Trial Title:
Feasibility Trial of Preoperative 5-Day Hypofractionated Radiotherapy for Primary Soft Tissue Sarcoma
NCT ID:
NCT05776667
Condition:
Soft Tissue Sarcoma
Conditions: Official terms:
Sarcoma
Conditions: Keywords:
STS
HFRT
SFRP2
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Radiation
Intervention name:
Hypofractionated Radiation Therapy
Description:
Participants will receive preoperative 5-day HFRT (30Gy/5fx once daily over consecutive
weekdays) followed by "standard of care" wide local excision 2-6 weeks later.
Arm group label:
Hypofractionated Radiation Therapy
Summary:
This study is investigating the feasibility of preoperative 5-day hypofractionated
radiotherapy (HFRT) for extremity soft tissue sarcoma (STS). The primary objective is to
assess the uptake of 5-day HFRT in patients with STS who are candidates for preoperative
radiotherapy and limb preserving surgery. Secondary objectives include evaluation of the
rates of favorable pathologic response, major wound complications, local control, acute
toxicity, and 1-year late toxicity will be assessed. Exploratory objectives include
evaluation of the impact of preoperative 5-day HFRT on access to care, the
socio-demographic profile of the trial participants will be compared to that of extremity
STS patients seen within Hollings Cancer Center (HCC) and recommended preoperative
conventional fractionation radiotherapy (CFRT) in the 3 years prior to the study opening.
The retention rate for radiotherapy at HCC in patients meeting trial criteria during the
prior 3 years will be compared with the retention rate for radiotherapy during the study
period. An exploratory analysis will measure serum SFRP2 pre- and post- radiotherapy to
assess changes in response to preoperative 5-day HFRT. Changes in serum SFRP2 will be
evaluated for association with a favorable pathologic response to determine the potential
of serum SFRP2 as a predictive biomarker. Patient satisfaction with the decision to
participate in a trial of preoperative 5-day HFRT will be assessed.
Detailed description:
The current standard approach to the management of extremity STS is a combination of
radiotherapy and limb preserving surgery. Currently guidelines recommend preoperative
conventionally fractionated radiotherapy (CFRT) given at 1.8-2.0 Gy/fx, which involves
5-6 weeks of daily treatments. Preoperative hypo-fractionated radiotherapy (HFRT) is an
approach that can shorten the duration of treatment. Clinical outcomes with preoperative
HFRT in STS have been reported from retrospective case series, prospective institutional
registries and phase I-II trials. However, preoperative HFRT has not been compared in a
prospective randomized trial to CFRT and due to the rarity of extremity soft tissue
sarcoma, attempts to develop such a trial would face feasibility challenges. Therefore,
single arm trials of preoperative HFRT will be critical to defining the feasibility,
toxicity, efficacy, and potential improvement in access to care associated with this
approach.
Radiation therapy combined with wide local excision in the preoperative or postoperative
setting optimizes local control for extremity STS. Preoperative radiotherapy confers a
higher rate of wound complications but a lower rate of irreversible sequela such as
fibrosis and lymphedema compared with postoperative radiotherapy. Resultantly,
preoperative radiotherapy is the preferred approach in most cases. Preoperative
radiotherapy with CFRT given at 1.8-2.0 Gy/fx, involves 5-6 weeks of daily treatments.
The burden of daily travel and time away from work or care giving can be a barrier to
utilization of radiotherapy. A recent analysis of the National Cancer Database
demonstrated that farther distance to treatment was a negative predictor for receipt of
radiotherapy in extremity STS. Sociodemographic factors such as female sex, older age
(>70 years), Black race, and noncommercial insurance coverage were also negatively
associated with receipt of radiotherapy. The authors summarized that radiotherapy is
underutilized in the treatment of STS and that sociodemographic disparities exist in
access to radiotherapy. Receipt of radiation therapy and surgery within a high volume
(HV) sarcoma center has been associated with improved overall survival, while Black race
and non-metropolitan residents were negative predictors for treatment within such
centers. To address disparities in access to radiation therapy, the American Society for
Radiation Oncology Committee on Health Equity, Diversity, and Inclusion has proposed
studying novel HFRT schedules. As validation of this strategy, Kalbasi et al. increased
retention of extremity STS patients within a HV sarcoma center by 3-fold with the
utilization of preoperative HFRT. Further, the decreased time and travel associated with
HFRT, can address an established barrier to clinical trial participation, particularly
for those living remote from clinical trial sites. Clinical trial participation is
particularly low in rural areas which results in these populations being underrepresented
in the clinical research. A survey of South Carolina based medical researchers,
identified rural residents as a group that are difficult to find and recruit to clinical
trials. In a survey of urban and rural South Carolina residents, there was no difference
in reported willingness to participate in clinical trials, but rural residents were more
likely to perceive limited access to clinical trial sites. Investigating cancer treatment
approaches that decreased the economic and logistical burdens incurred by patients, such
as preoperative 5-day HFRT, may increase clinical trial participation by rural South
Carolina residents and ultimately address disparities in representation of these
populations in cancer research.
HFRT, using >2.2 Gy/fx, has resulted in equivalent oncologic outcomes to CFRT in other
tumor sites such as breast, prostate and rectum. For STS, HFRT may confer a radiobiologic
advantage in that the linear-quadratic model predicts larger doses per fraction provide
better tumor control for tumors with a lower α/β ratio. For liposarcomas and
rhabdomyosarcomas, their α/β ratio (~4 Gy) is similar to breast and prostate cancer,
malignancies in which HFRT has been widely adopted. While histologic variability
certainly exists, most STSs have estimated α/β ratios lower than 10, suggesting increased
sensitivity to larger fraction size.
Clinical outcomes with preoperative HFRT in STS have been reported from retrospective
case series, prospective institutional registries and phase I-II trials. Comparing
oncologic outcomes across these series is hindered by heterogeneous clinicopathological
features, surgical techniques, samples sizes, and radiation fractionation schedules.
However, the local control and rates of wound complications associated with HFRT and CFRT
regimens appear similar as summarized Spalek and Rutkowski.
This study will utilize a 30Gy/5fx preoperative regimen as it has an estimated EQD2 of 50
Gy (based on a α/β ratio=4) and therefore would be expected to closely parallel the
biologic effect of CFRT. This preoperative 5-day HFRT regimen was studied in a phase II
trial at UCLA and the 2-year rates of acute wound complications were favorable compared
to historical controls.
Exploratory Analysis of SFRP2 as a Predictive Biomarker:
Secreted Frizzled-Related Protein 2 (SFRP2) is a secretory protein involved in activation
of the Wnt signaling pathway. Wnt signaling regulates normal embryonic development but
aberrations in this pathway have been linked with tumor progression. SFRP2 is a tumor
promotor that which exerts effects on endothelial cells, tumor cells and T-cells. SFRP2
has been shown to stimulate angiogenesis in endothelial cells through activation of the
non-canonical Wnt/Ca2 pathway. SFRP2 mediated activation of the Wnt/Ca2 pathway results
in downstream dephosphorylation of the nuclear factor of activated T-cells (NFAT). NFAT
then can translocate from the cytoplasm to the nucleus where it mediates processes
involving tumor cell growth, survival, invasion, and angiogenesis. Inhibition of SFRP2
has been shown to inactivate NFAT in tumor cells and imped tumor cell migration. NFAT
also is involved in regulation of T-cell activity. SFRP2 has been shown to promote
NFATc3, CD38 and PD-1 expression in T-cells, which are mechanisms for immunotherapeutic
resistance. Monoclonal antibodies to SFPR2 in an osteosarcoma model lowered serum SFPR2
levels, lowered CD38 levels in tumor-infiltrating lymphocytes and T-cells and lowered
PD-1 levels in T-cells.
SFRP2 has been identified as a tumor promotor in multiple histological subtypes of STS.
In mouse angiosarcoma models, a humanized monoclonal antibody to SFRP2 has been shown to
lower serum levels of the protein and inhibit tumor proliferation.
In humans with breast cancer, serum SFRP2 levels are elevated over healthy controls and
correlate with increasing tumor size, presence of lymph node metastasis, increasing TMN
stage and higher Ki67, a marker of proliferation.
In humans with STS, the levels of serum SFRP2 expression and the response of serum SFRP2
levels to therapeutic interventions such as radiotherapy are unknown. This study will
compare serum levels of SFRP2 before and after preoperative 5-day HFRT to define levels
of expression in patients with STS and assess the effect of radiotherapy on SFRP2
expression. Further, we will evaluate the association of the change in serum SFRP2 levels
with extent of tumor fibrosis/hyalinization, a histologic predictor of oncologic outcome,
to determine the potential of SFRP2 as a predictive biomarker for favorable pathologic
response. If a preoperative predictive biomarker were established in STS, then it
potentially could be utilized to intensify neoadjuvant therapies.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. AJCC 8th edition stage I-III histologically confirmed STS of the extremity or trunk
2. Male or female, aged > 18 years old
3. ECOG Performance Status 0-3
4. Meets screening criteria for receipt of radiotherapy
5. Deemed eligible for wide local excision
Exclusion Criteria:
1. Distant metastatic disease
2. Prior radiation therapy in the proposed treatment area
3. Simultaneous treatment of another malignancy
4. Planned neoadjuvant or adjuvant chemotherapy
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Medical University of South Carolina
Address:
City:
Charleston
Zip:
29425
Country:
United States
Status:
Recruiting
Contact:
Last name:
Alan Brisendine, BS, CCRP
Phone:
843-792-9007
Email:
brisend@musc.edu
Contact backup:
Last name:
Jasmin Brooks
Email:
brooksjm@musc.edu
Investigator:
Last name:
Jennifer Harper, MD
Email:
Principal Investigator
Start date:
August 15, 2023
Completion date:
March 30, 2025
Lead sponsor:
Agency:
Medical University of South Carolina
Agency class:
Other
Source:
Medical University of South Carolina
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05776667
