Preoperative Radiotherapy In Extremity Soft Tissue Sarcoma
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Preoperative Radiotherapy In Extremity Soft Tissue Sarcoma
- 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
- 3. 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
- 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) 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%)
- 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) 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)
- 7. 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%)
- 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%) 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
- 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 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%)
- 11. 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)
- 12. 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
- 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 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
- 14. 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)
- 15. 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
- 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 * 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.
- 18. 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.
- 19. Thank you for your attention!
- 20. 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
- 21. Infield Failure All infield failures were located in GTV or CTV.
Notas do Editor
- Radiation is widely used in extremity STS, pre or postoperatively. It has some potential advantages including increasing R0 resection and possible limb preservation. But it also has disadvantage of wound complications. Irradiated volume is considered one of the important factor affecting wound complications and late morbidities. So more efforts should be needed to reduce the irradiated volume.
- There is no consensus on the preoperative treatment volume for extremity soft tissue sarcoma. In several studies, the reported treatment volumes are very heterogeneous. Radial margins range from 2 cm to the entire compartment. And longitudinal margins are from 5 to 10 cm.
- To elucidate optimal radiation field, we retrospectively analyzed the pattern of local failures in the patients treated with preoperative RT using CT simulation. We also evaluate other results and prognostic factors.
- From July 2000 to Dec 2006, 56 patients treated at Mass General Hospital were included. Median FU was 41 months for all patients and 46 months for alive patients. Median age was 50.6 years old. 76.8% were lower extremities and thigh was the most common site in 31 patients.
- For pathologic confirmation, core needle biopsy was the most common used in 40 patients. Malignant Fibrous Histiocytoma was the most common histological subtype in 1/3 of the patients followed by liposarcoma and synovial sarcoma.
- 52 patients had high grade tumor and median clinical tumor size was 8 cm. Clinical stage was one in 4 patients, two in 14 and three in 38 patients.
- 21 patients received chemotherapy and MAID was the most commonly used regimen. Preoperatively, median 50 Gy was delivered using median 2 Gy fraction size. Postoperative boost was given to the patients with positive or multiple close resection margins. 12 patients received median 15 Gy tumor bed boost.
- Gross tumor volume was defined as the T1 contrast enhancing area on MRI. Clinical target volume was enlarged from GTV with 1-1.5 cm radial and 3.5 cm longitudinal margins. No less than 95% of the prescribed dose was delivered to PTV.
- Surgery was delivered at median 34 days after preoperative RT. All patients received limb preserving surgery and 50 patients received R0 resection. But only 6 patients, including 4 with no residual disease, had resection margins larger than 1 cm. 41 patients received primary wound closure.
- Clinical responses were evaluable in 47 patients. SD was most common in 37 patients and three patients showed disease progression on restaging MRI. But all showed marked necrosis (80, 90 and more than 95%) on surgical specimen. 9 patients received unplanned excision. 6 patients had residual disease ranged from 2 – 4 cm. There was no treatment failure in these patients.
- 5 Year overall survival was 82.8%. Disease free survival was 77.5% and freedom free distant metastasis was 80.0% at 5 years. If only considering first failure, actuarial local control rate was 93.2% at 5 years. Including 2 patients who had distant metastasis first, and then developed local failure later, actuarial local control rate was 88.5% at 5 years.
- As previously stated, three patients developed initial local failure and 2 patients developed late local failures. Only 1 patient had isolated local failure at last follow-up. All the local recurrences developed within the irradiated volume. But for 2 patients, local failures also extended to outside of the irradiated volume. For those two, 1 patient was treated with small CTV due to anatomic location of foot . The other, received unplanned incisional biopsy. had positive margin during operation. But further resection was not done for limb preservation. Distant metastases occurred in a total of 11 patients at median of 12 months. Lung was the most common site of metastasis.
- On univariate analyses, clinical stage and size, pathologic stage and size were significant prognostic factors on overall survival, disease free survival and freedom free distant metastasis. For local control, pathologic size and margin status were significant .
- All 3 initial local failures occurred in the patients with positive margin . 2 late local failures occurred in the patients with less than 1 mm resection margin. Margin status is a significant predictor for local control using three different commonly used definitions: positive or negative, less than 1 mm or less than and equal to 1 mm.
- On multivariate analysis, resection margin defined as positive or negative was the only definition that showed significant association with local control. For overall survival, age and clinical size were significant. Pathologic stage was the only significant factor on disease free survival and freedom free distant metastasis
- Major wound complications occurred in 17 patients. Twelve patients needed secondary operation for wound care. The volume of resected specimen, Clinical target volume and Diabetes were related to wound complications. For chronic complications, bone fractures occurred in 3 patients within irradiated area. But they also received periosteal peeling or bone resection. There was no complication requiring amputation or significant functional loss.
- In conclusion, for 3D treatment planning for extremity soft tissue sarcoma in the neo-adjuvant setting, theses margin definitions appear appropriate for the majority of patients. Patients with positive margin are considered at high risk for local failure. So more aggressive treatment may be needed. Wound complication rate was comparable to other studies and related to the volume of resected specimen, clinical target volume and presence of diabetes.
- Thank you very much!
- Acute skin reaction occurred in 52 patients. Most of skin toxicities were RTOG grade one or two. One patient showed grade 4 skin necrosis, but he also had skin involvement before preoperative RT on physical exam and MRI.
- All Local failures occurred usually occurred within GTV or CTV.