grade 2 or higher toxic effects was similar to the 2.8% rate observed in a phase 1 study involving an HA spacer before HFRT.14 For the control group, the 13.8% risk of acute grade 2 or higher toxic effects was similar to those reported in the PROFIT (10.3%),9 RTOG 0415 (10.3%),8 and FCCC (8%)6 randomized clinical trials. However, this toxic effects rate was less than those reported in the IRE (21.2%),11 CHIPP (60 Gy arm; 24.6%),7 and HYPRO (31.2%)10 studies, which had high ADT use rates.12 Without the spacer, a small subset of patients remains at risk for clinically significant GI toxic effects, even with modern IG-IMRT techniques and CT/MRI鈥揵ased contouring.
We found that a numerically smaller (26.5% vs 37.7%; P鈥�=鈥�.13) percentage of patients in the spacer group experienced a bowel MCID at 3 months. This difference may have not reached statistical difference, due to lack of power. In addition, the spacer reduced lower rectal DVH metrics (62.4% relative reduction in V38) to a smaller extent than higher metrics (85.0% relative reduction in V54; Table 2). As a result, patients in the spacer group could have remained susceptible to symptoms of intermediate rectal dose (eg, bowel frequency, fecal incontinence, and rectal pain) that were captured with patient-reported outcomes.20,21
Further follow-up is needed to characterize the long-term toxic effects22 and QOL outcomes with the HA spacer. We will test whether the decreased rectal dose, which led to reduced acute grade 2 or higher toxic effects in this study, will ultimately lead to improved bowel QOL at 3 years. The randomized polyethylene glycol hydrogel spacer trial for CFRT also reported that fewer patients in the spacer group experienced a bowel MCID and GI toxic effects at 3 years.16 With stratifications of ADT and baseline erectile function, we also hope to better understand the implications of rectal spacing on sexual function at 3 years.23
Strengths and Limitations
The strengths of this study included its randomized design, incorporation of modern radiotherapy techniques (eg, CT/MR simulation with IG-IMRT), inclusion of ADT, and prospective RT plan review by the core laboratory. Prospective RT plan review ensured that high-quality plans were generated for the spacer and control groups. Its limitations included short-term follow-up and that clinician investigators were not masked to the randomization group. Although the lack of masking could have biased toxic effect assignments, the toxic effects were adjudicated by a committee masked to patient randomization. Furthermore, toxic effects observed for both groups were consistent with those observed in prior prospective series, as noted previously. Also, a congruent signal, albeit not statistically significant, was observed in patient-reported bowel QOL, in which patients were masked to randomization.
Finally, this study adds to the extensive literature on the use of HA for spacing before IG-IMRT and brachytherapy applications.13,14,24-29 This study shows that positive dosimetric and clinical outcomes can be achieved with deliberate and customizable spacing with HA due to the absence of a time limit for injecting the substance, as well as clear visualization of the substance with TRUS. Further studies are warranted for evaluating clinical outcomes with stereotactic body RT.30
The results of this randomized clinical trial found that rectal spacing with HA improved rectal dosimetry and reduced acute grade 2 or higher GI toxic effects. Further prospective follow-up is planned to characterize the effect of rectal spacing on long-term toxic effects and QOL.
Accepted for Publication: November 15, 2022.
Published Online: February 9, 2023. doi:10.1001/jamaoncol.2022.7592
Corresponding Author: Martin King, MD, Brigham and Women's Hospital, 75 Francis St, ASB1-L2, Radiation Oncology, Boston, MA 02115 (martin_king@dfci.harvard.edu).
Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. 漏 2023 Mariados NF et al. JAMA Oncology.
Author Contributions: Dr King had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Mariados, Orio, Lopez, Martinez, King.
Acquisition, analysis, or interpretation of data: Mariados, Orio, Schiffman, Van, Engelman, Nurani, Kurtzman, Lopez, Chao, Boike, Gejerman, Lederer, Sylvester, Bell, Rivera, Shore, Miller, Sinayuk, Steinberg, Low, Kishan, King.
Drafting of the manuscript: Mariados, Orio, Lopez, Bell, Miller, King.
Critical revision of the manuscript for important intellectual content: Mariados, Orio, Schiffman, Van, Engelman, Nurani, Kurtzman, Lopez, Chao, Boike, Martinez, Gejerman, Lederer, Sylvester, Rivera, Shore, Sinayuk, Steinberg, Low, Kishan, King.
Statistical analysis: Mariados, Miller.
Obtained funding: King.
Administrative, technical, or material support: Orio, Van, Engelman, Nurani, Kurtzman, Chao, Martinez, Gejerman, Bell, Rivera, Sinayuk, Steinberg, Low, Kishan, King.
Supervision: Van, Engelman, Lopez, Chao, Martinez, Sinayuk, King.
Conflict of Interest Disclosures: Dr Mariados reported personal fees from and being a limited partner/investor in a venture capital fund that own position in Palette Life Sciences outside the submitted work. Dr Orio reported personal fees from Palette Life Sciences and Theragenics outside the submitted work. Dr Engelman reported grants from Palette Life Sciences during the conduct of the study. Dr Nurani reported research support from Palette Life Sciences during the conduct of the study and research support from Boston Scientific and Bioprotect Ltd outside the submitted work. Dr Chao reported personal fees from Palette Life Sciences during the conduct of the study and grants from Palette Life Sciences outside the submitted work. Dr Martinez reported grants from Palette Life Sciences during the conduct of the study. Dr Gejerman reported grants from Palette Life Sciences during the conduct of the study and consulting for Palette Life Sciences outside the submitted work. Dr Lederer reported consulting fees from Palette Life Sciences outside the submitted work. Dr Sylvester reported grants from Palette Life Sciences during the conduct of the study as well as personal fees from Boston Scientific outside the submitted work. Dr Bell reported grants from Palette Life Sciences during the conduct of the study as well as personal fees from Palette Life Sciences outside the submitted work. Dr Sinayuk reported personal fees from Palette Life Sciences during the conduct of the study as well as personal fees from Palette Life Sciences outside the submitted work. Dr Steinberg reported personal fees from Viewray outside the submitted work. Dr Low reported being a principal investigator of a UCLA core lab contract contracted by Palette during the conduct of the study as well as personal fees from ViewRay outside the submitted work. Dr Kishan reported honoraria, research funding, and stock from ViewRay, Inc, honoraria and consulting fees from Varian Medical Systems, advisory board service for Boston Scientific and Janssen Biotechnologies, and research funding from Point Biopharma outside the submitted work. Dr King reported grants and personal fees from Palette Life Sciences during the conduct of the study and grants from Bayer Healthcare outside the submitted work. No other disclosures were reported.
Funding/Support: Palette Life Sciences provided funding for this study.
Role of the Funder/Sponsor: Palette Life Sciences was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 5.
Additional Contributions: We acknowledge Daniel W. Cail, MS, DABR, and Douglas A. Cumming, BS, CMD, RT(T), Dana-Farber Cancer Institute, for their assistance in conducting the study. These individuals received funding for the contributions.
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