1. Adequate 3D Treatment Volume in Preoperative Radiotherapy in Extremity Soft Tissue Sarcoma Kim BK, Chen YL, Kirsch DG, Kobayashi W, Goldberg S, Wolfgang J, Kung JH, Doppke K, Raskin KA, Springfield DS, Schwab JH, Yoon SS, Hornicek FJ, Nielson GP, DeLaney TF Department of Radiation Oncology, Orthopedic Oncology, Surgical Oncology, Pathology, Massachusetts General Hospital, Boston, MA, USA

2. Background Radiotherapy in Extremity Soft Tissue Sarcoma (STS ) Preoperative Preoperative Postoperative Postoperative Potential Advantages of Preoperative RT More precise definition of tumor – accurate/small field More precise definition of tumor – accurate/small field Increase R0 resection/ possible limb preservation Increase R0 resection/ possible limb preservation Decrease the risk of tumor seeding Decrease the risk of tumor seedingComplications Increased wound complications vs. Increased wound complications vs. Decreased late morbidities Decreased late morbidities Adequate 3D Treatment Volume for Preoperative RT?

3. Target Volume of Preoperative RT Target Volume of Preoperative RT InstitutionLongitudinalMarginRadialMargin RT Schedule PreoperativeChemotherapy RTOG 9514 (2006) 9 cm > 2 cm 44 Gy/ 22 fx, SplitMAID MGH(2003) 6-9 cm > 2 cm 44 Gy/ 22 fx, SplitMAID SR2 NCI Canada (2002) 5 cm ? > 2 cm 50 Gy/ 25 fx MDACC(2004) 5-7 cm < 1/3 of circumference 50 Gy/ 25 fx CCRT with Doxorubicin MSKCC(2007) 5 cm 2 cm 50 Gy/ 25 fx, IMRT Peter MacCallum (2006) 6 cm (PTV) - 50.4 Gy/ 28 fx - Univ. of Florida (2002) 5-10 cm (av. 10) Involved compartment 50.4 Gy/ 42 fx, 1.2 bid Groningen Univ. (1999) Entire tumor region 35 Gy/ 10 fx IA Doxorubicin

4. Objectives Retrospective Study Analyze the pattern of local failure (LF). Patients with extremity STS Patients with extremity STS Curative preoperative irradiation (XRT) Curative preoperative irradiation (XRT) Treated with 3D XRT using CT simulation Treated with 3D XRT using CT simulation Elucidate optimal 3D radiation field design. Evaluate other results and prognostic factors.

5. Materials and Methods Accrual July 2000 – Dec 2006 (56 patients) Period of FU 15 - 76 months (median 41: alive 46, dead 20.5) Sex (M: FM) 37 (66.1%) : 19 (33.9%) Age 18 - 89 years (median: 50.6) Exclusion Criteria Age < 18 years, Recurrent disease, Initially diagnosed M1, Desmoid tumor, Dermatofibrosarcoma protuberance, Ewing’s sarcoma, Rhadomyosarcoma Performance (ECOG) 01234 11 (19.6%) 43 (76.8%) 1 (1.8%) 0 (0%) Tumor Sites Upper extremity : Lower extremity 13 (23.2%) : 43 (76.8%)

6. Materials and Methods Biopsy No (%) Core needle biopsy 40(71.4) Incision biopsy (planned : unplanned) 7 (3 : 4) (12.5) Unplanned excision 9(16.1) Histology No (%) Malignant Fibrous Histiocytoma (MFH) 19(33.9) Liposarcoma13(23.2) Synovial sarcoma 7(12.5) Fibrosarcoma5(8.9) Malignant Peripheral Nerve Sheath Tumor (MPNST) 3(5.4) Myxofibrosarcoma3(5.4) Leiomyosarcoma2(3.6) Others4(7.1)

7. Materials and Methods Location Superficial : Deep 8 (14.3%) : 48 (85.7%) Pathologic Grade (3-Tier system) 1 : 2 : 3 1 : 2 : 3 5 (8.9%) : 27 (48.2%) : 24 (42.9%) 5 (8.9%) : 27 (48.2%) : 24 (42.9%) Initial Clinical Tumor size : 1.8-22 cm (median 8, mean 8.9 + 0.68) <44-5 5< < 10 10< <15 15< <20 * > 20 7 (12.5%) 9 (16.1%) 24 (42.9%) 10 (17.9%) 5 (7.1%) 1 (3.6%) * 20 cm (3), 19 cm (1) Initial Clinical Stage (2002 AJCC Staging System) 1 : 2 : 3 4 (7.1%) : 14 (25.0%) : 38 (67.9%) 4 (7.1%) : 14 (25.0%) : 38 (67.9%)

8. Treatment Chemotherapy 21 (37.5%) *,† MAID#6 *, † MAID#3+HDMTX#3 * Avastin † Postop. MAID#6 17 (30.4%) 2 (3.6%) 1 (1.8%) * Pre & Postoperative, † MAID : Mesna, Adriamycin, Ifosfamide, Dacarbazine Radiotherapy Total Dose 44-70 Gy (median : 50) 44-70 Gy (median : 50) Preoperative Radiotherapy 44-50.4 Gy ‡ (median : 50) 44-50.4 Gy ‡ (median : 50) Duration Duration 31-48 days (median : 36) 3D-CRT : 3D-CRT+ Proton : IMRT : Proton 3D-CRT : 3D-CRT+ Proton : IMRT : Proton 46 : 3: 6 : 1 ‡ Median Fraction size 2.0 Gy Postoperative RT § 12 (21.4%), 10-20 Gy (median : 15) 12 (21.4%), 10-20 Gy (median : 15) EBRTIORT HDR Brachytherapy 7 (3D-CRT (5), IMRT (2)) 32 § Postoperative boost RT was given to the patients with (+) or multiple close RM

9. Radiotherapy (Preoperative RT Volume) GTV Gross Tumor Volume (GTV) : T1 Gd CE (+) area on MRI Clinical Target Volume (CTV) : GTV + 1-1.5 cm radial margin : GTV + 3.5 cm proximal/distal margin Planning Target Volume (PTV) : CTV + 0.5- 0.8 cm margin Dose Prescription : PTV covered by > 95 % isodoseline

10. Treatment Period between Preop. RT & Surgery 19-77 days (median: 34) Surgical Extent Limb-preserving surgery : Amputation 56 : 0 56 : 0 R0 resection : R1 resection 50 * (89.3%) : 6 (10.7%) 50 * (89.3%) : 6 (10.7%) * Re-excision (1), No residual disease (4) Margin Status (mm) Positive < 1 1 1 < < 5 5 < < 10 > 10 6 (10.7%) 14 (25.0%) 10 (17.9%) 16 (28.6%) 4 (7.1%) 6 † (10.7%) † No residual disease in 4 patients out of 6 (Unplanned excision (3), Incision biopsy (1)) Wound Closure Primary : Secondary ‡ 41 (73.2%) : 15 (26.8%) ‡ Secondary: Flap (6, 10.7%), Flap + STSG (8, 14.3%), STSG (1, 1.8%)

11. Results (Treatment Responses) Pathologic Stage 1 : 2 : 3: 4 (8.9%) : 18 (32.1%) : 32 (57.1%) : 1 * (1.8%) 1 : 2 : 3: 4 (8.9%) : 18 (32.1%) : 32 (57.1%) : 1 * (1.8%) * Regional lymph node metastasis (+) Pathologic Tumor Size 0 - 22.5 cm (median : 6.0) Clinical Response † (47) RECIST Criteria CRPRSDPD 1 (2.1%) 6 (12.8%) 37 (78.7%) 3 ‡ (6.4%) † Excluding 9 patients received unplanned excision ‡ All showed marked necrosis (% necrosis: > 95, 90 & 80) on surgically resected specimen. Patients Underwent Unplanned Excision (9) No residual disease : Residual disease § 3 : 6 (2-4 cm) There was no treatment failure. § RM (+) 0 ‡, < 1 mm (1), 1 mm (1), 1< < 5 mm (3), 5< <10 mm (1)

12. Survival & Local Control Results (%) OSCSSDFS FFDM * 3 Yr 82.8 + 5.3 86.3 + 4.9 77.5 + 5.8 80.0 + 5.4 5 Yr 82.8 + 5.3 86.3 + 4.9 77.5 + 5.8 80.0 + 5.4 Remained † 33 / 12 29 / 11 30 / 11 * Freedom From Distant Metastasis : Actuarial, † Number of remained patients at 3/ 5 Year 93.2 % (31) 93.2%(12) 91.5%(31)88.5%(12) Local Recurrence as First Failure (3) Local Recurrence as Cumulative Failure (5)

13. Patterns of Failure Sequence of Failure LF alone (1), LF + DM (1), LF – DM (1), DM – LF (2), DM alone (7) Local Failure (LF) Initial (3) Cumulative (5) Onset (months) 12 - 35 12 - 38 Infield13 Infield & Extend to outfield 2 *,† 2 *,† * Small CTV due to anatomic site (1) : Foot, synovial sarcoma † Unplanned incision with positive resection margin (1) : Leg, MFH Distant Metastases (DM) Initial (10) Cumulative (11) Onset (months) 3 - 26 3 - 26 Lung (single : multiple) 10 (4 : 6) 11 (1 : 10) 11 (1 : 10) Bone23 Liver11 Kidney01 Adrenal01

14. Prognostic Factors (Univariate) FactorsOSCSSDFSLCRFFDM Age0.03870.20200.17860.14270.2916 pGrade0.16460.91420.93340.07270.6416 Site0.25490.44030.60470.06550.4979 cStage0.02210.05670.00930.09320.0142 cSize0.00060.01560.00650.05500.0122 pSize0.0456 0.0297 * 0.0297 *0.01090.01300.0308 pStage0.02480.11140.00840.22590.0157 RM (neg/pos) 0.94320.83280.1262 < 0.0001 0.5081 RM ( 1 mm) 0.75900.70640.07210.00160.1593 Chemo0.40620.28220.08160.8665 0.0455 † 0.0455 † Postop. RT 0.42360.63250.2994 0.0003 † 0.0003 †0.0682 * pSize ( 10 cm), † Negative correlation (Poor results treated with chemotherapy or RT) Age ( 50), pGrade (1+2 vs. 3), Site (Proximal vs. Distal), cStage & pStage (1+2 vs. 3), cSize ( 15 cm), pSize ( 8 cm)

15. Margin Status & Local Failures Surgical No of pts Resection No of pts with LR Extent Margin (RM) InitialCumulative R16Positive633 R050 < 1 mm 1402 1 mm 1000 > 1 mm 2600 p = < 0.0001 RM Positive vs. Negative p = 0.0016 RM 1 mm p = 0.0364

16. Prognostic 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)

17. Complications Wound Complications (SR2 criteria) No (%) 17(30.4) Secondary operations for wound care * Secondary operations for wound care *12(70.6) Readmission for wound care Readmission for wound care0(0) Invasive procedures for wound management Invasive procedures for wound management2(11.8) Deep wound packing to the wound > 2 cm at any time Deep wound packing to the wound > 2 cm at any time0(0) Prolonged dressing changes Prolonged dressing changes3(17.6) * Debridement (5), Operative drainage (2), Secondary wound closure (5) Factors Related to Wound Complications Volume of resected specimen (p=0.0216), CTV (p= 0.0433), DM (p= 0.0490), ? Unplanned excision (p= 0.0926) Chronic Complications No (%) Fracture 3† 3† 3† 3† (5.4) (5.4) † Femur(2), ulnar (1): Prior periosteal peeling (2) or bone resection (1) There was no chronic complication requiring amputation for management or causing significant functional loss.

18. Conclusions 1. These margin definitions (CTV: radial 1-1.5 cm & longitudinal 3.5 cm, PTV: CTV + 0.5-0.8 cm) (CTV: radial 1-1.5 cm & longitudinal 3.5 cm, PTV: CTV + 0.5-0.8 cm) appear appropriate for the majority of patients. appear appropriate for the majority of patients. 2. Patients with positive margin are at highest risk for LF & may be treated more aggressively. may be treated more aggressively. 3. Wound complication rate was comparable to other studies. 4. Wound complications were significantly related to the Vol. of resected specimen, CTV, and presence of diabetes. Vol. of resected specimen, CTV, and presence of diabetes.

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20. Acute Skin Toxicity Grade RTOG Definition No (%) 0 No change over baseline 4(7.1) 1 Follicular, faint or dull erythema, epilation, dry desquamation, decreased sweating 39(69.6) 2 Tender or bright erythema, patchy moist desquamation, moderate erythema 12(21.4) 3 Confluent moist desquamation other than skin folds, pitting edema 0(0) 4 Ulceration, hemorrhage, necrosis * 1(1.8) * P/E prior to XRT, skin involvement (+), MFH, Gr 3/3, 75% necrosis after preoperative RT RT

21. Infield Failure All infield failures were located in GTV or CTV.