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Sarcomas ASTRO Refresher 2025 - Coggle Diagram
Sarcomas ASTRO Refresher 2025
Review data for rationale for and evidence-based use of RT for localized STS of extremity and superficial trunk
Review and highlight some limitations of current state of data for Hfx for STS
Discuss recent trials in STS that have changed management approaches w/ RT
ASTRO Clinical Practice Guideline: Radiation Therapy for Treatment of Soft Tissue Sarcoma in Adults
Executive Summary:
Salerno et al. Pract Radiat Oncol. 2021; 11(5):339-351
Key Question 1: What are the roles and indications for RT in the treatment of extremity and superficial truncal adult STS?
60+ different subtypes.
Treat at a tertiary cancer center.
in resectable pts, RT recommended postop for those with
increased risk of LR
there are a many factors
morbidity of an upfront surgery → combined modality with RT
Limb sparing Sx and RT improves LR
Limb sparing sx vs LSS/RT
NCI (Yang et al. JCO 1998;16:197-203)
NCI External Beam Trial
Locally resectable STS of extremity
Gross total resection w/o violating tumor
Post-operative randomization
71 no RT; 78 RT
Target area: ‘wide field’ to 45 Gy; cone-down to clips to 63 Gy (1.8 Gy per fx)
m f/u 10 yr
LR (5 yr)
Sx + RT: ~96%
Sx: ~77%
p < 0.01
DM rate same in both arms
high-grade ~20% at 5 yr
OS
same in both arms
high-grade: ~75% at 10 yr
low-grade: not stated
benefit evident in low & high grade
High Grade
RT: 0% LR
No RT: 22% LR
P = 0.003
External Beam
Low Grade
RT: 4% LR
No RT: 37% LR
P = 0.016
MSKCC (Harrison et al. IJROBP 1993;27:259-265)
Locally resectable STS of extremity & superficial trunk
Gross total resection w/o violating tumor
Intra-operative randomization RCT
86 to no brachy; 78 to brachy
Target area: 2 cm margin superior & inferior; 1.5 cm lateral; single-plane, high dose 1 cm above & below plane
slightly smaller margins than NCIC
Surgical scar & drain holes not treated
Min dose 45 Gy in 4 to 6 days
Skin dose ≤ 20 Gy
m f/u 76 mo
LR (5-yr)
Sx + Brachy: 82%
Sx: 69%
p=0.04
DM
Same in both arms: ~25% at 5 yr
DSS
Same in both arms: ~82% at 5 yr
Grade
High
RT LR: 11%
No RT LR: 34%
P = 0.0025
Low Grade
RT LR: 33%
No RT LR: 24%
P = 0.49
Brachytherapy
Benefit of Brachy limited to high grade STS
high grade: LC 89% S+B vs. 66% S (p=0.04)
low grade: LC ~72% S or S+B
T-size, primary vs. recurrent, margin (- or +), depth not significant for LC
in first pub (-long term update margin was significant w/ match historical augmented cohort).
this was the only study to initially state margin status not significant. But we now know it does matter.
Wound breakdown was main complication
loading < 5 days → 22%
loading > 5 days → 14%
Brachy for STS is rare, for boards. Matters how long the catheters were loaded.
Non-exhaustive list of factors associated w/ LR or indication for RT
SM status*
Tumor grade* (most associated w/ DM risk)
Histologic subtype
e.g. low grade fibromyxoid sarcoma has high risk of spread...
Tumor size and anatomic site influence via SM- surgery feasibility.
Morbidity of potential salvage resection if recurs
Preop vs Postop
where indicated for primary local extremity or truncal STS,
Preop is recommended over postop.
Pre-op vs Post-op RT: Efficacy
EQUIVALENT
Several non-RCT have shown similar LC rates
NCI Canada RCT 7 yr update:
Similar LC rates (92%, 93%)
Similar DFS and OS rates
The preference for RT pre-operatively over post-operative is driven by the permanence of side-effects
PRE OP RT:
Lower dose: 50 Gy
Smaller volume: Tumor/tumor bed + 3-4 cm longitudinal margins
More acute wound complications (35% vs. 17%); usually reversible
POST OP RT:
Higher dose: 60-66 Gy
Larger volume: operative bed + 3-4 cm longitudinal margins
More edema, fibrosis, decreased range of motion, fracture risk (small risk but severe complication);
usually irreversible
Radiotherapy for Management of Extremity Soft Tissue Sarcomas: Why, When, and Where?
Haas review IJROBP 84:572; 2012
T1-weighted post-contrast MRI
fused to the planning CT is used to delineate the
GTV
. Does not include the peritumoral edema.
CTV transversely expanded
1.5 cm and longitudinally 4 cm
but constrained around fascia and bones unless invaded.
Note: peritumoral edema should be assessed on
T2-weighted MRI
and the CTV should be manually edited to include any peritumoral edema.
CTV
GTV + 4 cm proximal/distal,
1.5 cm radial
Edit CTV at bone
PTV
CTV + 5-10mm per institutional standard and IGRT
Is 4cm long exp enough?
White et all IJROBP 2005
in 27% of pts cells found up to a max 4cm from tumor
Postop Volumes
T1-weighted post-contrast pre op MRI fused to planning CT as well as post-op imaging may facilitate delineation of "GTV". Surgical bed is included here.
CTV constrained around fascia and bones unless invaded.
If 4 cm expansion of reconstructed surgical volume in longitudinal direction is shorter than the surgical scar, the CTV1 will need to be expanded to include the surgical scar. (1.5cm radially)
cone down and sequential boost to a smaller volume
Drain sites can be omitted in wide SM- resections, low-risk scenarios, or when field size increase significantly increases risks of RT-tox.
we dont often chase drain sites
First Course- (50 Gy)
Contour GTV and operative bed
CTV(1) = op bed + 1.5 cm radially, 4 cm longitudinally
Cone Down (60 Gy)
CTV(2) = GTV + 1-1.5 cm radially, 2 cm longitudinally
CTV(3-if relevant) for positive margins there can be a 3rd dose level of 0.5-1 cm expanded around GTV or area of known SM+ (e.g., clips)-Dose needs to be at least 64 Gy for SM+.
CTV to PTV expansion = 5-10 mm per institutional standard and per image guidance
Haas review IJROBP 84:572; 2012
Positive Margins
Positive Margins -> Higher LR
DeLaney, (MGH) IJROBP 2007; 67(5):1460-9
For pts w/ positive margins:
Dose > 64 Gy: 85% 5-yr LC
Dose ≤ 64 Gy: 66% 5-yr LC, p<.05
In post-op setting, recommended dose:
Positive Margins: 66-68 Gy
SM-: 60-63 Gy
OAR considerations-For pre-op RT the major RT-related tox is wound complication after surgery.
major wound complication (e.g., reoperation, acute care admission, dehiscence requiring prolonged packing)
risk is 35%.
Difficult to mitigate, but one planning consideration is a
3mm contraction on skin and avoidance of use of bolus.
ENI is not recommended for sarcoma.
The one exception arises in alveolar rhabdomyosarcoma.
OAR considerations-RT-tox risk is dependent on dose and field size
Inclusion > 50% of joint to 50 Gy
Contracture
Dose > 63 Gy
Pain
Edema
Decreased ROM
Field length > 35 cm
Edema
LE tumor & 75% diameter irradiated (pre IMRT era for the latter)
Chronic ulcer or infection
OAR Dosimetric parameter/constraint
Skin/subcutaneous or limb circumference
Spare ≥ 2 cm strip of limb circumference;
V20Gy < 100% of limb circumference
not evidence based
Femoral head/humeral head
V50Gy < 5%; V45Gy < 25-50%
Joint (arthrothis)
V50Gy ≤ 50%
Stinson et al, IJROBP 1991; Wang et al, JCO 2015
Bone fractures are rare but can be catastrophic.
V 40 Gy < 64%*
Mean < 37 Gy*
Max < 59 Gy to 2cc of bone
*denominated 2cm proximal/distal to PTV
V50 Gy < 100% of the circumference of weight-bearing bone
If bone constraints are not met, recommend discussion of fracture prophylaxis w/ orthopedic surgeon.
Dickie et al. IJROBP 2009; Bishop et al. PRO 2015
Dose and Rx
Preop: 50 Gy in 25 fx
Post-operative RT (1.8 - 2 Gy)
First Course 45-50.4 Gy
Cone Down 16-20 Gy
Total Dose 60-66 Gy if SM+
If SIB, CTV1 may need to receive 54 Gy to ensure 1.8 Gy/day at least for STS
HFx? Preop, RT alone
Historical standard for benchmarking LR (multiple studies) with combined modality local therapy for STS: LC=85-95%
a/b: 4, probably 3-5
Limitations of the linear-quadratic model: Biology ≠ Math
Much of the data used to generate this model is from cell culture experiments.
Some observed disconnect between the model’s predictions and observed in vivo effects at higher doses per fx.
The model does not depict vascular and stromal tissue damage resulting from higher doses per fx.
Polish Trial
Prospective phase 2,
5 x 5 Gy
(EQD2=38 Gy, assuming α/β=4), surgery within a wk of completion of RT
1st publication (n=272) stated 1º EP was LRFS.
2nd publication (n=311), cohort of all treatment at one center: w/ co-1º EPs of:
1)wound complications benchmarked against NCIC-SR2 rate
2) LRFS
5 yr LRFS was 81% (both series)
lower than considered acceptable
32% acute wound complications,
not all were major complications (12% wound dehiscence, 7% reoperation rate)
Late tox 12% for first publication
9% for the updated series (edema was most common)
5x5 seems to be too low
50Gy
Neoadjuvant stereotactic ablative radiotherapy (SABR) for soft tissue sarcomas of the extremities
Prospective phase 2,
5 x 8 Gy (EOD)
(EQD2=80 Gy, assuming α/β=4), surgery minimum 4 wk (median 8.6) after completion of RT.
Smaller target volumes (CTV 2-3cm longitudinal, 0.3-0.5 cm radial)
1º EP: rate of wound complications within 4 mo of surgery (SR2 definition)
25 pts, m f/u 21 mo
Wound complication rate 28%
100% LRFS
4/25 (16%) needed amputations—all for complications: 3 hip disarticulations for vascular occlusion after plastic surgery reconstruction and one for joint tox/limb dysfunction
this is too high!
Focusing on 2 published regimens : one ultrahypofractionated one moderately Hfx (approx 49-50 Gy, alpha/beta=4 (STS))
Ultra- Hfx 30 Gy in 5 fx, 6 Gy/fx
Kalbasi 2020
Kendal 2022
Nikitas 2024
A Phase II Trial of 5-Day Neoadjuvant Radiotherapy for Patients with High-Risk Primary Soft Tissue Sarcoma
UCLA
prospective phase II study to evaluate the safety and tox of a 5-day pre-op RT
30 Gy over 5 fx,
EqD2= 50 Gy, assuming α/β=4
1º EP of this study was the rate of grade ≥ 2 radiation morbidity (fibrosis, lymphedema, or joint stiffness) at m 2-yr f/u (minimum 1 yr).
Results: Over 2 yr, 52 pts were enrolled w/ m f/u of 29 mo.
7 of 44 evaluable pts
(16%) developed grade ≥2 late tox
BUT 34 pts had 2 yr f/u
Major wound complications
occurred in 16 of 50 pts (
32%
); significant in lower extremity
Conclusions: results favourable
CTOS 2022
Surgery performed within 4 wk of completing pre-op UHFx (Range 1-213 days)
m f/u: 25 mo (IQR: 11-44 mo)
86 pts included: 58% lower extremity
85 pts- primary closure, 1 split skin graft
26/85 (31%) local tissue advancement for closure
MWC
: 18/86
(21%)
median of 43.5 days (IQR: 40-85); higher in local tissue advancement
Second surgery
27/86
(31%)
: irrigation/debridement
Bone complications: 4/86- 3 fractures, 1 osteoradionecrosis (all upper extremity per communication w/ lead investigator)
UE is unusual
3/86- amputation for disease progression
Longer term accrual and follow up
ASTRO 2024
110 pts between 2016-2023
m post-RT f/u was 37 mo; (IQR: 20-61 mo) for all pts and 45 mo (IQR, 28-66 mo) for all evaluable pts.
Rates of grade ≥2 fibrosis, joint stiffness, and edema were 12%, 12%, and 4%, respectively.
fracture rates not updated at this report
5% amputation rate (LR, salvage)
Among all pts (N = 110), major wound complications occurred in 33 pts (30%).
2-yr and 5-yr LC rates were 92% and 86%, respectively.
Mod Hfx 42.75 Gy in 15 fx, 2.85 Gy/fx
Guadagnolo 2022
Bishop 2024
Hypofractionated, 3-wk, preoperative RT for pts w/ soft tissue sarcomas (HYPORT-STS): a single-centre, open-label, single-arm, phase 2 trial
Phase 2: 1º EP
Bayesian stopping rule design for MWC development
120 pts Dec 2018-Jan 2021
m f/u 24 mo,
65% lower extremity, median size: 8 cm
42.75 Gy in 15 fx. (EqD2= 49 Gy, assuming α/β=4)
Surgery 4-8 wk after RT
LR: 95%; 30-mo LRFS was 93%
At publication:
grade ≥3 late RT tox in 4 pts (3%): 2 femoral fractures, surgically stabilized,
1 lymphedema w/ lymphatic bypass procedure,
1 late skin ulceration (in pt w/ MWC treated w/ multiple procedures, pre-tibial persistent ulceration);
no grade ≥3 fibrosis at last f/u.
Update
m f/u: 43 mo (IQR: 7-52 mo)
4 yr LR free survival: 93%
crude: 7 pts- 5 in field, 1 at field edge and 1 wide of field
Late tox
RT related tox improved over time
grade ≥2 skin tox 2%
grade ≥2 fibrosis 2%
grade ≥2 lymphedema 3%
grade ≥2 joint stiffness 1%
4/120:
3% bone fractures
occurred at m 17 mo [ range, 15-46 mo]
6-7% in just femurs
Functional o/c (MSTS and FACT) both better/stable at 2 yr compared to baseline
QOL worse w/ grade ≥2
Caution going forward w/ Hfx pre op:
Focusing only on the tox of:
1) Acute major wound complications (within 120 days of surgery)
+
*2) "SR2 triad" of late tox (fibrosis, edema, joint limitation)
overlooks 3 other important tox concerns w/ Hfx.
Amputations increase with daily fractional dose increases.
more amputations for
non LR
causes.
not seen in 50/25
Ongoing trials in Hfx for STS
Mayo clinic, single arm phase 2 study of 15 x 2.85 Gy preoperatively (NCT04562480)-1º EP: MWC, abstract CTOS2024
Netherlands Cancer Institute (NKI) is conducting a phase 2 RCT study of 25 x 2 Gy vs. 14 x 3 Gy (NCT04425967)-1º EP: MWC
UCLA→Stanford has ongoing accrual to phase 2 study of 5 x 6 Gy (NCT02701153)
Open wounds at 6 months post surgery
European Journal of Surgical Oncology
Time dependent dynamics of wound complications after preoperative RT in Extremity Soft Tissue Sarcomas
191 pts treated w/ pre op RT, 25 x 2 Gy
surgery m 6 wk post RT end date
m tumor size 11 cm
64% in prox lower extremity
9 of 191
(5%) w/ wound not healed at 180 days
UCLA-30 Gy in 5 daily fx-late skin tox
Time to wound closure
7 pts
(14%) w/ wound not closed beyond 180 days.
Additional pt who died at 180 days w/ wound not closed.
(ASTRO 2024, lead author on abstract reported
new rate of 16% w/ 110 pt cohort)
This is 3x the rate as 50/25
Bone Tox can be catastrophic
2 fractures Post HYPORT-STS
17 and 19 mo post RT, respectively
Dickie et al. IJROBP 2009, bone max < 59 Gy to reduce fracture risk
increase in daily doses for UFx far exceed EQD2 50Gy for bone
Where does this leave us?
Current data need to be contextualized more thoroughly w/ respect to tox concerns.
Studies must include systematically collected data on fracture, amputations, delayed wound healing and late tox.
Need comparative data and expert consensus on planning metrics.
pts need to understand short term convenience may be at expense of long-term inconvenience to manage toxicities-need their preferences.
New trials
SU2C-SARC-032: Mowery et al. Lancet 2024.
RCT, stage III STS (UPS and related histologies) extremity
G2-3
Dediff/pleo Liposarcoma
more of an expansive definition of UPS
Pre op RT (50 Gy/25 fx ) vs pembrolizumab + RT (50 Gy 25 fx)
1º EP was DFS
20 centers (US, Canada, Italy, Australia)
143 pts randomized, 126 evaluable
m f/u of 43 mo
15% DFS benefit with pts with Pembro + RT vs RT only
2 yr DFS increased by 15% abs for pembro+RT vs. RT alone (67% vs. 52%); HR: 0.61
More grade 3-4 tox in pembro group (56% vs. 31%)
No significant diff in MWC (n=13 vs 15 in control vs exp, respectively)
various centers are incorporating this in different ways
3 pts on the study got HFx
We dont know the ideal regimen (50/25 of most people)
Sarcomas have a low risk of micro metastases so RLN are not targeted.
STRASS trial for Retroperitoneal Sarcomas
Bonvalot S GA, Le Péchoux C, et al. Lancet Onc.2020: 21(10): 1366-1377
RCT: pre op 50.4 Gy vs. surgery alone
1º EP was abdominal recurrence free survival (ARFS)
ARFS=
LR after complete resection
Peritoneal sarcomatosis
R2 surgery
Progressive disease during RT
Unresectable disease
pts becoming medically unfit for surgery
controversially expansive EP
266 pts, Europe, Canada, USA (2012-2017)
88 pts had WDLPS, 105 DDLPS ( ~ 75% of pts were thus LPS)
18 pts ineligible
~ 50 evaluable pts not LPS
m f/u 43 mo
Surgery was multi-visceral en bloc surgery within 4 wk of randomization or 4-8 wk from end of RT
32% had peri-operative complication-not diff btw the 2 arms
ARFS-no diff btw S vs. RT/S
STRASS liposarcoma post hoc analyses
pts w/
LPS receiving pre operative RT had a 10% abs ARFS benefit at 3 yr (65% vs 75%)
Study not powered for this, so hypothesis generating
Modern IMRT for RP STS
*Baldini et al. IJROBP, 2015
Comparing the STRASS vs STREXIT data: Callegaro et al. Ann Surg 2023
Compared 266 STRASS enrolled to 831 not enrolled at 10 ctrs (STREXIT).
Excluded those who got pre op CHT or had missing data (n=727 remaining) and created propensity matched cohort of 202 pts; pooled STRASS and STREXIT cohorts-468 pts.
Significantly
improved ARFS for pts w/ LPS treated w/ pre operative RT:
HR: 0.61
Benefit more likely for
WDLPS/gr 1-2 DDLPS rather than grade 3 DDLPS
STRASS trial for Retroperitoneal Sarcomas
These are the data we have.
Not likely there is going to be another prospective study of RT role anytime soon.
Case by case decision; need multidisciplinary discussion. We tend to treat WDLPS of the RP pre-operatively.
Hard to justify routinely recommending RT for de novo presentations after this study, but study has many caveats.
Hard “no” to post op RT is our practice.
complications are worse, O/c not better, OARs are hard to meet (60-66Gy)