Adequate 3D Treatment Adequate 3D Treatment Volume Volume

in Preoperative Radiotherapy in Preoperative Radiotherapy in Extremity Soft Tissue in Extremity Soft Tissue

SarcomaSarcoma

Kim BK, Chen YL, Kirsch DG, Kobayashi W, Goldberg S, Wolfgang J, Kim BK, Chen YL, Kirsch DG, Kobayashi W, Goldberg S, Wolfgang J,

Kung JH, Doppke K, Raskin KA, Springfield DS, Schwab JH, Kung JH, Doppke K, Raskin KA, Springfield DS, Schwab JH,

Yoon SS, Hornicek FJ, Nielson GP, DeLaney TFYoon SS, Hornicek FJ, Nielson GP, DeLaney TF

Department of Radiation Oncology, Orthopedic Oncology, Department of Radiation Oncology, Orthopedic Oncology,

Surgical Oncology, Pathology, Massachusetts General Hospital, Boston, MA, USASurgical Oncology, Pathology, Massachusetts General Hospital, Boston, MA, USA

BackgroundBackground

Radiotherapy in Extremity Soft Tissue Sarcoma Radiotherapy in Extremity Soft Tissue Sarcoma (STS(STS ) )

PreoperativePreoperative PostoperativePostoperative

Potential Advantages of Preoperative RT Potential Advantages of Preoperative RT More precise definition of tumor – accurate/small More precise definition of tumor – accurate/small

fieldfield Increase R0 resection/ possible limb preservationIncrease R0 resection/ possible limb preservation Decrease the risk of tumor seedingDecrease the risk of tumor seeding

Complications Complications Increased wound complications vs.Increased wound complications vs. Decreased late morbiditiesDecreased late morbidities

Adequate 3D Treatment Volume for Preoperative Adequate 3D Treatment Volume for Preoperative RT?RT?

Target Volume of Preoperative RTTarget Volume of Preoperative RT

InstitutionInstitution LongitudinLongitudinalal

MarginMargin

Radial Radial MarginMargin

RT RT Schedule Schedule

PreoperativPreoperativee

ChemotheraChemotherapypy

RTOG 9514 RTOG 9514 (2006)(2006)

9 cm9 cm >> 2 cm 2 cm 44 Gy/ 22 44 Gy/ 22 fx,fx,

SplitSplit

MAIDMAID

MGHMGH(2003)(2003)

6-9 cm6-9 cm >> 2 cm 2 cm 44 Gy/ 22 44 Gy/ 22 fx,fx,

SplitSplit

MAIDMAID

SR2 NCI SR2 NCI CanadaCanada(2002)(2002)

5 cm5 cm ? ? >> 2 cm 2 cm 50 Gy/ 25 50 Gy/ 25 fxfx

MDACCMDACC(2004)(2004)

5-7 cm5-7 cm << 1/3 of 1/3 ofcircumferecircumfere

ncence

50 Gy/ 25 50 Gy/ 25 fxfx

CCRT with CCRT with DoxorubicinDoxorubicin

MSKCCMSKCC(2007)(2007)

5 cm5 cm 2 cm2 cm 50 Gy/ 25 50 Gy/ 25 fx,fx,

IMRTIMRT

Peter Peter MacCallumMacCallum(2006)(2006)

6 cm (PTV)6 cm (PTV) -- 50.4 Gy/ 28 50.4 Gy/ 28 fxfx

--

Univ. of Univ. of FloridaFlorida(2002)(2002)

5-10 cm 5-10 cm (av. 10)(av. 10)

Involved Involved compartmecompartme

ntnt

50.4 Gy/ 42 50.4 Gy/ 42 fx,fx,

1.2 bid1.2 bid

Groningen Groningen Univ.Univ.(1999)(1999)

Entire Entire tumor tumor regionregion

Entire Entire tumor tumor regionregion

35 Gy/ 10 35 Gy/ 10 fxfx

IA IA DoxorubicinDoxorubicin

ObjectivesObjectives

Retrospective StudyRetrospective Study

Analyze the pattern of local failure (LF). Analyze the pattern of local failure (LF).

Patients with extremity STSPatients with extremity STS

Curative preoperative irradiation (XRT)Curative preoperative irradiation (XRT)

Treated with 3D XRT using CT simulationTreated with 3D XRT using CT simulation

Elucidate optimal 3D radiation field design.Elucidate optimal 3D radiation field design.

Evaluate other results and prognostic Evaluate other results and prognostic factors. factors.

Materials and MethodsMaterials and Methods

AccrualAccrual July 2000 – Dec 2006 (56 patients)July 2000 – Dec 2006 (56 patients)Period of FU Period of FU 15 - 76 months (median 41: alive 46, 15 - 76 months (median 41: alive 46,

dead 20.5)dead 20.5)

Sex (M: FM)Sex (M: FM) 37 (66.1%) : 19 (33.9%)37 (66.1%) : 19 (33.9%)AgeAge 18 - 89 years (median: 50.6)18 - 89 years (median: 50.6)

Exclusion CriteriaExclusion Criteria

Age < 18 years, Recurrent disease, Initially diagnosed M1, Age < 18 years, Recurrent disease, Initially diagnosed M1, Desmoid tumor, Dermatofibrosarcoma protuberance, Ewing’s Desmoid tumor, Dermatofibrosarcoma protuberance, Ewing’s sarcoma, Rhadomyosarcoma sarcoma, Rhadomyosarcoma

Performance (ECOG)Performance (ECOG)

00 11 22 33 44

11 11 (19.6%)(19.6%)

43 43 (76.8%)(76.8%)

1 (1.8%)1 (1.8%) 1 (1.8%)1 (1.8%) 0 (0%)0 (0%)

Tumor SitesTumor Sites

Upper extremity : Lower Upper extremity : Lower extremityextremity

13 (23.2%) : 43 (76.8%)13 (23.2%) : 43 (76.8%)

Materials and MethodsMaterials and Methods

Biopsy Biopsy No (%) No (%)

Core needle biopsyCore needle biopsy 4040 (71.4)(71.4)

Incision biopsy (planned : unplanned) Incision biopsy (planned : unplanned) 7 (3 : 4)7 (3 : 4) (12.5)(12.5)

Unplanned excisionUnplanned excision 99 (16.1)(16.1)

Histology Histology No (%) No (%)

Malignant Fibrous Histiocytoma (MFH)Malignant Fibrous Histiocytoma (MFH) 1919 (33.9)(33.9)

LiposarcomaLiposarcoma 1313 (23.2)(23.2)

Synovial sarcomaSynovial sarcoma 77 (12.5)(12.5)

FibrosarcomaFibrosarcoma 55 (8.9)(8.9)

Malignant Peripheral Nerve Sheath Tumor Malignant Peripheral Nerve Sheath Tumor (MPNST)(MPNST)

33 (5.4)(5.4)

MyxofibrosarcomaMyxofibrosarcoma 33 (5.4)(5.4)

LeiomyosarcomaLeiomyosarcoma 22 (3.6)(3.6)

OthersOthers 44 (7.1)(7.1)

Materials and MethodsMaterials and Methods

LocationLocation

Superficial : DeepSuperficial : Deep 8 (14.3%) : 48 (85.7%)8 (14.3%) : 48 (85.7%)

Pathologic Grade (3-Tier system)Pathologic Grade (3-Tier system)

1 : 2 : 31 : 2 : 3 5 (8.9%) : 27 (48.2%) : 24 5 (8.9%) : 27 (48.2%) : 24 (42.9%)(42.9%)

Initial Clinical Tumor size : 1.8-22 cm (median 8, Initial Clinical Tumor size : 1.8-22 cm (median 8, mean 8.9 mean 8.9 ++ 0.68) 0.68)

<4<4 4-54-5 5< 5< << 10 10 10< 10< <<1515 15< 15< <<2020** > 20> 20

7 7 (12.5%)(12.5%)

9 9 (16.1%)(16.1%)

24 24 (42.9%)(42.9%)

10 10 (17.9%)(17.9%)

5 (7.1%)5 (7.1%) 1 (3.6%)1 (3.6%)

* * 20 cm20 cm (3), 19 cm (1) (3), 19 cm (1)

Initial Clinical Stage (2002 AJCC Staging System)Initial Clinical Stage (2002 AJCC Staging System)

1 : 2 : 31 : 2 : 3 4 (7.1%) : 14 (25.0%) : 38 4 (7.1%) : 14 (25.0%) : 38 (67.9%)(67.9%)

TreatmentTreatment

Chemotherapy Chemotherapy 21 (37.5%) 21 (37.5%)

*,†*,†MAID#6MAID#6 *, † *, †

MAID#3+HDMTX#3MAID#3+HDMTX#3**AvastinAvastin ††Postop. MAID#6Postop. MAID#6

17 (30.4%)17 (30.4%) 2 (3.6%)2 (3.6%) 1 (1.8%)1 (1.8%) 1 (1.8%)1 (1.8%)**Pre & Postoperative, Pre & Postoperative, ††MAID :MAID : Mesna, Adriamycin, Ifosfamide, DacarbazineMesna, Adriamycin, Ifosfamide, Dacarbazine

RadiotherapyRadiotherapyTotal DoseTotal Dose 44-70 Gy (median : 50)44-70 Gy (median : 50)

Preoperative RadiotherapyPreoperative Radiotherapy 44-50.4 Gy44-50.4 Gy‡ ‡

(median : 50)(median : 50) DurationDuration 31-48 days (median : 36)31-48 days (median : 36) 3D-CRT : 3D-CRT+ Proton : IMRT : 3D-CRT : 3D-CRT+ Proton : IMRT : ProtonProton

46 : 3: 6 : 146 : 3: 6 : 1

‡ ‡ Median Fraction size 2.0 Gy Median Fraction size 2.0 Gy

Postoperative RTPostoperative RT§§ 12 (21.4%), 10-20 Gy 12 (21.4%), 10-20 Gy (median : 15)(median : 15)

EBRTEBRT IORTIORT HDR HDR BrachytherapyBrachytherapy

77 (3D-CRT (5), IMRT (3D-CRT (5), IMRT (2))(2))

33 22

§ § Postoperative boost RT was given to the patients with (+) or multiple Postoperative boost RT was given to the patients with (+) or multiple close RMclose RM

Radiotherapy (Preoperative RT Radiotherapy (Preoperative RT Volume)Volume)

GTVGTV

Gross Tumor Volume (GTV)Gross Tumor Volume (GTV): T1 Gd CE (+) area on MRI: T1 Gd CE (+) area on MRI

Clinical Target Volume (CTV)Clinical Target Volume (CTV): GTV + 1-1.5 cm radial margin: GTV + 1-1.5 cm radial margin: GTV + 3.5 cm proximal/distal : GTV + 3.5 cm proximal/distal marginmargin

Planning Target Volume (PTV)Planning Target Volume (PTV): CTV + 0.5- 0.8 cm margin: CTV + 0.5- 0.8 cm margin

Dose PrescriptionDose Prescription : PTV covered by : PTV covered by >> 95 % 95 % isodoseline isodoseline

TreatmentTreatment

Period between Preop. RT & Surgery 19-77 days Period between Preop. RT & Surgery 19-77 days (median: 34)(median: 34)

Surgical ExtentSurgical ExtentLimb-preserving surgery : Limb-preserving surgery : AmputationAmputation

56 : 056 : 0

R0 resection : R1 resectionR0 resection : R1 resection 5050* * (89.3%) : 6 (10.7%)(89.3%) : 6 (10.7%)**Re-excision (1), No residual disease (4)Re-excision (1), No residual disease (4)

Margin Status (mm)Margin Status (mm)PositivePositive < 1< 1 11 1 < 1 < << 5 5 5 < 5 < << 10 10 > 10> 10

6 (10.7%)6 (10.7%) 14 14 (25.0%)(25.0%)

10 10 (17.9%)(17.9%)

16 (28.6%)16 (28.6%) 4 (7.1%)4 (7.1%) 66†† (10.7%)(10.7%)

††No residual disease in 4 patients out of 6 (Unplanned excision (3), No residual disease in 4 patients out of 6 (Unplanned excision (3), Incision biopsy (1))Incision biopsy (1))

Wound ClosureWound ClosurePrimary : SecondaryPrimary : Secondary‡‡ 41 (73.2%) : 15 (26.8%)41 (73.2%) : 15 (26.8%)‡‡Secondary:Secondary: Flap (6, 10.7%), Flap + STSG (8, 14.3%), STSG (1, 1.8%)Flap (6, 10.7%), Flap + STSG (8, 14.3%), STSG (1, 1.8%)

Results (Treatment Responses)Results (Treatment Responses)

Pathologic StagePathologic Stage 1 : 2 : 3: 4 (8.9%) : 18 (32.1%) : 32 1 : 2 : 3: 4 (8.9%) : 18 (32.1%) : 32

(57.1%) : 1(57.1%) : 1**(1.8%)(1.8%)**Regional lymph node metastasis (+)Regional lymph node metastasis (+)

Pathologic Tumor Size 0 - 22.5 cm Pathologic Tumor Size 0 - 22.5 cm (median : 6.0)(median : 6.0)

Clinical ResponseClinical Response†† (47) (47) RECIST CriteriaRECIST Criteria

CRCR PRPR SDSD PDPD1 (2.1%)1 (2.1%) 6 (12.8%)6 (12.8%) 37 (78.7%)37 (78.7%) 33‡‡ (6.4%)(6.4%)

†† Excluding 9 patients received unplanned excisionExcluding 9 patients received unplanned excision‡‡ All showed marked necrosis (% necrosis: > 95, 90 & 80) on surgically All showed marked necrosis (% necrosis: > 95, 90 & 80) on surgically resected specimen.resected specimen.

Patients Underwent Unplanned Excision (9)Patients Underwent Unplanned Excision (9)

No residual disease : Residual diseaseNo residual disease : Residual disease§ § 3 : 6 (2-4 cm) 3 : 6 (2-4 cm) There was no treatment failure.There was no treatment failure.§§RM (+) 0RM (+) 0‡‡, < 1 mm (1), 1 mm (1), 1< , < 1 mm (1), 1 mm (1), 1< << 5 mm (3), 5< 5 mm (3), 5< <<10 mm (1)10 mm (1)

Survival & Local ControlSurvival & Local Control

Results Results (%)(%)

OSOS CSSCSS DFSDFS FFDMFFDM**

3 Yr 3 Yr 82.8 82.8 ++ 5.3 5.3 86.3 86.3 ++ 4.9 4.9 77.5 77.5 ++ 5.8 5.8 80.0 80.0 ++ 5.4 5.45 Yr5 Yr 82.8 82.8 ++ 5.3 5.3 86.3 86.3 ++ 4.9 4.9 77.5 77.5 ++ 5.8 5.8 80.0 80.0 ++ 5.4 5.4

RemaineRemainedd††

33 / 1233 / 12 33 / 1233 / 12 29 / 1129 / 11 30 / 1130 / 11

* * Freedom From Distant Metastasis : Actuarial, Freedom From Distant Metastasis : Actuarial, ††Number of remained Number of remained patients at 3/ 5 Yearpatients at 3/ 5 Year

93.2 93.2 %%

(31)(31)

93.2%93.2%(12)(12) 91.591.5

%%(31)(31)

88.5%88.5%(12)(12)

Local Recurrence as First Local Recurrence as First Failure (3) Failure (3)

Local Recurrence as Cumulative Local Recurrence as Cumulative Failure (5)Failure (5)

Patterns of FailurePatterns of Failure

Sequence of FailureSequence of FailureLF alone (1), LF + DM (1), LF – DM (1), DM – LF (2), DM LF alone (1), LF + DM (1), LF – DM (1), DM – LF (2), DM alone (7)alone (7)

Local Failure (LF) Initial (3) Local Failure (LF) Initial (3) Cumulative (5) Cumulative (5)Onset (months)Onset (months) 12 - 3512 - 35 12 - 3812 - 38InfieldInfield 11 33Infield & Extend to Infield & Extend to outfieldoutfield

22*,†*,† 22*,†*,†

**Small CTV due to anatomic site (1) : Foot, synovial sarcomaSmall CTV due to anatomic site (1) : Foot, synovial sarcoma††Unplanned incision with positive resection margin (1) : Leg, MFHUnplanned incision with positive resection margin (1) : Leg, MFH

Distant Metastases (DM) Initial (10) Distant Metastases (DM) Initial (10) Cumulative (11) Cumulative (11)Onset (months)Onset (months) 3 - 263 - 26 3 - 263 - 26

Lung (single : multiple)Lung (single : multiple) 10 (4 : 6)10 (4 : 6) 11 (1 : 10)11 (1 : 10)

BoneBone 22 33

LiverLiver 11 11

KidneyKidney 00 11

AdrenalAdrenal 00 11

Prognostic Factors (Univariate)Prognostic Factors (Univariate)

FactorsFactors OSOS CSSCSS DFSDFS LCRLCR FFDMFFDM

AgeAge 0.03870.0387 0.20200.2020 0.17860.1786 0.14270.1427 0.29160.2916pGradepGrade 0.1646 0.1646 0.91420.9142 0.93340.9334 0.0727 0.0727 0.64160.6416SiteSite 0.25490.2549 0.44030.4403 0.60470.6047 0.06550.0655 0.49790.4979cStagecStage 0.02210.0221 0.05670.0567 0.00930.0093 0.09320.0932 0.01420.0142cSizecSize 0.00060.0006 0.01560.0156 0.00650.0065 0.05500.0550 0.01220.0122pSizepSize 0.04560.0456

0.02970.0297**0.01090.0109 0.01300.0130 0.03080.0308

pStagepStage 0.02480.0248 0.11140.1114 0.00840.0084 0.22590.2259 0.01570.0157RM (neg/pos)RM (neg/pos) 0.94320.9432 0.83280.8328 0.12620.1262 < <

0.00010.00010.50810.5081

RM (<1/ RM (<1/ >>1 1 mm)mm)

0.75900.7590 0.70640.7064 0.07210.0721 0.00160.0016 0.15930.1593

ChemoChemo 0.40620.4062 0.28220.2822 0.08160.0816 0.86650.8665 0.04550.0455††

Postop. RTPostop. RT 0.42360.4236 0.63250.6325 0.29940.2994 0.00030.0003†† 0.06820.0682**pSize (pSize (<< 10 vs. >10 cm), 10 vs. >10 cm), † †Negative correlation (Poor results treated with Negative correlation (Poor results treated with chemotherapy or RT)chemotherapy or RT)Age (Age (<<50 vs. > 50), pGrade (1+2 vs. 3), Site (Proximal vs. Distal), cStage & pStage 50 vs. > 50), pGrade (1+2 vs. 3), Site (Proximal vs. Distal), cStage & pStage (1+2 vs. 3), (1+2 vs. 3), cSize (cSize (<< 5 cm vs. 5 < 5 cm vs. 5 < << 10 cm vs. 10 < 10 cm vs. 10 < << 15 cm vs. > 15 cm), pSize ( 15 cm vs. > 15 cm), pSize (<< 8 cm vs. > 8 8 cm vs. > 8 cm)cm)

Margin Status & Local FailuresMargin Status & Local Failures

SurgicSurgical al

No of No of ptspts

ResectionResection No of No of ptspts

No of pts with LRNo of pts with LR

ExtentExtent Margin Margin (RM)(RM)

InitialInitial CumulatiCumulativeve

R1R1 66 PositivePositive 66 33 33

R0R0 5050 < 1 mm< 1 mm 1414 00 22

1 mm1 mm 1010 00 00

> 1 mm> 1 mm 2626 00 00

p = < 0.0001p = < 0.0001

RM Positive vs. NegativeRM Positive vs. Negative

p = 0.0016p = 0.0016

RM < 1 mm vs. RM < 1 mm vs. >> 1 mm 1 mm RM RM << 1 mm vs. > 1 mm 1 mm vs. > 1 mm

p = 0.0364p = 0.0364

Prognostic Factors (MultivariatePrognostic Factors (Multivariate))

Variables

OS Age (p= 0.0360, HR 1.039), cSize (p=0.0056, HR 1.195)

DFS pStage (p=0.0040, HR 15.420)

LC RM (negative vs. positive, p=0.0029, HR 16.512)

FFDM pStage (p=0.013, HR 12.374)

ComplicationsComplications

Wound Complications (SR2 criteria) Wound Complications (SR2 criteria) No (%) No (%)

1717 (30.4(30.4))

Secondary operations for wound careSecondary operations for wound care** 1212 (70.6(70.6))

Readmission for wound care Readmission for wound care 00 (0)(0) Invasive procedures for wound management Invasive procedures for wound management 22 (11.8(11.8

)) Deep wound packing to the wound Deep wound packing to the wound >> 2 cm at 2 cm at any time any time

00 (0)(0)

Prolonged dressing changes Prolonged dressing changes 33 (17.6(17.6))

**Debridement (5), Operative drainage (2), Secondary wound closure (5)Debridement (5), Operative drainage (2), Secondary wound closure (5)

Factors Related to Wound ComplicationsFactors Related to Wound ComplicationsVolume of resected specimen (p=0.0216), CTV (p= 0.0433), Volume of resected specimen (p=0.0216), CTV (p= 0.0433), DM (p= 0.0490), DM (p= 0.0490), ? Unplanned excision (p= 0.0926)? Unplanned excision (p= 0.0926)

Chronic Complications Chronic Complications No (%) No (%)

Fracture Fracture 33†† (5.4)(5.4)

††Femur(2), ulnar (1): Prior periosteal peeling (2) or bone resection (1)Femur(2), ulnar (1): Prior periosteal peeling (2) or bone resection (1)

There was no chronic complication requiring amputation There was no chronic complication requiring amputation for management or causing significant functional loss.for management or causing significant functional loss.

ConclusionsConclusions

1. These margin definitions1. These margin definitions (CTV: radial 1-1.5 cm & longitudinal 3.5 cm, PTV: CTV + (CTV: radial 1-1.5 cm & longitudinal 3.5 cm, PTV: CTV + 0.5-0.8 cm)0.5-0.8 cm)

appear appropriate for the majority of appear appropriate for the majority of patients.patients.

2. Patients with positive margin are at highest 2. Patients with positive margin are at highest risk for LF &risk for LF & maymay be treated more aggressively.be treated more aggressively.

3. Wound complication rate was comparable to 3. Wound complication rate was comparable to other studies.other studies.

4. Wound complications were significantly 4. Wound complications were significantly related to the related to the Vol. of resected specimen, CTV, and presence Vol. of resected specimen, CTV, and presence of diabetes.of diabetes.

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Acute Skin ToxicityAcute Skin Toxicity

Grade Grade RTOG Definition RTOG Definition No (%) No (%)

00 No change over baselineNo change over baseline 44 (7.1)(7.1)

11 Follicular, faint or dull erythema, Follicular, faint or dull erythema, epilation, dry desquamation, epilation, dry desquamation, decreased sweatingdecreased sweating

3939 (69.(69.6)6)

22 Tender or bright erythema, Tender or bright erythema, patchy moist desquamation, patchy moist desquamation, moderate erythemamoderate erythema

1212 (21.(21.4)4)

33 Confluent moist desquamation other Confluent moist desquamation other than skin folds, pitting edemathan skin folds, pitting edema

00 (0)(0)

44 Ulceration, hemorrhage, necrosisUlceration, hemorrhage, necrosis** 11 (1.8)(1.8)**P/E prior to XRT, skin involvement (+), MFH, Gr 3/3, 75% necrosis after P/E prior to XRT, skin involvement (+), MFH, Gr 3/3, 75% necrosis after preoperative RT preoperative RT RTRT

Infield FailureInfield Failure

All infield failures were located in GTV or CTV. All infield failures were located in GTV or CTV.