Preoperative Radiotherapy In Extremity Soft Tissue Sarcoma

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

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

Target Volume of Preoperative RT Institution Longitudinal Margin Radial Margin RT Schedule Preoperative Chemotherapy RTOG 9514 (2006) 9 cm > 2 cm 44 Gy/ 22 fx, Split MAID MGH (2003) 6-9 cm > 2 cm 44 Gy/ 22 fx, Split MAID 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 Entire tumor region 35 Gy/ 10 fx IA Doxorubicin

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

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) 0 1 2 3 4 11 (19.6%) 43 (76.8%) 1 (1.8%) 1 (1.8%) 0 (0%) Tumor Sites Upper extremity : Lower extremity 13 (23.2%) : 43 (76.8%)

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) Liposarcoma 13 (23.2) Synovial sarcoma 7 (12.5) Fibrosarcoma 5 (8.9) Malignant Peripheral Nerve Sheath Tumor (MPNST) 3 (5.4) Myxofibrosarcoma 3 (5.4) Leiomyosarcoma 2 (3.6) Others 4 (7.1)

Materials and Methods Location Superficial : Deep 8 (14.3%) : 48 (85.7%) Pathologic Grade (3-Tier system) 1 : 2 : 3 5 (8.9%) : 27 (48.2%) : 24 (42.9%) Initial Clinical Tumor size : 1.8-22 cm (median 8, mean 8.9 + 0.68) <4 4-5 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%)

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

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

Treatment Period between Preop. RT & Surgery 19-77 days (median: 34) Surgical Extent Limb-preserving surgery : Amputation 56 : 0 R0 resection : R1 resection 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%)

Results (Treatment Responses) Pathologic Stage 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 CR PR SD PD 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)

Survival & Local Control 93.2 % (31) 93.2% (12) 91.5% (31) 88.5% (12) Local Recurrence as First Failure (3) Local Recurrence as Cumulative Failure (5) Results (%) OS CSS DFS 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 33 / 12 29 / 11 30 / 11 * Freedom From Distant Metastasis : Actuarial, † Number of remained patients at 3/ 5 Year

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 Infield 1 3 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) Bone 2 3 Liver 1 1 Kidney 0 1 Adrenal 0 1

Prognostic Factors (Univariate) Factors OS CSS DFS LCR FFDM Age 0.0387 0.2020 0.1786 0.1427 0.2916 pGrade 0.1646 0.9142 0.9334 0.0727 0.6416 Site 0.2549 0.4403 0.6047 0.0655 0.4979 cStage 0.0221 0.0567 0.0093 0.0932 0.0142 cSize 0.0006 0.0156 0.0065 0.0550 0.0122 pSize 0.0456 0.0297 * 0.0109 0.0130 0.0308 pStage 0.0248 0.1114 0.0084 0.2259 0.0157 RM (neg/pos) 0.9432 0.8328 0.1262 < 0.0001 0.5081 RM (<1/ > 1 mm) 0.7590 0.7064 0.0721 0.0016 0.1593 Chemo 0.4062 0.2822 0.0816 0.8665 0.0455 † Postop. RT 0.4236 0.6325 0.2994 0.0003 † 0.0682 * pSize ( < 10 vs. >10 cm), † Negative correlation (Poor results treated with chemotherapy or RT) Age ( < 50 vs. > 50), pGrade (1+2 vs. 3), Site (Proximal vs. Distal), cStage & pStage (1+2 vs. 3), cSize ( < 5 cm vs. 5 < < 10 cm vs. 10 < < 15 cm vs. > 15 cm), pSize ( < 8 cm vs. > 8 cm)

Margin Status & Local Failures p = < 0.0001 RM Positive vs. Negative p = 0.0016 RM < 1 mm vs. > 1 mm RM < 1 mm vs. > 1 mm p = 0.0364 Surgical No of pts Resection No of pts No of pts with LR Extent Margin (RM) Initial Cumulative R1 6 Positive 6 3 3 R0 50 < 1 mm 14 0 2 1 mm 10 0 0 > 1 mm 26 0 0

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)

Complications Wound Complications (SR2 criteria) No (%) 17 (30.4) Secondary operations for wound care * 12 (70.6) Readmission for wound care 0 (0) Invasive procedures for wound management 2 (11.8) Deep wound packing to the wound > 2 cm at any time 0 (0) Prolonged dressing changes 3 (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 † (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.

Conclusions 1. These margin definitions (CTV: radial 1-1.5 cm & longitudinal 3.5 cm, PTV: CTV + 0.5-0.8 cm) appear appropriate for the majority of patients. 2. Patients with positive margin are at highest risk for LF & 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.

Thank you for your attention!

Acute Skin Toxicity RT 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

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

Preoperative Radiotherapy In Extremity Soft Tissue Sarcoma

by fondas vak on Mar 20, 2010

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