A Phase 2 Trial of Five-Day Neoadjuvant Radiation Therapy for Patients with High-Risk Primary Soft Tissue Sarcoma

Abstract

Purpose:

In a single-institution phase II study, we evaluated the safety of a five-day dose-equivalent neoadjuvant radiation therapy (RT) regimen for high-risk primary soft tissue sarcoma (STS).

Methods:

Patients received neoadjuvant RT alone (30 Gy in five fractions) to the primary tumor with standard margins. The primary endpoint was grade ≥2 late radiation toxicity. Major wound complications, local recurrences and distant metastases were also examined. In exploratory analysis, we evaluated germline biomarkers for wound toxicity and the effects of the study on treatment utilization.

Results:

Over two years, 52 patients were enrolled with median follow-up of 29 months. Seven of 44 evaluable patients (16%) developed grade ≥2 late toxicity. Major wound complications occurred in 16 of 50 patients (32%); a signature defined by 19 germline single nucleotide polymorphisms in miRNA binding sites of immune and DNA damage response genes, in addition to lower extremity tumor location, demonstrated strong predictive performance for major wound complications. Compared to the preceding two-year period, the number of patients treated with neoadjuvant RT alone at our institution increased three-fold, with a concomitant increase in the catchment area.

Conclusions:

A shorter five-day neoadjuvant RT regimen results in favorable rates of wound complications and grade ≥2 toxicity after two years follow-up. Five-day RT significantly increased utilization of neoadjuvant RT at our high-volume sarcoma center. With further validation, a putative germline biomarker for wound complications may guide safer RT utilization.

INTRODUCTION

Radiation therapy (RT) significantly improves local control for patients with high-risk primary extremity and trunk soft tissue sarcomas (STS)⁷. Neoadjuvant RT is generally preferred due to its favorable toxicity profile, shorter course, and potential operative benefits¹. Although widely considered a standard approach for high-risk STS, many patients do not receive RT, in part due to the difficulty of daily treatments for five or six weeks^8,9.

More condensed RT regimens have been adopted in the treatment of several malignancies as radiation oncologists can more easily spare normal tissues with modern radiation techniques and image guidance^3,10. There is also a biological rationale for this approach in sarcoma, a tumor that is less sensitive to smaller RT fraction sizes (lower α/β ratio)¹¹. Although late toxicities are still a concern, these condensed RT regimens can be well tolerated with appropriate dosimetry^12,13.

For STS patients who also receive neoadjuvant chemotherapy, a condensed (hypofractionated) form of neaodjuvant RT has been used at our institution for decades. This regimen of neoadjuvant chemoradiation (the “Eilber” protocol, 28 Gy over eight fractions with ifosfamide-based chemotherapy) demonstrated an actuarial local recurrence rate of 11% and 17% at three and six-years^14,15. Another Polish study utilizing five-day neaodjuvant radiation (25 Gy over 5 fractions) for STS resulted in 19.1% rate of local recurrence at median follow-up of 35 months¹⁶. The risk of local recurrence in these two studies was higher than modern studies using standard fractionation (50 Gy over 25 fractions in five weeks), which have reported <10% local recurrence rates^2,3,17,18. We hypothesized that this may be due to the lower biologically equivalent or effective dose used in both hypofractionation studies.

We initiated a prospective phase 2 study to evaluate the safety and toxicity of a five-day neoadjuvant RT regimen for STS that delivers 30 Gy over 5 fractions, a dose that may more closely mimic the biological effect of conventional 5-week RT(EQD₂ = 50 Gy). This calculation is based on a presumed α/β = 4 for STS^11,19, though this is a generalized estimate of a value that is more likely histology- and tumor-specific. Here, we report the feasibility, safety, and early onocologic outcomes of this prospective phase 2 study.

PATIENTS AND METHODS

Patients

The protocol for this prospective study (NCT012701153) was approved by the UCLA Institutional Review Board. Informed written consent was obtained from eligible patients with histologically confirmed STS of the extremity or trunk with planned neaodjuvant RT and surgery. The study was performed according to institutional regulations as well as ethical principles summarized in the Belmont Report. All patients were 18 or older and had Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. Exclusion criteria included evidence of distant metastases, planned neoadjuvant or adjuvant chemotherapy; prior RT to the area to be irradiated; and active treatment of a second malignancy.

Study Design and Treatments

Eligible patients were assigned to receive neaodjuvant RT followed by surgery 2 to 6 weeks later. Radiation CT and/or MRI simulation was performed with custom immobilization. The gross, clinical and planning target volumes were defined according to RTOG 0630³: the gross tumor volume (GTV) was defined by T1 weighted MRI and CT. The clinical target volume (CTV) was defined as a margin of 3 cm in the longitudinal directions on the GTV and a 1.5 cm radial expansion on the GTV, in addition to any suspicious edema as seen on T2 weighted MRI, and cropped out of any uninvolved bone and non-adjacent muscle compartments. This clinical target volume (CTV) was then expanded to a planning treatment volume (PTV) using a 5 mm expansion. The PTV was cropped at least 2mm from the skin for superficial lesions unless there was skin involvement.

A dose of 6 Gy × 5 fractions (30 Gy) was delivered on consecutive days to at least 95% of the PTV. Intensity modulated (IMRT), 3D conformal, or electron planning techniques were used. Radiation plans were deemed acceptable if they met dosimetric parameters outlined in Supplementary Table S1. All patients underwent daily image guidance except two patients receiving electron RT. All surgeries were performed at UCLA by one of four dedicated sarcoma surgeons.

Assessments

The primary endpoint of this study was the rate of grade ≥ 2 radiation morbidity (fibrosis, lymphedema or joint stiffness) at median two-year follow-up (minimum one year). Fibrosis and joint stiffness were graded based on Radiation Therapy Oncology Group/EuropeanOrganisation for Research and Treatment of Cancer (RTOG/EORTC) criteria, and lymphedema was graded by Stern’s scale. Other secondary endpoints included acute toxicities as assessed by the frequency and severity of adverse events (AEs) using CTCAE v4.0 toxicity criteria, the rate of major wound complications, pathologic treatment effect, and the rate of local and distant recurrences. Major wound complications were defined as per established criteria from prospective clinical trials of extremity soft tissue sarcoma^1,2. We also evaluated patient and physician-reported functional outcomes at baseline and 12, 18 and 24 months using the Toronto Extremity Salvage Score (TESS) and the Musculoskeletal Tumor Society (MSTS score), respectively^20,21. Pathologic treatment effect was defined as the percentage of surgical tissue with hyalinization or necrosis relative to pre-treatment biopsy²². Time-to-event end points were measured from enrollment.

Patients were seen after the completion of radiation and prior to surgery by the radiation oncologist and/or the sarcoma surgeon. Patients were followed closely in the postoperative setting. The patients’ status was reviewed 3 months after surgery, and then at least every 6 months thereafter. The patients were followed both clinically and radiographically after treatment with CT or MRI of the primary site and CT of the chest at least every 6 months for the first two years and then at least annually in the third year. Patients with myxoid liposarcoma were also evaluated with CT of the abdomen and pelvis.

A subset of patients were consented to a parallel imaging study under IRB approval from May 2016 to June 2018. Diffusion-weighted images (DWI) were acquired up to four times for each patient using a 0.35T MR-guided radiotherapy machine (ViewRay, MRIdian, Mountain View, CA) including before the first fraction of treatment and and at least 14 days after RT but prior to surgical resection.

Statistical Analysis

The study was designed to evaluate the rate of grade ≥2 radiation morbidity (subcutaneous tissue fibrosis, joint stiffness, or edema at 2 years to mirror the initial design of RTOG-0630³ with a target absolute improvement of 20% in the rate of grade ≥ 2 radiation-associated toxicity at two years compared to the historical neaodjuvant RT arm of the CAN-NCIC-SR2 study from 37% to 17%. Between May 2016 and May 2018, 52 patients with localized high-risk STS of the extremity or trunk were enrolled. Of these, 50 patients ultimately underwent neaodjuvant RT and surgery (Supplementary Figure S1, CONSORT diagram).

We examined whether major wound complications were related to relevant clinical variables, including tumor size, tumor site, tumor depth, time interval from radiation to surgery, and two radiation dosimetric variables using univariate logistic regression. Dosimetric variables included the maximum radiation dose (Gy) to the skin (minimum 0.5 cc volume), and volume of the skin (cc) receiving 12 Gy. Likelihood ratio test (LRT) was used to assess the significance of categorical variables.

Pathologic outcomes were reported with descriptive statistics. Differences in pre- and post-treatment tumor volumes by diffusion-weighted MRI were assed by paired t-test. Comparisons of average distance traveled and volume of patients between the two years prior to study enrollment and the study period were made using unpaired t-tests.

Exploratory Germline Biomarker Analysis

Genomic DNA from blood or saliva was analyzed for single nucleotide polymorphisms (SNPs) disrupting miRNA binding sites, promoter regions or coding sequences as previously identified²³. Biomarkers in binding sites in genes involved in the immune system and DNA damage response, as well as promoters and coding sequences of miRNAs that regulated key genes known to be critical in the DNA damage or immune response were enriched in our analysis. We reduced to a final list of ~116 variants (see Supplemental Methods). We evaluated the relationship of this set of 116 SNPs with the incidence of major wound complications. We also included lower extremity tumor site as a variable as it was the only clinical variable associated with major wound complications. The association between this panel of potential germ-line biomarkers and tumor site with wound toxicity was assessed using four classifiers: classification trees (CT)²⁴, random forests (RF)²⁵, boosted trees (BT)²⁶, and LASSO-regularized logistic regression (LASSO-LR)²⁷, which were fit in R (version 3.6.0)²⁸.

Retrospective analysis of neaodjuvant RT patients prior to clinical trial period

Patients treated with neaodjuvant RT alone prior to surgical resection during the two-year period (May 2014 to May 2016) before study initiation were extracted from the facility electronic health record system. Distance to facility was calculated using the patients’ residential zip codes and the facility zip code in R package ggmap²⁹.

RESULTS

Patient characteristics and accrual

Patient clinical and pathologic details and demographics are summarized in Table 1 and Supplementary Figure S2. The study enrolled patients across a broad age spectrum, including five patients between age 80 and 90, three of whom had ECOG performance status of 2. With the exception of one patient’s tumor, all were intermediate- or high-grade. Tumor size among enrolled patients was heterogenous (1.2 – 28 cm), and twelve patients had tumors >10 cm. Twelve patients (24%) received neoadjuvant RT prior to re-resection for gross (n=9, 18%) or microscopic (n=3, 6%) residual disease. The median time between completion of RT and surgery was 28 days (range 14 – 55). Nine of 50 patients (18%) had initial R1 resection, of whom 5 underwent R0 re-resection.

Table 1.

Clinical characteristics and demographics of the study population.

	n	%
All Patients	50
Disease Characteristics
Tumor Size
≤5	13	26
>5 and ≤10	25	50
>10	12	24
Tumor Depth
Superficial	10	20%
Deep	40	80%
Tumor Site
Upper Extremity	9	18%
Lower Extremity	34	68%
Trunk/Girdle	7	14%
Tumor Histology
Undifferentiated	24	48%
Myxofibrosarcoma	8	16%
Myxoid Liposarcoma	11	22%
Angiosarcoma	2	4%
Well-diff Liposarcoma	2	4%
Other	3	6%
Tumor Grade
Low	1	2%
Intermediate	19	38%
High	30	60%
Patient Characteristics
Age
<50	14	28%
50–64	11	22%
65–79	20	40%
>79	5	10%
ECOG
0	39	78%
1	6	12%
2	5	10%
Diabetes
No	46	92%
Yes	4	8%
Smoking
No	41	82%
Yes	9	18%
Demographic
Race
White	36	72%
Black	5	10%
Hispanic/Latino	5	10%
Asian	4	8%
Sex
Female	22	44%
Male	28	56%
Distance to Facility
≤10 miles	3	6%
>10, ≤25 miles	10	20%
>25, ≤50 miles	8	16%
>50, ≤100	9	18%
>100, ≤200	10	20%
>200	10	20%
Treatment Characteristics
Radiation Type
3D-conformal	10	20%
IMRT	38	76%
Electron	2	4%
Prior R1/R2 Resection
No	38	76%
Yes	12	24%
Adjuvant Chemo
No	44	88%
Yes	6	12%

Radiation-associated toxicities

The five-day neaodjuvant RT regimen was well-tolerated without grade 3 or higher acute or toxicities. The most severe radiation dermatitis was grade 2 and occurred in four patients (8%); other grade 2 toxicities were pain flare (n=3, 6%) and nausea (n=1, 2%).

Radiation-associated toxicities (fibrosis, joint stiffness or lymphedema) as measured by RTOG/EORTC criteria are summarized in Table 2. No grade 3 or higher toxicities were observed after 29 months median follow-up (minimum 17 months). Overall, 7 of 44 evaluable patients (16%) developed at least one grade 2 radiation-associated toxicity, which met the primary endpoint. Grade 2 fibrosis (11%) and joint stiffness (11%) were more frequent than grade 2 lymphedema (4%). Of evaluable patients, 34 patients had minimum two years follow-up; five (14.7%) developed grade ≥2 fibrosis, lymphedema and/or joint stiffness. We observed a non-significant trend toward increased grade ≥2 radiation-associated toxicities in patients with tumors larger than the median size of 6.5 cm (p = 0.101, χ² test), We did not observe any association between RT modality (IMRT, 3D, or electron) and toxicities, but the limited number of patients treated with 3D-conformal and electron RT limits this comparison (data not shown).

Table 2.

Late Toxicities of Five-Day Preoperative Radiation Therapy

	Fibrosis
Number of Patients	G1	G2	G3
	11 (24%)	5 (11%)	0 (0%)
	Joint Stiffness
	G1	G2	G3
	5 (11%)	5 (11%)	0 (0%)
	Lymphedema
	G1	G2	G3
	2 (4%)	2 (4%)	0 (0%)

We also examined patient and physician-reported outcomes using TESS and MSTS score surveys, respectively, at baseline, 12, 18 and 24 months. Baseline and at least one evaluable follow-up data point were available in 34 of 50 patients. We did not observe a significant decline in functional outcome at 12, 18 or 24 months using either survey (Supplementary Figure 2A–B).

Wound Complications

Major wound complications were observed in 16 of 50 patients (32%). This rate is on par with rates of major wound complications observed in prospective studies of neaodjuvant RT (35% in the neoadjuvant RT arm of the NCIC Phase 3 study; 30.5% in multi-institutional phase 2 study of image-guided IMRT, and 36.6% in RTOG 0630) as well as retrospective analyses (Figure 1A)^1–6. By CTCAE criteria, 12 patients (24%) experienced grade 3 or higher wound complication or wound dehiscence, including three patients who required a reconstruction flap (grade 4 complication). In the 16 patients with major wound complications, 14 have achieved wound closure at a median time to closure of 6.4 months (Figure 1B). There were more wound complications in patients with lower extremity tumors (p = 0.01; Figure 1C, Supplementary Table S2 and S3), including five out of nine patients with adductor compartment involvement. Wound complications were not associated with smoking history, time interval from radiation to surgery, tumor depth, tumor size or either of two parameters for radiation dose to the skin (Supplementary Figure S3A–D). The low rate of diabetes (n=4) in our study population precluded meaningful statistical analysis. We did not find an association of prior R1/R2 surgery on the incidence of major wound complications (p>0.99, Fisher’s exact test).

Figure 1.

Characteristics of major wound complications. (A) The rate of major wound complications in the present study, alongside major wound complication rates from prospective studies (preoperative RT arm of the NCIC Randomized Phase 3 Study; image-guided IMRT phase 2 study of preoperative RT; and RTOG 0630)^1–3 and modern retrospective studies^4–6. (B) Time to wound closure in days. Patients who died (x) or underwent amputation (o) prior to wound closure are labeled. (C) Frequency of wound complications according to lower extremity tumor location compared to other sites (upper extremity and trunk).

Association of germline biomarkers with wound complications

Given the paucity of clinical factors that predict for wound complications, we hypothesized that inherent patient radiosensitivity may contribute to the risk of wound complications after neaodjuvant RT. In exploratory analysis, among lower extremity tumor site and a panel of 116 annotated SNPs in miRNA binding sites, tumor site and 19 SNPs were identified as the top 20 predictors for major wound complication rate (Supplementary Table S4). The prediction performance for four proposed classifiers (classification tree, random forest, boosted tree, and LASSO-LR) using these 20 predictors jointly were fairly similar (Table 3), with random forests performing the best, with an accuracy of 0.855, a specificity of 0.792, sensitivity of 0.917, AUC of 0.952 and F1 of 0.868.

Table 3.

Performance measures for prediction of major wound toxicity using germline biomarker and lower extremity tumor site.

	acc	specificity (TNR)	sensitivity (TPR)	npv	ppv	AUC	F1
Classification Tree	0.692	0.650	0.733	0.750	0.757	0.757	0.696
Random Forest	0.855	0.792	0.917	0.922	0.850	0.952	0.868
Boosted Tree	0.792	0.667	0.917	0.875	0.770	0.798	0.827
LASSO-LR	0.780	0.667	0.892	0.917	0.767	0.839	0.790

Early Oncologic Outcomes

Of the 50 patients who underwent surgery, a minimium of 2 years follow-up is available for 38 patients, of whom 35 are evaluable for local control (three patients have died). To date, two of these evaluable patients with minimum 2 years follow-up developed a local recurrence after surgery (5.7%); both local recurrences occurred within the first year of study enrollment. Ten of 47 evaluable patients (21.2%) have developed metastatic disease. There was a preponderance of high-grade tumors among patients who developed metastatic disease (80% versus 54%, p = 0.16), but no difference in size, tumor depth, or re-excision status (data not shown). Forty-two of 50 patients (84%) are alive, including six patients with metastatic disease. Of eight deaths, four patients have died due to causes unrelated to sarcoma or treatment (median age 81, range 70 – 90). Among 45 patients with evaluable pre- and post-treatment tumor, the average pathologic treatment effect was 44.2% (range 0 – 100%, standard deviation 31.6%) (Figure 2A)¹⁴.

Figure 2.

Early surrogates for clinical response to five-day neoadjuvant RT. (A) Treatment effect as measured by the percentage of necrosis and hyalinization in the surgical specimen relative to the biopsy specimen in patients treated on the five-day neoadjuvant RT protocol. Box plot represents 10^th to 90^th percentile, with mean (+), median, and outliers shown. (B) Pre-to-post treatment change in tumor volume by diffusion-weighted ViewRay MRI for n=25 patients with available data, according to histology (undifferentiated sarcoma, myxoid liposarcoma, and other). *, p<0.05; **, p<0.005 according to unpaired t test.

Twenty-five patients had matched pre- and post-treatment MRI available for analysis on the parallel imaging study (Supplementary Table S5). The median time between pre- and post-treatment scans was 20 days (range 16 – 35). Overall, there was no difference in DWI tumor volume between pre- and post-treatment scans, and there was no association between time interval between scans and change in DWI tumor volume. We observed a significant decrease in DWI tumor volume between pre- and post-treatment myxoid liposarcoma specimens (Δ = −43.2 cm³ +/− 13.7 cm³; p = 0.025), but not in non-myxoid liposarcoma tumors (Figure 2B).

Study-Associated Changes in Access and Utilization of RT

In the two-year period just prior to the initation of this study, 14 patients were treated with neaodjuvant RT at our institution. This value increased by three-fold (n=52) during the subsequent two-year study period (Figure 3A). In the two-year period just prior to the initiation of this study, patients treated with neaodjuvant RT lived at a median distance of 11 miles from our facility, and there were no patients who traveled over 100 miles to receive treatment. During the study period, the size of the catchment area increased; enrolled study patients traveled a median 56 miles from their primary residence to receive treatment (p<0.0001; Figure 3B) and 40% of patients traveled over 100 miles to receive treatment.

Figure 3.

Impact of 5-day protocol on utilization of neoadjuvant RT at a high volume sarcoma center. (A) Cumulative accrual of patients to the phase 2 prospective study of five-day neoadjuvant RT, shown alongside target accrual rate and accrual of patients treated with standard 5-week neoadjuvant RT alone during the 2-year period preceding study initiation. (B) Distance traveled to our high volume sarcoma center for neoadjuvant RT by patients enrolled on the five-day phase 2 study and by patients in the 2-year period preceding study initation. ****, p<0.0001 (Mann-Whitney test).

DISCUSSION

STS is a rare malignancy and treatment at high-volume sarcoma centers has been associated with improved outcomes^30–32. Conventional five-week RT is known to have poor utilization among patients traveling a long distance^33,34 and is a barrier to treatment at high-volume sarcoma centers. Shorter RT regimens are not only preferred by patients³⁵, but they reduce travel burden and increase the access to care at high-volume centers. To date, limited data exist on the morbidity of shorter, condensed neoadjuvant RT for the treatment of STS of the extremities and trunk. In our single-institution phase 2 study, five-day neoadjuvant RT to a total of 30 Gy was well-tolerated.

Shorter, condensed RT regimens with higher daily dose historically have not been used due to concerns about toxicities. The rate of grade ≥2 radiation-associated toxicity (fibrosis, joint stiffness, or lymphedema) after median follow-up of two years was tolerable (16%). However, while these rates are favorable compared to the CAN-NCIC-SR2 study¹ against which our study was powered (16% versus 37%), and comparable to a more recent multi-institutional phase 2 study using modern image-guided RT³ that used 5-week neoadjuvant RT, longer follow-up is needed for a more robust comparison.

Another concern with RT dose intensification in the neoadjuvant setting was the rate of wound complications, which is the primary drawback of neaodjuvant RT for STS¹. The rate of major wound complications in our study (32%) is consistent with results from previous prospective and retrospective studies that used conventional 5-week neaodjuvant RT (22 to 37%)^1,3,4. The pattern of wound complications was also consistent with what is observed using 5-week neaodjuvant RT, with a propensity for complications in the lower extremity³. However, the median duration prior to wound closure was prolonged compared to a retrospective study of patients receiving conventionally fractionated RT³⁶.

Given the complex and multifactorial nature of wound complications³⁷, we examined whether specific clinical or dosimetric predictors could better identify patients at greatest risk. While clinical or dosimetric predictors other than lower extremity tumor location were not associated with wound toxicity, an exploratory analysis of germline SNPs in miRNA binding sites suggests a role for patient-intrinsic biology as a factor in the development of wound complications after neaodjuvant RT. There are indeed germline differences in radiosensitivity of normal tissues between individuals^38–47. The majority of existing evidence on this topic centers on late skin and tissue response to radiotherapy of the breast. Our exploratory analysis identified a set of 19 germline alterations in microRNA binding sites in genes with roles in immune and DNA damage response that, in combination with lower extremity tumor location, are associated with major wound complications. These data are limited by the sample size of our phase 2 study, and validation of this set is necessary and ongoing. Nonetheless, these data highlight the potential for using patient germline features to stratify the risk of major wound complications prior to treatment. For these at-risk patients, more aggressive dosimetric constraints, consideration of adjuvant radiotherapy, alternative surgical approacheas or changes in post-surgical wound care may be warranted.

We observed both an increase in the number of patients treated with neoadjuvant RT and the distance traveled by patients to our high-volume center that coincided with study initiation. These results are consistent with prior studies demonstrating that shorter RT regimens are preferred by patients³⁵ and suggest that five-day neoadjuvant RT would increase the utilization of neaodjuvant RT and access to care at high-volume sarcoma centers.

While local control results have yet to mature, early results are promising with two (5%) local failures among 35 evaluable patients with at least 2 years follow-up. The pathologic treatment effect observed in our study may serve as an early indicator of the anti-tumor efficacy of this regimen. Because the time interval from treatment initiation to surgery in our study is shorter, we anticipated pathologic response rates would be slightly lower than results from studies using standard 5-week neoadjuvant RT^22,48 or studies using neoadjuvant chemoradiation⁴⁹. As a secondary early indicator of clinical efficacy, we evaluated longitudinal diffusion-weighted MRI imaging of a subset of 25 patients. In the brief period between radiation and surgery (median 28 days), a brisk decrease in DWI tumor volume was noted in patients with myxoid liposarcoma, a histologic subtype characterized by inherent radiosensitivity, supporting the anti-tumor efficacy of the five-day radiation dose and fractionation.

Although we routinely incorporate neoadjuvant systemic therapy for high risk extremity and trunk STS, systemic therapy is not always recommended by our multidisciplinary conference due to age, comorbidities, clinicopathologic characteristics, and patient preference. The data presented here are not generalizable to patients with planned neoadjuvant or adjuvant chemotherapy. We are currently accruing to an expansion cohort of this phase 2 study to evaluate the safety of a five-day neoadjuvant RT regimen in combination with systemic therapy.

In conclusion, our results demonstrate that five-day neoadjuvant RT in extremity and trunk STS shows a favorable radiation toxicity profile at a median follow-up of 29 months and an acceptable rate of major wound complications. Importantly, we found a statisticaly significant increase in the number of patients treated with this short course of neoadjuvant RT at our high volume sarcoma treatment center, which suggests this protocol could improve neoadjuvant RT use and access to care of STS at high-volume sarcoma centers. Early local control, pathologic treatment effect and imaging outcomes support the bioactivity of this dose and fractionation scheme, though longer follow-up is needed. Finally, we identified a putative germline biomarker profile for major wound complications; further validation of this profile may guide safer utilization of neoadjuvant RT. In summary, five-day neoadjuvant RT is a safe, effective, and accessible alternative for patients with localized STS of the extremity and trunk that warrants evaluation in a larger multi-institutional study.

STATEMENT OF TRANSLATIONAL RELEVANCE.

A five-day neoadjuvant radiation therapy (RT) regimen for primary soft tissue sarcoma (STS) of the extremity and trunk demonstrates a toxicity profile similar to modern studies using conventional 5-week neaodjuvant RT. This less-burdensome five-day course of neoadjuvant RT increased access to care of STS at our high-volume sarcoma center, while early local control, pathologic and imaging outcomes support the bioactivity of this dose and fractionation scheme. We identified a putative germline biomarker profile for major wound complications; further validation of this profile may guide safer utilization of neoadjuvant RT. Together, these results support the evaluation of the five-day neoadjuvant RT regimen and its associated germline toxicity biomarker in a larger multi-institutional study for patients with primary soft tissue sarcoma (STS) of the extremity and trunk.