A – Documentation of exact extent of primary tumor

Clinical examination, X-ray, MRI (MRI has become the premier imaging modality for the evaluation of musculoskeletal tumors because of its excellent soft tissue contrast, its sensitivity to bone marrow and soft tissue edema, and its multiple imaging planes).

B – Pathological confirmation of diagnosis by biopsy

A needle biopsy can often confirm the diagnosis. If tissue is inadequate or diagnosis uncertain an open biopsy is indicated. The closed needle biopsy technique has proven to be an extremely effective means of procuring representative tissue, is associated with low morbidity, and avoids many of the potential complications of biopsy. If limb-sparing surgery is contemplated, the biopsy should be performed by the surgeon who will do the definitive operation, since incision placement is crucial.

C- Classification , Staging and biochemical investigations

CT chest, Bone scan, S. Alkaline phosphatase, S. LDH

The World Health Organization’s histologic classification of bone tumors separates the osteosarcomas into central (medullary) and surface (peripheral) tumors and recognizes a number of subtypes within each group.

Central (Medullary)

- Conventional central osteosarcoma.
- Telangiectatic osteosarcoma.
- Intraosseous well-differentiated (low-grade) osteosarcoma.
- Small cell osteosarcoma.

Surface (Peripheral)
- Parosteal (juxtacortical) well-differentiated (low-grade) osteosarcoma.
- Periosteal osteosarcoma: low-grade to intermediate-grade osteosarcoma.
- High-grade surface osteosarcoma

D – Chemotherapy

Chemotherapy constitutes a fundamental initial approach to the management of osteosarcoma and, if effective, an important prognostic determinant. (Level II, Grade A)

Neoadjuvant chemotherapy in OGS is the norm and seems to offer following advantages:

- enhancement of limb sparing surgery
- provision of a window time during which customized endoprosthetic devices could be made
- delivery of early systemic treatment against micro-metastasis
- tailoring of the postoperative chemotherapy based on the primary tumor response.

With the possible exception of the first two, these advantages are no longer true. There is no significant difference in disease free survival with neoadjuvant chemotherapy in comparison with standard adjuvant chemotherapy. (Level II,Grade A)

Chemotherapy is multiagent and drugs used include : Adriamycin (as a continuous infusion), Ifosfamide, Etoposide, Cisplatinum and Methotrexate, Non methotrexate based regimes offer similar survivals to methotrexate based regimes in operable, non-metastatic osteosarcoma. (level II,
Grade B)

The strategy of salvaging poor responders with alternative agents has not been proven to be beneficial. (Level III, Grade B)

Chemotherapy for certain histologic subtypes

Round cell osteosarcoma
Round cell osteosarcoma is a definite reproducible histologic entity. Treatment should be based on a protocol for osteosarcoma. It seems reasonable to treat tumors with spindling small cells on a protocol for OGS. When matrix production is definite, these tumors should also be treated on a protocol for OGS. If the tumor cells are small, round and uniform and matrix production is questionable, it probably is best to treat it as Ewing’s sarcoma.

DOES LIMB SALVAGE COMPROMISE SURVIVAL ?
HOW IMPORTANT IS ADEQUATE LOCAL CONTROL ?
PROGNOSTIC SIGNIFICANCE OF HISTOPATHOLOGIC RESPONSE FOR LOCAL CONTROL AND OVERALL SURVIVAL

Surgical outcomes in osteosarcoma.
Grimer RJ, Taminiau AM, Cannon SR et al.
J Bone Joint Surg Br. 2002 Apr;84(3):395-400.

Abstract : From the European Osteosarcoma Intergroup study 202 patients were assessed with respect to their surgical treatment. Although treated in three different centres the survival of the three groups was identical (57% at five years). Two of the centres had rates of limb salvage of 85% and 83%, respectively, while the third had a rate of 49%. The corresponding risks of local recurrence were 13.3%, 6.8% and 2.5%, with all local recurrences arising in limbs with attempted limb salvage. Local recurrence was closely related to the adequacy of the margins of excision and to the chemotherapeutic response. Patients who had undergone limb-salvage surgery and who developed local recurrence still had a better survival than those who had primary amputation (37% v 31% survival at five years). Of patients who relapsed, 31% of those with local recurrence alone were cured by further treatment, as compared with only 10% of those with metastases. Limb-salvage surgery with effective chemotherapy remains the optimum treatment for osteosarcoma.

Risk factors for local recurrences after limb-salvage surgery for high-grade osteosarcoma of the extremities.
Picci P, Sangiorgi L, Bahamonde L et al.
Ann Oncol. 1997 Sep;8(9):899-903.

BACKGROUND : Improvements in preoperative staging as well as in chemotherapeutic regimens have made limb-salvage surgery a reliable modality of treatment for high-grade osteosarcomas of the extremities, with local recurrences in most series of less than 10% after this type of surgery. The quality of surgical margins and local response to preoperative chemotherapy are known to be the most significant factors in recurrence [1, 8-10, 12], and complications related to the biopsy procedure may also be a significant factor. The study reported here comprised a histopathological analysis of our recurrent cases as part of an effort to identify the impact of each of the factors cited above. MATERIALS AND METHODS : Five hundred fourteen cases of high-grade, non-multicentric osteosarcoma of the extremities were treated at the Istituto Ortopedico Rizzoli between March 1983 and August 1991. In this study we analyzed 23 cases of local recurrence in patients with classic osteosarcoma who underwent limb-salvage procedures. RESULTS : In 15 cases we found correlation between the site of local recurrence and the site where the margins were less than wide. In five cases the recurrence was secondary to complications of the biopsy procedure (hematoma, delayed healing). In one case we suspect a previously undetected skip lesion. In the remaining two cases no clear explanation was found for the recurrence. There was also a statistically significant difference in the time of appearance of recurrences related to the tumor response to chemotherapy. CONCLUSIONS : For only two cases of recurrence was there no clear explanation. In one we suspect an undetected skip metastasis, and in the other there were certain factors which may have increased its risk of recurrence (non diagnostic trochar biopsy followed by an incisional biopsy, fair tumor necrosis, recurrence in a ‘problem’ anatomical site, i.e., the popliteal space). In the remaining cases the following factors were found to be directly related to the development of a local recurrence: a) the quality of the surgical margins, b) site of the biopsy as well as complications related to the biopsy procedure, c) local response to preoperative chemotherapy.

Pulmonary metastases of stage IIB extremity osteosarcoma and subsequent pulmonary metastases.
Ward WG, Mikaelian K, Dorey F et al.
Journal of Clinical Oncology 12(9): 1849-1858,1994.

Purpose : This study investigated prognostic factors in nonmetastatic high-grade extremity osteosarcoma and the prognosis following resection of subsequent pulmonary metastases, with emphasis on the effect of chemotherapy-induced tumor necrosis. Patients and Methods : We reviewed 111 consecutive patients with high-grade nonmetastatic extremity osteosarcoma treated with preoperative chemotherapy and surgical resection, with additional review of 36 patients who had subsequent pulmonary metastases resected. Results : The overall 5-year survival rate was 53%. In resected primary tumors, tumor-free resection margin (P<.001) and increasing chemotherapy-induced tumor necrosis (> 90% threshold, P<.003) correlated with increased metastasis-free survival. Relative risk factors for metastases were as follows : tumor-containing resection margin (most likely to metastasize); poor response to preoperative chemotherapy and/or lack of postoperative chemotherapy (next worse prognosis); and excellent response to preoperative chemotherapy (>or=90% necrosis) combined with postoperative chemotherapy (best prognosis). The 5-year survival rate following pulmonary metastasis resection was 23%, whereas a 0% 4-year survival rate followed development of bony metastases (P<.001). The extent of tumor necrosis in resected pulmonary metastases did not affect prognosis. Survival was best in patients with three or fewer pulmonary nodules (P<.048), four or fewer recurrent pulmonary nodules (P<.047), unilateral pulmonary metastases (P<.037), or longer intervals between primary tumor resection and metastases (P<.082). Conclusion : Intensive preoperative and postoperative chemotherapy combined with complete resection of both primary and metastatic pulmonary osteosarcomas is justified, with a goal of 100% tumor necrosis and excision. Although current treatment regimens allow effective salvage therapy for a few patients with pulmonary metastases, more effective systemic treatment is needed.

The effect of local recurrence on survival in resected osteosarcoma.
Weeden S, Grimer RJ, Cannon SR et al.
European Journal of Cancer 37(1): 39-46, 2001.

Abstract : The aim of this study was to assess the effect of local recurrence on survival in primary osteosarcoma. 559 patients entered into two randomised trials of the European Osteosarcoma Intergroup who received surgery for primary operable high-grade osteosarcoma of the extremities were included in this analysis. Proportional hazards modelling techniques were used to assess the relative importance of sex, age, site, surgery performed and local recurrence. The last of these was considered as a time-dependent covariate. 42/559 (8%) patients had a local recurrence. In the multivariate analysis, local recurrence was found to greatly increase the risk of death (hazard ratio (HR)=5.10, 95% confidence interval (CI) 3.51-7.41). Site and surgery performed also had a significant influence within this model. Using the technique of landmark analysis, with thelandmark time set at 18 months, local recurrence alone had a significant influence on survival (HR=4.60, 95% CI 2.80-7.57). Local recurrence is an indicator of poorer survival for patients with operable primary osteosarcoma.

Osteosarcoma of the limb. Amputation or limb salvage in patients treated by neoadjuvant chemotherapy.
Bacci G, Ferrari S, Lari S et al.
J Bone Joint Surg Br. 2002 Jan;84(1):88-92.

Abstract : We have studied 560 patients with osteosarcoma of a limb, who had been treated by neoadjuvant chemotherapy, in order to analyse the incidence of systemic and local recurrence according to the type of surgery undertaken. Of these, 465patients had a limb-salvage procedure and 95 amputation or rotationplasty. At a median follow-up of 10.5 years there had been 225 recurrences. The five-year disease-free survival and overall survival rates were 60.5% and 68.5%, respectively, with no significant difference between patients undergoing amputation and patients undergoing resection. The incidence of local recurrence was the same for patients treated by either amputation or limb salvage and correlated significantly with the margins of surgical excision and the histological response to chemotherapy. The outcome for patients with local recurrence was significantly worse than those who had recurrent disease with metastases only.We conclude that limb-salvage procedures are relatively safe in osteosarcoma treated with neo-adjuvant chemotherapy. They should, however only be performed in institutions where the margins of surgical excision and the histological response to chemotherapy can be accurately assessed. If the margins are inadequate and the histological response to chemotherapy is poor an immediate amputation should be considered.

PATHOLOGIC FRACTURE IN OSTEOSARCOMA - LIMB SALVAGE IS POSSIBLE

Pathologic fracture in osteosarcoma : prognostic importance and treatment implications.
Scully SP, Ghert MA, Zurakowski D et al.
J Bone Joint Surg Am.2002,Jan.;84-A(1):49-57

BACKGROUND : The presence of a pathologic fracture in an osteosarcoma has been considered a poor prognostic factor and an indication for immediate amputation. The purpose of the present study was to determine, in the current era of neoadjuvant chemotherapy, whether a pathologic fracture in an osteosarcoma has prognostic importance and whether limb salvage can be safely performed in such patients without compromising clinical outcome. METHODS : In a cooperative effort of the Musculoskeletal Tumor Society, members from eight institutions provided retrospective data on fifty-two patients with osteosarcoma who had a pathologic fracture and on fifty-five patients with osteosarcoma who had not had a pathologic fracture and had been followed for at least two years or until disease recurrence, metastasis, or death. The two groups were matched for patient age and tumor location. Outcomes examined were survival and local recurrence. A subgroup analysis was performed to assess differences in outcome within the group with the pathologic fracture. RESULTS : The five-year estimated survival rates were 55% for the group with a pathologic fracture and 77% for the group without a fracture (p=0.02). The rate of survival without a local recurrence at five years was 75% for the group with a fracture and 96% for the group without a fracture (p=0.007). In the group with a fracture, seven (23%) of the thirty patients managed with limb salvage and four (18%) of the twenty-two managed with an amputation had a local recurrence (p=0.75). Eleven (37%) of the thirty patients with a fracture who were managed with limb salvage and ten (45%) of the twenty-two patients with a fracture who were managed with an amputation died of the disease (p=0.50). Five patients underwent open reduction and internal fixation followed by limb-salvage surgery. Two of them had a local recurrence and died at an average of eight months postoperatively. The remaining three patients were alive at an average of 6.1 years postoperatively. Local disease control and the survival of these patients were not significantly different from those for the thirty-three patients who were treated with nonoperative immobilization of the fracture followed by limb-salvage surgery. CONCLUSIONS : Patients with osteosarcoma who present with a pathologic fracture or sustain one during preoperative chemotherapy have an increased risk of local recurrence and a decreased rate of survival compared with patients who have not sustained a pathologic fracture. The performance of a limb-salvage procedure in carefully selected patients with a pathologic fracture does not significantly increase the risk of local recurrence or death. Factors predictive of improved outcome, such as the response to chemotherapy and union of the fracture, should be taken into account when limb salvage is being considered.

Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy.
Bacci G, Ferrari S, Longhi A et al.
Acta Orthop Scand. 2003 Aug;74(4):449-54.

Abstract : To determine whether a pathologic fracture in osteosarcoma of long bones has prognostic importance, and limb salvage can be safely performed in such cases, we reviewed the surgical treatment and oncologic results in 46 patients with nonmetastatic osteosarcoma of the extremity and pathologic fracture at presentation who had been treated in our Institution with neoadjuvant chemotherapy, between 1983 and 1999. Neoadjuvant chemotherapy was given according to 6 consecutive protocols. Surgery consisted of limb salvage (34 patients), amputation (11 patients) and rotationplasty (1 patient). The average follow-up was 11 (3-20) years. 28 patients remained continuously disease-free, 17 patients relapsed and 1 died of chemotherapy-related toxicity. Despite the high rate of limb salvage, only 2 local failures occurred, 1 after amputation and 1 after limb salvage. The 5-year disease-free survival and overall survival rates were 59% and 65%, respectively, with no differences between amputated and resected patients. These results are similar to those obtained in 689 contemporary patients having an osteosarcoma without a pathologic fracture treated in our Institution, and using the same protocols for chemotherapy. We conclude that with neoadjuvant chemotherapy, osteosarcoma patients presenting with a pathologic fracture can be surgically treated like those with no fracture, and that limb salvage procedures do not increase the risk of local recurrence or death of these patients.

PTV :
    Phase I : Pre-chemotherapy volume + 2cm. margin
    Phase II : Post - surgery site of residual disease + 2cm. margin

TOTAL DOSE
    Phase I : 45Gy / 25# / 5wks (@1.8Gy / fr.)
    Phase II : 1) If R0 :
            <100% necrosis – no further boosts

     2) If Marginal resection/ close margins :
            100% necrosis – no further boost
            <100% necrosis – 5.4Gy / 3# / 0.5wk (@1.8Gy / fr.)
    3) If R1 :
            100% necrosis – no further boost
            <100% necrosis – 5.4Gy / 3# / 0.5wk (@1.8Gy / fr.)
    4) If R2 :
            100% necrosis – 5.4Gy / 3# / 0.5wk (@1.8Gy / fr.)
            <100% necrosis – 10.8Gy / 6# / 1 wk (@1.8Gy / fr.)

B) Borderline Resectable (As evaluated by multidisciplinary Joint Clinic)
    All patients to receive radical RT doses
    Patients to be evaluated for surgery at 6th week after completion of RT

PTV:
    Phase I : Pre-chemotherapy volume + 3cm. margin
    Phase II : Post-chemotherapy volume + 2cm. margin
            (There is no field reduction for bony component).

TOTAL DOSE :
    Phase I : 45Gy / 25# / 5wks (@1.8Gy / fr.)
    Phase II : 1) If complete response after induction
                    No further boost
                   2) If >50% regression after induction
                    10.8Gy / 6# / 1wk (@1.8Gy / fr.)
                    3) If <50% regression after induction
                    14.4Gy / 8# /1.5wks (@1.8Gy / fr.)

C) Unresectable
Same as borderline resectable lesions

D) Hyperfractionation
Unresectable lesions of the extremity. Although there is no evidence of significant improvement in disease free & overall survival, there is evidence to show that it is possible to do concurrent Chemo + RT using hyperfractionated RT with equivalent or marginally superior local control.

PTV :
       Phase I : Pre-chemotherapy volume + 3cm. margin
       Phase II : Post-chemotherapy volume + 2cm. margin
                (There is no field reduction for bony component).

TOTAL DOSE :
    Phase I : 45.6 Gy / 38# / 4wks (@1.2 Gy/ fr. X 2 # / day)
    Phase II : 20.4 Gy / 17# / 1.5wks (@1.2 Gy/ fr. X 2 # / day)

                24.0 Gy / 20 # / 2wks (@1.2 Gy/ fr. X 2 # / day)

     Total Dose : 66 Gy / 55# / 5.5wks (@1.2 Gy/ fr. X 2 # / day)

                        69.6Gy / 37# / 7wks (@1.2 Gy/ fr. X 2 # / day)

E) Lung Bath (Whole Lung Irradiation)

All patients with metastatic disease to the lungs at presentation receive whole lung irradiation (“Lung Bath”), even if complete remission of pulmonary metastatic disease has been achieved after chemotherapy.

Rt Target Volume : Bilateral Lung
                        No Cardiac Shield
                        Shield Bilateral Shoulder

Dose : 12.6Gy/ 7#/ 1week

F – Histopathology report and its importance
The specimen is evaluated for margins of surgical resection. Response to chemotherapy is noted based on percentage necrosis of tumor cells. This is an important prognostic factor. (Level III, Grade A)

The radiation dose is adjusted depending upon the percentage necrosis of tumor and margins of resection. (Level III, Grade B)
Grading of response in Ewing’s sarcoma is based on percentage of viable tumor.

Grade I : Tumor specimen contains at least one macroscopic nodule of viable tumor mass which is larger than one 10 X magnification field.

Local and systemic control in Ewing’s sarcoma of the femur treated with chemotherapy, and locally by radiotherapy and/or surgery.
Bacci G, Ferrari S, Longhi A et al.
J Bone Joint Surg Br. 2003 Jan;85(1):107-14.

Abstract : The role of radiotherapy and/or surgery in the local treatment of Ewing’s sarcoma has still to be determined. The outcome of Ewing’s sarcoma may differ according to its location and a selection bias towards surgery limits the ability to compare methods of local treatment. We have carried out a retrospective review of 91 consecutive patients treated for non-metastatic Ewing’s sarcoma of the femur. They received chemotherapy according to four different protocols. The primary lesion was treated by surgery alone (54 patients), surgery and radiotherapy (13) and radiotherapy alone (23). One was treated bychemotherapy alone. At a median follow-up of ten years, 48 patients (53%) remain free from disease, 39 (43%) have relapsed, two (2%) have died from chemotherapeutic toxicity and two (2%) have developed a radio-induced second tumour. The probability of survival without local recurrence was significantly (p=0.01) higher in patients who were treated by surgery with or without radiotherapy (88%) than for patients who received radiotherapy alone (59%). The five- and ten-year overall survival rates were 64% and 57%, respectively. Patients who were treated by surgery, with or without radiotherapy, had a five- and ten-year overall survival of 64%. Patients who received only radiotherapy had a five and ten-year survival of 57% and 44%, respectively. Our results indicate that in patients with Ewing’s sarcoma of the femur, better local control is achieved by surgical treatment (with or without radiotherapy) compared with the use of radiotherapy alone. Further studies are needed to verify the impact of this strategy on overall survival.

Role of Surgery and Resection Margins in the Treatment of Ewing´s Sarcoma.
Maria Sluga, Reinhard Windhager, Susanna Lang et al.
Clinical Orthopaedics And Related Research 2001;2001:394-399.

Because of the enormous progress in surgery in the treatment of patients with tumors, the current study analyzed the influence of wide surgical resection margins on the outcome of patients with Ewing´s sarcoma. Between 1980 and 1994, 86 patients were treated with systemic therapy and surgery (biopsy in six patients, tumor resection in 80 patients). Forty-four patients also had radiation therapy. The 5-year overall survival was 56.8% (5-year disease-free survival, 59.4%). The 5-year overall survival after radical or wide resection was 60.2% (5-year disease-free survival, 58.2%), in comparison with 40.1% (46.7%) after marginal or intralesional resection. Two patients with inadequate resection margins had local recurrences. In addition to the influence of neoadjuvant chemotherapy for higher survival rates (5-year overall survival with a good response was 80.2% versus 41.7% with a poor response), adequate surgical margins significantly affect the outcome for patients with Ewing´s sarcoma.

Significance of surgical margin on the prognosis of patients with Ewing’s sarcoma. A report from the Cooperative Ewing’s Sarcoma Study.
Ozaki T, Hillmann A, Hoffmann C et al.
Cancer. 1996 Aug 15;78 (4): 892-900.

BACKGROUND : There is little information regarding an adequate surgical margin for local control of Ewing’s sarcoma. METHODS : Two hundred and forty-four patients (PTS) with Ewing’s sarcoma who were registered in the Cooperative Ewing’s Sarcoma Studies underwent surgical treatment. Ninety-four PTS underwent definitive surgery (surgery alone), 131 PTS received postoperative irradiation, and 19 PTS received preoperative irradiation. The surgical margins were distributed as follows: radical, 29 PTS; wide, 148 PTS; marginal, 39 PTS; and intralesional, 28 PTS. The impact of the surgical margin on the treatment outcome of PTS was analyzed statistically. RESULTS : The local or combined (local recurrence and systemic metastasis) relapse rate after surgery with or without irradiation was significantly lower compared with that after definitive irradiation (irradiation alone) (7% vs. 31%, P<0.0001). The local or combined relapse rate after complete resection (radical or wide margin) with or without irradiation was less compared with that after incomplete resection (marginal or intralesional margin) with or without irradiation (5% vs. 12% P=0.0455). The local or combined relapse rate did not greatly decreased after irradiation after incomplete surgery (from 14% to 12%). In both groups of good (viable tumor cells < 10%) and poor (viable cells > or = 10%) histologic response, the difference in systemic or combined relapse rate between patients undergoing complete and incomplete surgery was not significant. The 10-year overall survival of the PTS for each of the margins was distributed as follows: radical, 58%; wide, 65%; marginal, 61%; and intralesional, 71% (P = not significant). CONCLUSIONS : Surgery in patients with Ewing’s sarcoma adds to the safety of local control. Under the current treatment regimen with intensive chemotherapy and irradiation, complete resection of the tumor appears capable of decreasing the risk of local recurrence.

HISTOPATHOLOGY REPONSE TO CHEMOTHERAPY – A PROGNOSTIC INDICATOR
The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma.
Wunder JS, Paulian G, Huvos AG et al.
J Bone Joint Surg Am; 80(7):1020-33, 1998.

Abstract : Seventy-four patients who had a Ewing sarcoma of bone were managed with preoperative and postoperative chemotherapy and operative resection, with or without postoperative irradiation. The primary objectives of the study were to determine the histological response to preoperative chemotherapy in terms of the percentage of tumor necrosis and to assess the relationship between the histological response and the oncological outcome. The minimum duration of follow-up of the surviving patients who were continuously free of disease was five years. Sections of each operative specimen were examined, and the histological response to chemotherapy was graded semiquantitatively. Grade I indicated necrosis of 50 per cent of the tumor or less; grade II, necrosis of more than 50 per cent but less than 90 per cent; grade III, necrosis of 90 to 99 per cent; and grade IV, necrosis of 100 per cent of the tumor. Of the seventy-four tumors, forty-four (59 per cent) were exquisitely sensitive to chemotherapy and had complete (grade-IV) or nearly complete (grade-III) necrosis. In contrast, fourteen tumors (19 per cent) had little or no response to chemotherapy (grade I) and sixteen (22 per cent) had a moderate degree of necrosis (grade II). The histological response to preoperative chemotherapy (p=0.0001), followed by the size of the tumor (p=0.001), were the most important predictors of event-free survival. At five years, the rate of event-free survival was zero of fourteen patients who had had a grade-I response, six of sixteen who had had a grade-II response, and thirty-seven (84 per cent) of forty-four who had had a grade-III or IV response. The risk of local recurrence was most strongly associated with the operative margins; there were only four local recurrences (6 per cent) after sixty-seven resections with negative margins. Local recurrence may also have been influenced by the histological response and the use of local radiation. There were no local recurrences after operative treatment of six tumors that had been associated with pathological fracture. The histological response to preoperative chemotherapy and the size of the primary tumor are the most important clinical predictors of the outcome of operative treatment of non-metastatic Ewing sarcoma. These indicators should be used to identify patients who are at high risk for metastasis as such patients may be candidates for more intensive or novel therapies.

Predictive factors of histological response to primary chemotherapy in Ewing’s sarcoma.
Bacci G, Picci P, Mercuri M et al.
Acta Oncol; 37(7-8):671-6, 1998.

Abstract : Clinicopathologic variables associated with a good histological response to primary chemotherapy in Ewing’s sarcoma are identified. The histological response to preoperative chemotherapy in 243 cases of Ewing’s sarcoma treated with neoadjuvant chemotherapy was analyzed in relation to different clinicopathological features (sex and age of the patients, tumor size, serum lactate dehydrogenase (LDH) levels, tumor site) and to the type and schedule of anticancer drugs delivered preoperatively according to three consecutive chemotherapy regimens. A higher rate of good responses was achieved with the use of ifosfamide and dactinomycin in addition to a conventional three-drug VAC regimen, suggesting that these drugs should be included from the beginning in neoadjuvant regimens for the treatment of Ewing’s sarcoma. The analysis of event-free survival in 158 patients with a 4-year minimum follow-up confirmed that histological response to preoperative chemotherapy is a reliable predictor of outcome in Ewing’s sarcoma.

RADIOTHERAPY TARGET VOLUME

A multidisciplinary study investigating radiotherapy in Ewing’s sarcoma: end results of POG #8346. Pediatric Oncology Group.
Donaldson SS, Torrey M, Link MP et al.
Int J Radiat Oncol Biol Phys 1998; 42: No 1: 125-135 .

PURPOSE : To determine if involved field radiation (IF) is equivalent to standard whole bone radiation (SF) in local tumor control; to establish patterns of failure following treatment; and to determine response, event-free survival (EFS), and overall survival rates from multidisciplinary therapy in Ewing’s sarcoma. METHODS AND MATERIALS : Between 1983 and 1988, 184 children with Ewing’s sarcoma were enrolled onto Pediatric Oncology Group 8346 (POG 8346). A total of 178 (97%) met eligibility criteria; 6 had pathology other than Ewing’s sarcoma. Induction chemotherapy of cyclophosphamide/doxorubicin (adriamycin) (C/A) x 12 weeks was followed by local treatment either surgery or radiation therapy and C/A, dactinomycin, and vincristine for 50 weeks. Resection was advised for patients with small primary tumors if accomplished without functional loss. Forty patients were randomized to receive SF, whole bone radiation to 39.6 Gy plus a 16.2 Gy boost (total 55.8 Gy) or IF to 55.8 Gy, and the remainder were assigned to IF radiation. RESULTS : Of 178 eligible patients, 141 (79%) had localized disease and 37 (21%) had metastases at presentation. Their 5-year EFS was 51% (SE 5%) and 23% (SE 7%) respectively. The response rate to induction chemotherapy was 88% (28% complete, 60% partial), but after radiotherapy the response rate increased to 98%. Thirty-seven of the localized patients underwent resection, of whom 16 (43%) required postoperative radiotherapy; the 5-year EFS of these surgical patients was 80% (SE 7%). The remaining 104 localized patients were eligible for randomization or assignment to receive radiotherapy; the 5-year EFS of these patients was 41% (SE 5%), with no significant difference in EFS between those randomized to SF vs. IF. Site of primary tumor correlated with 5-year EFS: distal extremity 65% (SE 8%), central 63% (SE 10%), proximal extremity 46% (SE 8%), and pelvic-sacral 24% (SE 10%) (p=0.004). Initial tumor size did not correlate significantly with EFS. Patterns of failure among the 141 localized patients revealed 23% of patients experienced a local failure, while 40% had a systemic failure. The 5-year local control rate for the surgical patients +/- postoperative radiotherapy was 88% (SE 6%), while for the patients undergoing radiotherapy alone it was 65% (SE 7%). There was no difference in local control between those randomized to SF vs. IF. The 5-year local control rate for the patients with pelvic-sacral tumors was 44% (SE 15%), significantly worse than the local control rates for those with central tumors 82% (SE 8%), distal extremity 80% (SE 8%), or proximal extremity 69% (SE 9%) (p=0.023). However, quality of radiotherapy correlated with outcome. Patients who had appropriate radiotherapy had a 5-year local control of 80% (SE 7%), while those with minor deviations had 5-year local control of 48% (SE 14%), and those with major deviations had a local control of only 16% (SE 15%) (p=0.005). The local failure was within an irradiated volume in 62% of patients, outside the irradiated volume in 24% of cases, while the precise location could not be determined in the remaining 14%. CONCLUSIONS : As most failures in Ewing’s sarcoma are systemic, improved EFS requires more effective systemic chemotherapy. Adequate IF radiotherapy requires treatment to appropriate volumes as defined by MRI imaging and full radiation doses. Pretreatment review of radiologic images with a musculoskeletal radiologist to determine appropriate tumor volumes, as well as use of conformal radiotherapy techniques are important for improved outcome.

Ewing’s sarcoma: local tumor control and patterns of failure following limited-volume radiation therapy.
Arai Y, Kun LE, Brooks MT et al.
Int J Radiat Oncol Biol Phys 1991; 21: 1501-1508.

Abstract : Sixty children with localized osseous Ewing’s sarcoma were treated between 1978 and 1988 with induction chemotherapy (cyclophosphamide, adriamycin), irradiation and/or surgery, and 10 months of maintenance chemotherapy (cyclophosphamide, adriamycin, dactinomycin, vincristine). Following induction chemotherapy, 43 patients received primary radiation therapy to limited radiation volumes defined by post-chemotherapy residual soft tissue tumor extension and initial osseous tumor extent. Irradiation was defined as low dose at 30-36 Gy (median 35 Gy) for 31 cases with objective response to induction chemotherapy and high dose at 50-60 Gy (median 50.4 Gy) for 12 patients with poor response to induction chemotherapy or with tumors greater than or equal to 8 cm. Overall event-free survival at 5 years is 59% and local tumor control is 68%. Initial failures have been local (12), simultaneous local and distant failures (7), and distant (6). In the surgical resection group, 14 patients had complete resection without radiation therapy, and 3 patients had microscopic residual plus 35-41 Gy; 100% local control has been maintained. In 43 patients with primary radiation therapy group, local tumor control is 58% (p=.004). Despite limited radiation volume, 18/19 local failures occurred centrally within the bone, well within the radiation volume. Imaging response to induction chemotherapy predicted local tumor control in the radiation therapy group: 62% with complete response/partial response versus 17% with no response/progressive disease (p less than 0.01). Local tumor control related strongly to primary tumor size in the radiation therapy group; among 31 cases receiving 35 Gy, local tumor control is 90% for lesions less than 8 cm versus 52% for tumors greater than or equal to 8 cm (p=.054). The central pattern of local failure in this experience suggests the effectiveness of limited radiation volume. The overall local tumor control rate following the tested dose level of 35 Gy appears to be inadequate, although results in selected cases with tumors less than 8 cm in greatest tumor dimension indicate potential efficacy in a yet limited experience.

Radiation therapy in Ewing’s sarcoma: an update of the CESS 86 trial.
Dunst J, Jurgens H, Sauer R et al.
J Radiat Oncol Biol Phys 1995; 32:No 4: 919-930.

PURPOSE : We present an update analysis of the multiinstitutional Ewing’s sarcoma study CESS 86. METHODS AND MATERIALS: From January 1986 through June 1991, 177 patients with localized Ewing’s sarcoma of bone, aged 25 years or less, were recruited. Chemotherapy consisted of four 9-week courses of vincristine, actinomycin D, cyclophosphamide, and adriamycin (VACA) in low-risk (extremity tumors < 100 cm3), or vincristine, actinomycin D, ifosfamide, and adriamycin (VAIA) in high-risk tumors (central tumors and extremity tumors > or = 100 cm3). Local therapy was an individual decision in each patient and was either radical surgery (amputation, wide resection) or resection plus postoperative irradiation with 45 Gy or definitive radiotherapy with 60 Gy (45 Gy plus boost). Irradiated patients were randomized concerning the type of fractionation in either conventional fractionation (once daily 1.8-2.0 Gy, break of chemotherapy) or hyperfractionated split-course irradiation simultaneously with the VACA/VAIA chemotherapy (twice daily 1.6 Gy, break of 12 days after 22.4 Gy and 44.8 Gy, total dose and treatment time as for conventional fractionation). For quality assurance in radiotherapy, a central treatment planning program was part of the protocol. RESULTS : Forty-four patients (25%) received definitive radiotherapy; 39 (22%) had surgery, and 93 (53%) had resection plus postoperative irradiation. The overall 5-year survival was 69%. Thirty-one percent of the patients relapsed, 30% after radiotherapy, 26% after radical surgery, and 34% after combined local treatment. The better local control after radical surgery (100%) and resection plus radiotherapy (95%) as compared to definitive radiotherapy (86%) was not associated with an improvement in relapse-free or overall survival because of a higher frequency of distant metastases after surgery (26% vs. 29% vs. 16%). In irradiated patients, hyperfractionated split-course irradiation and conventional fractionation yielded the same results (5-year overall survival of definitively irradiated patients 63% after conventional fractionation and 65% after hyperfractionation; relapse-free survival 53% vs. 58%; local control 76% vs. 86%, not significant). The six local failures after radiotherapy did not correlate with tumor size or response to chemotherapy. Radiation treatment quality (target volume, technique, dosage) was evaluated retrospectively and was scored as unacceptable in only 1 out of 44 patients (2%) with definitive radiotherapy. Grade 3-4 complications developed in 4 out of 44 (9%) patients after definitive radiotherapy. CONCLUSIONS : Under the given selection criteria for local therapy, radiation therapy yielded relapse-free and overall survival figures comparable to radical surgery. Hyperfractionated split-course irradiation simultaneously with multidrug chemotherapy did not significantly improve local control or survival.

INDICATIONS & DOSE MODULATION FOR POST OPERATIVE RADIOTHERAPY

Prognostic Factors in Localized Ewing’s tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study).
Oberlin O, Deley Le MC, Bui N’Guyen B, et al.
British Journal of Cancer (2001) 85(11), 1646-1654.

PURPOSE : (1) To improve survival rates in patients with Ewing’s sarcoma (ES) or peripheral neuroectodermal tumours (PNET) using semi-continuous chemotherapy and aiming to perform surgery in all; (2) To identify early prognostic factors to tailor therapy for future studies. PATIENTS AND METHODS : One hundred and forty-one patients were entered onto the trial between January 1988 and December 1991. Induction therapy consisted of five courses of Cytoxan, 150 mg/m(2) x 7 days, followed by Doxorubicin, 35 mg/m(2) i.v on day 8 given at short intervals. Surgery was recommended whenever possible. The delivery of radiation therapy was based on the quality of resection and the histological response to CT. Maintenance chemotherapy consisted of vincristine + actinomycin and cytoxan + doxorubicin. The total duration of therapy was 10 months. RESULTS : After a median follow-up of 8.5 years, the projected overall survival at 5 years was 66% and disease-free survival (DFS) was 58%. In patients treated by surgery, only the histological response to CT had an influence on survival: 75% DFS for patients with a good histological response (less than 5% of cells), 48% for intermediate responders and only 20% for poor responders (> or = 30% of cells), P < 0.0001. The initial tumor volume by itself had no influence on DFS in these patients. In contrast, the tumour volume had a strong impact on DFS in patients treated by radiation therapy alone. Age had no impact on outcome. CONCLUSION: Therapeutic trials for localized Ewing’s sarcoma should be based on the histological response to chemotherapy or on the tumour volume according to the modality used for local therapy.

Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials.
Schuck A, Ahrens S, Paulussen M et al.
Int J Radiat Oncol Biol Phys. 2003 Jan 1;55(1):168-177.

PURPOSE : The impact of different local therapy approaches on local control, event-free survival, and secondary malignancies in the CESS 81, CESS 86, and EICESS 92 trials was investigated. METHODS AND MATERIALS : The data of 1058 patients with localized Ewing tumors were analyzed. Wherever feasible, a surgical local therapy approach was used. In patients with a poor histologic response or with intralesional and marginal resections, this was to be followed by radiotherapy (RT). In EICESS 92, preoperative RT was introduced for patients with expected close resection margins. Definitive RT was used in cases in which surgical resection seemed impossible. In CESS 81, vincristine, adriamycin, cyclophosphamide, and actinomycin D was used. In CESS 86, vincristine, adriamycin, ifosfamide, and actinomycin D was introduced for patients with central tumors or primaries >100 cm(3). In CESS 92, etoposide, vincristine, adriamycin, ifosfamide, and actinomycin D was randomized against vincristine, adriamycin, ifosfamide, and actinomycin D in patients with primaries >100 cm(3). RESULTS : The rate of local failure was 7.5% after surgery with or without postoperative RT, and was 5.3% after preoperative and 26.3% after definitive RT (p=0.001). Event-free survival was reduced after definitive RT (p=0.0001). Irradiated patients represented a negatively selected population with unfavorable tumor sites. Definitive RT showed comparable local control to that of postoperative RT after intralesional resections. Patients with postoperative RT had improved local control after intralesional resections and in tumors with wide resection and poor histologic response compared with patients receiving surgery alone. Patients with marginal resections with or without postoperative radiotherapy showed comparable local control, yet the number of patients with good histologic response was higher in the latter treatment group (72.2% vs. 38.5%). CONCLUSION : Patients with resectable tumors after initial chemotherapy had a low local failure rate. With preoperative RT, local control was comparable. RT is indicated to avoid intralesional resections. After intralesional or marginal resections and after a poor histologic response and wide resection, postoperative RT may improve local control.

Second malignancies after Ewing’s sarcoma: radiation dose-dependency of secondary sarcomas.
Kuttesch JF Jr, Wexler LH, Marcus RB et al.
J Clin Oncol; 14(10):2818-25, 1996.

BACKGROUND : An excess risk of second malignancies has been reported in survivors of Ewing’s sarcoma. We examined a multiinstitutional data base to reevaluate the risk among survivors of Ewing’s sarcoma and to identify possible causal factors. METHODS : Information was derived from a data base that included 266 survivors of Ewing’s sarcoma. Cumulative incidence rates of second malignancies were calculated. Contributions of clinical features, type and dose of chemotherapy, and cumulative radiation dose to the risk of second malignancies were evaluated. RESULTS : After a median follow-up duration of 9.5 years (range, 3.0 to 30), 16 patients have developed second malignancies, which included 10 sarcomas (five osteosarcomas, three fibrosarcomas, and two malignant fibrous histiocytomas) and six other malignancies (acute myeloblastic leukemia, acute lymphoblastic leukemia, meningioma, bronchioalveolar carcinoma, basal cell carcinoma, and carcinoma-in-situ of the cervix). The median latency to the diagnosis of the second malignancy was 7.6 years (range, 3.5 to 25.7). The estimated cumulative incidence rates at 20 years for any second malignancy and for secondary sarcoma were 9.2% (SD = 2.7%) and 6.5% (SD = 2.4%), respectively. The cumulative incidence rate of secondary sarcoma was radiation dose-dependent (P=.002). No secondary sarcomas developed among patients who had received less than 48 Gy, while the absolute risk of secondary sarcoma was 130 cases per 10,000 person-years of observation among patients who had received > or = 60 Gy. CONCLUSION : The overall risk of second malignancies after Ewing’s sarcomas is similar to that associated with treatment for other childhood cancers. The radiation dose-dependency of secondary sarcomas justifies modification in therapy to reduce radiation doses.

ROLE OF LUNG BATH IN PULMONARY METASTASIS :

Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies.
Paulussen M, Ahrens S, Burdach S et al.
Annals of Oncology 9(3): 275-281, 1998.

BACKGROUND : In the multicenter European Intergroup Cooperative Ewing’s Sarcoma Studies, localized Ewing tumors of bone were treated by combination chemotherapy with surgery and/or radiotherapy. Patients with primary metastases (pm-pts) were treated in high risk protocols. PATIENTS AND METHODS : One hundred seventy-seven pm-pts were registered from January 1990 to December 1995, 171 were evaluable for survival analyses. Thirty-six pm-pts received myeloablative megatherapy with stem cell rescue following conventional treatment. Bilateral whole lung irradiation (WLI) was administered in 57 pm-pts with pulmonary involvement. Event-free survival (EFS) rates were estimated by Kaplan-Meier analysis. Prognostic factors were identified by log-rank statistics, Cox procedures and logistic regression. RESULTS: Eighty-nine deaths were recorded by 1 February 1997, EFS four years after diagnosis for all 171 pm-pts was 0.27. EFS for isolated lung metastases was 0.34, for bone/bone marrow (BM) metastases, 0.28, and for combined lung plus bone/BM metastases, 0.14 (P<0.005). WLI improved outcome in case of isolated pulmonary involvement (0.40 vs. 0.19, P<0.05). In pm-pts with combined pulmonary/skeletal metastases, intensification by megatherapy and/or WLI improved EFS from 0.00 to 0.27 (P=0.0001). CONCLUSIONS : EFS four years after diagnosis in patients with disseminated Ewing tumors is 0.27. Whole lung irradiation and megatherapy improve outcome in subgroups of patients with disseminated Ewing tumors is 0.27. Whole lung irradiation and megatherapy improve outcome in subgroups of patients with disseminated Ewing disease.

Selective use of whole-lung irradiation for patients with Ewing sarcoma family tumors and pulmonary metastases at the time of diagnosis.
Spunt SL, McCarville MB, Kun LE et al.
Journal of Pediatric Hematology/Oncology 23(2): 93-98, 2001.

PURPOSE : The benefit of whole-lung irradiation (WLI) for patients who have pulmonary metastases (PM) of Ewing sarcoma family tumors (ESFT) is unclear. At our institution, WLI is reserved for patients with PM that do not respond completely to induction chemotherapy. We reviewed our experience to assess the impact of WLI on clinical outcome. PATIENTS AND METHODS : Twenty-eight patients with ESFT and PM were treated in three consecutive institutional trials (1979-1996). Extent of pulmonary involvement at diagnosis, response of PM after induction chemotherapy, local treatment of PM thereafter, and clinical outcome were recorded. Treatment included primary tumor surgery and/or radiotherapy and 42 to 58 weeks of multiagent chemotherapy. RESULTS : Only eight patients (29%) received WLI. For the entire study group, the estimated 5-year event-free survival was 22.9% +/- 9.0%; the 5-year survival was 37.3% +/- 9.8%. Complete resolution of PM after induction chemotherapy was not correlated with survival (P=0.53), nor was treatment with WLI (P=0.87). CONCLUSIONS : The comparable survival of patients with poor and good response of PM to induction chemotherapy suggests that WLI may benefit poor responders. The use of WLI in good responders may provide similar benefit and merits further study.

D – Local control
Limb conservation is done wherever possible. Organ and function preserving surgery with or without radiation therapy is done wherever possible. The combination of conservative surgery and post-operative radiotherapy maintains a functional limb in patients with extremity lesions and survival results are comparable to those attained with radical surgery. (Level II, Grade A)
Every effort should be made to achieve a wide (2cm is often an arbitrary choice) margin around the tumor mass, except in the immediate vicinity of functionally important neuro-vascular structures, where in the absence of frank tumor involvement, dissection is performed in the immediate perineural or perivascular tissue planes. (Level III, Grade B)

Stage IA, IB Surgery. External radiotherapy is added if margins are positive. (Level II, Grade B)

Stage II A, II B, III Surgery ± Brachytherapy + Ext. radiotherapy. If margins are grossly positive, attempt re-excision (if feasible) to get negative margins, wherever possible. (Level II, Grade A)

Stage IV N1 Mo Surgery ± Brachy + Ext. RT + Lymph Node Dissection
No M1 Surgery ± Brachy + Ext. radiotherapy
Indications for metastectomy of pulmonary metastasis.

• No extrathoracic disease
• Locoregional disease controlled or controllable
• R0 metastectomy is possible
• Good general condition

E – Radiotherapy
Post-operative adjuvant Radiotherapy is given to all high grade and margin positive cases in the form of Brachytherapy and/or External Radiotherapy or a combination of the two. (Level II, Grade B)

Pre-op vs. Post-op radiation :
Currently we prefer post op radiotherapy. Pre-op radiotherapy is associated with a slightly increased wound complication rate with equivalent control and overall survival in patients of extremity STS. (Level II, Grade B)
All patients should have silver clips inserted during surgery to delineate tumor bed.

Patients suitable for Intraoperative Brachytherapy :
Brachytherapy catheters inserted uniformly to cover the entire tumor bed with 1.5 - 2.0 cm margin.

Simulation and dosimetry to be done on 4-5th postoperative day.
Dose prescription for brachytherapy - 0.5cm on either side of the implant plane.

Brachytherapy Dose : LDR - 20Gy to 25Gy @ 45 - 50cGy / hr
                              HDR - 15Gy / 5# @ 3Gy / # (2# / day with 6hrs gap)
Ext. Radiotherapy :
Radiotherapy to be started 2-3 weeks after completion of Brachytherapy
Planning Target Volume : Gross tumor volume + 3-5cm margin

Dose : After LDR Brachytherapy - 50Gy / 25# / 5 weeks
          After HDR Brachytherapy - 50Gy / 25# / 5 weeks

Patients receiving only Ext. Radiotherapy :

Planning Target Volume (PTV) : Phase I : Gross tumor volume +
                                           Grade I : 3cm margin
                                           Grade II & III : 5cm margin
                                           Phase II - Gross tumor volume + 2cm margin

Essential to spare at least 1.5 - 2.0cm of limb circumference from radiotherapy portal.
Spare half circumference of uninvolved bone if possible.
Try to keep uninvolved compartment out of radiation port as far as possible.

Dose : Phase I - 50Gy / 25# / 5 weeks
Phase II - R 0 : 10Gy / 5# / 1 week
              R 1 :16Gy / 8# / 1.5 weeks
              R 2 : 20Gy /10# / 2 weeks
In some situations, radiation therapy or chemotherapy may be used prior to surgery to convert a marginally resectable tumor to one that can be adequately resected with limb preservation; this treatment may be followed by postop radiation therapy.

F – Chemotherapy
The role of adjuvant chemotherapy in localized STS is still unestablished. Adjuvant ifosfamide, doxorubicin/epirubicin based chemotherapy is offered to high risk patients ( large, deep , high grade limb tumors or recurrent tumors). (Level II, Grade B)

G - Recurrent STS
Non metastatic - Re-excision ± Brachytherapy ± External RT
Metastatic - Re-excision ± Brachytherapy ± External RT
Indications for metastectomy of pulmonary metastasis.

• No extrathoracic disease
• Locoregional disease controlled or controllable
• R0 metastectomy is possible
• Good general condition

H – Follow up schedule
Patient is followed up at 3 monthly intervals for the first 2 years, 6 monthly intervals for next 3 years and annually thereafter.
At every follow up, clinical examination of the local part & chest radiograph is done. For high grade tumors a CT scan of the chest is done at 6 monthly intervals for the first 2 years and annually for the next 3 years.
USG-Abdomen and pelvis at 6 monthly intervals for the first 2 years and annually for the next 3 years in cases of for myxoid liposarcoma, synovial sarcoma, epithelioid sarcoma, angiosarcoma and undifferentiated sarcomas.
(Currently there is inadequate evidence to suggest that intensive follow up with early detection of recurrent disease would significantly impact on survival).

I – Referred cases in which unplanned excision has been done with positive or unknown margins
Repeat excision followed by radiotherapy for high grade tumors.
(Level III, Grade B)

IS LIMB SALVAGE SAFE?

The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy.
Rosenberg SA, Tepper J, Glatstein E et al.
Ann Surg. 1982 Sep;196(3):305-15.

Abstract : Between May 1975 and April 1981, 43 adult patients with high-grade soft tissue sarcomas of the extremities were prospectively randomized to receive either amputation at or above the joint proximal to the tumor, including all involved muscle groups, or to receive a limb-sparing resection plus adjuvant radiation therapy. The limb-sparing resection group received wide local excision followed by 5000 rads to the entire anatomic area at risk for local spread and 6000 to 7000 rads to the tumor bed. Both randomization groups received postoperative chemotherapy with doxorubicin (maximum cumulative dose 550 mg/m2), cyclophosphamide, and high-dose methotrexate. Twenty-seven patients randomized to receive limb-sparing resection and radiotherapy, and 16 received amputation (randomization was 2:1). There were four local recurrences in the limb-sparing group and none in the amputation group (p1=0.06 generalized Wilcoxon test). However, there were no differences in disease-free survival rates (71% and 78% at five years; p2=0.75) or overall survival rates (83% and 88% at five years; p2=0.99) between the limb-sparing group and the amputation treatment groups. Multivariate analysis indicated that the only correlate of local recurrence was the final margin of resection. Patients with positive margins of resection had a higher likelihood of local recurrence compared with those with negative margins (p1 less than 0.0001) even when postoperative radiotherapy was used. A simultaneous prospective randomized study of postoperative chemotherapy in 65 patients with high-grade soft-tissue sarcomas of the extremities revealed a marked advantage in patients receiving chemotherapy compared with those without chemotherapy in three-year continuous disease-free (92% vs. 60%; p1=0.0008) and overall survival (95% vs. 74%; p1=0.04). Thus limb-sparing surgery, radiation therapy, and adjuvant chemotherapy appear capable of successfully treating the great majority of adult patients with soft tissue sarcomas of the extremity.

ROLE OF RADIOTHERAPY IN SOFT TISSUE SARCOMA

Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity.
Yang JC, Chang AE, Baker AR et al.
J Clin Oncol; 16(1):197-203, 1998.

PURPOSE : This randomized, prospective study assesses the impact of postoperative external-beam radiation therapy on local recurrence (LR), overall survival (OS), and quality of life after limb-sparing resection of extremity sarcomas. PATIENTS AND METHODS : Patients with extremity tumors and a limb-sparing surgical option were randomized to receive or not receive postoperative adjuvant external-beam radiotherapy. Patients with high-grade sarcomas received postoperative adjuvant chemotherapy whereas patients with low-grade sarcomas or locally aggressive nonmalignant tumors were randomized after surgery alone. RESULTS : Ninety-one patients with high-grade lesions were randomized; 47 to receive radiotherapy (XRT) and 44 to not receive XRT. With a median follow-up of 9.6 years, a highly significant decrease (P2=.0028) in the probability of LR was seen with radiation, but no difference in OS was shown. Of 50 patients with low-grade lesions (24 randomized to resection alone and 26 to resection and postoperative XRT), there was also a lower probability of LR (P2=.016) in patients receiving XRT, again, without a difference in OS. A concurrent quality-of-life study showed that extremity radiotherapy resulted in significantly worse limb strength, edema, and range of motion, but these deficits were often transient and had few measurable effects on activities of daily life or global quality of life. CONCLUSION : This study indicates that although postoperative external-beam radiotherapy is highly effective in preventing LRs, selected patients with extremity soft tissue sarcoma who have a low risk of LR may not require adjuvant XRT after limb-sparing surgery.

Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma.
Pisters PW, Harrison LB, Leung DH et al.
J Clin Oncol 1996 Mar;14(3):859-68.

PURPOSE : This trial was performed to evaluate the impact of adjuvant brachytherapy on local and systemic recurrence rates in patients with soft tissue sarcoma. PATIENTS AND METHODS : In a single-institution prospective randomized trial, 164 patients were randomized intraoperatively to receive either adjuvant brachytherapy (BRT) or no further therapy (no BRT) after complete resection of soft tissue sarcomas of the extremity or superficial trunk. The adjuvant radiation was administered by iridium-192 implant, which delivered 42 to 45 Gy over 4 to 6 days. The two study groups had comparable distributions of patient and tumor factors, including age, sex, tumor site, tumor size, and histologic type and grade. RESULTS : With a median follow-up time of 76 months, the 5-year actuarial local control rates were 82% and 69% in the BRT and no BRT groups (P=.04), respectively. Patients with high-grade lesions had local control rates of 89% (BRT) and 66% (no BRT) (P=.0025). BRT had no impact on local control in patients with low-grade lesions (P=.49). The 5-year freedom-from-distant-recurrence rates were 83% and 76% in the BRT and no BRT groups (P=.60), respectively. Analysis by histologic grade did not demonstrate an impact of BRT on the development of distant metastasis, despite the improvement in local control noted in patients with high-grade lesions. The 5-year disease-specific survival rates for the BRT and no BRT groups were 84% and 81% (P=.65), respectively, with no impact of BRT regardless of tumor grade. CONCLUSION : Adjuvant brachytherapy improves local control after complete resection of soft tissue sarcomas. This improvement in local control is limited to patients with high-grade histopathology. The reduction in local recurrence in patients with high-grade lesions is not associated with a significant reduction in distant metastasis or improvement in disease-specific survival.

Role of radiotherapy in soft tissue sarcoma, Review article
Calais G;
Cancer Radiother 1997.
Radiation therapy is generally used as a surgical adjuvant in the treatment of soft tissue sarcomas. Postoperative external beam irradiation is the most commonly applied treatment. The majority of retrospective studies have suggested that radiation therapy could reduce the incidence of local recurrence. Radiation is recommended in case of deep tumor location, inadequate surgical margins and grade 3 tumor. A total dose of 55 to 65 Gy using large volume with initial field margin of 5 cm are recommended. Radiation therapy can also be delivered in preoperative fashion, but the majority of the studies have reported a higher wound complication rate. The value of brachytherapy for reducing the risk of local recurrence has been demonstrated in a randomized trial, especially for patients with high grade tumors. The combination of external radiation (40 to 45 Gy) and brachytherapy (15 to 20 Gy) seems to be the optimal adjuvant local strategy.

TIMING OF RADIOTHERAPY

Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial.
O’Sullivan B, Davis AM, Turcotte R et al.
Lancet. 2002 Jun 29;359(9325):2235-41.

BACKGROUND : External-beam radiotherapy (delivered either preoperatively or postoperatively) is frequently used in local management of sarcomas in the soft tissue of limbs, but the two approaches differ substantially in their potential toxic effects. We aimed to determine whether the timing of external-beam radiotherapy affected the number of wound healing complications in soft-tissue sarcoma in the limbs of adults. METHODS : After stratification by tumour size (< or = 10 cm or >10 cm), we randomly allocated 94 patients to preoperative radiotherapy (50 Gy in 25 fractions) and 96 to postoperative radiotherapy (66 Gy in 33 fractions). The primary endpoint was rate of wound complications within 120 days of surgery. Analyses were per protocol for primary outcomes and by intention to treat for secondary outcomes. FINDINGS : Median follow-up was 3.3 years (range 0.27-5.6). Four patients, all in the preoperative group, did not undergo protocol surgery and were not evaluable for the primary outcome. Of those patients who were eligible and evaluable, wound complications were recorded in 31 (35%) of 88 in the preoperative group and 16 (17%) of 94 in the postoperative group (difference 18% [95% CI 5-30], p=0.01). Tumour size and anatomical site were also significant risk factors in multivariate analysis. Overall survival was slightly better in patients who had preoperative radiotherapy than in those who had postoperative treatment (p=0.0481). INTERPRETATION : Because preoperative radiotherapy is associated with a greater risk of wound complications than postoperative radiotherapy, the choice of regimen for patients with soft-tissue sarcoma should take into account the timing of surgery and radiotherapy, and the size and anatomical site of the tumour.

Preoperative vs. postoperative radiotherapy in the treatment of soft tissue sarcomas: a matter of presentation
Pollack A, Zagars GK, Goswitz MS et al.
Int J Radiat Oncol Biol Phys. 1998 Oct 1;42(3):563-72.

PURPOSE : Radiotherapy for soft tissue sarcoma is typically preoperative or postoperative, with advocates of each. In this study, the relationship of the sequencing of radiotherapy and surgery to local control was examined. METHODS AND MATERIALS : The cohort consisted of 453 patients with Grade 2-3 malignant fibrous histiocytoma, synovial sarcoma, or liposarcoma treated from 1965-1992. Retroperitoneal sarcomas were excluded. Median follow-up was 97 months. There were 3 groups of patients that were classified by the treatment administered at our institution: preoperative radiotherapy to a median dose of 50 Gy given before excision at MDACC (Preop; n=128); postoperative radiotherapy to a median dose of 64 Gy given after excision at MDACC (Postop; n=165); and radiotherapy to a median dose of 65 Gy without excision at MDACC (RT Alone; n=160). Those in the RT Alone Group had gross total excision at an outside center prior to referral. RESULTS : Histological classification, whether locally recurrent at referral, and final MDACC margins were independent determinants of local control in Cox proportional hazards multivariate analysis using the entire cohort. The type of treatment was not significant; however, tumor status at presentation (gross disease vs. excised) affected these findings greatly. Gross disease treated with Preop was controlled locally in 88% at 10 years, as compared to 67% with Postop (p=0.01). This association was independently significant for patients treated primarily (not for recurrence). In contrast, for those presenting after excision elsewhere, 10-year local control was better with Postop (88% vs. 73%,p=0.07), particularly for patients treated primarily (91% vs. 72%, p=0.02 in univariate analysis; p=0.06 in multivariate analysis). Re-excision at MDACC (Postop) resulted in enhanced 10-year local control over that with RT Alone (88% vs. 75%, p=0.06), and was confirmed to be an independent predictor in multivariate analysis (p=0.02). CONCLUSION : Local control was highest with Preop in patients presenting primarily with gross disease, and with Postop in patients presenting primarily following gross total excision. The data suggest that 50 Gy is inadequate after gross total excision, possibly due to hypoxia in the surgical bed.

TARGET VOLUME IN RADIOTHERAPY

Conservative surgery and adjuvant radiation therapy in the management of adult soft tissue sarcoma of the extremities : clinical and radiobiological results.
Mundt AJ, Awan A, Sibley GS et al.
Int J Radiat Oncol Biol Phys. 1995 Jul 15;32 (4):977-85.

PURPOSE : The outcome of adult patients with soft tissue sarcoma of the extremities treated with conservative surgery and adjuvant irradiation was evaluated to (a) determine the appropriate treatment volume and radiation dosage in the postoperative setting, and (b) correlate in vitro radiobiological parameters obtained prior to therapy with clinical outcome. METHODS AND MATERIALS : Sixty-four consecutive adult patients with soft tissue sarcoma of the extremities (40 lower, 24 upper) who underwent conservative surgery and adjuvant irradiation 7 preoperative, 50 postoperative, 7 perioperative) between 1978 and 1991 were reviewed. The initial radiation field margin surrounding the tumor bed/scar was retrospectively analyzed in all postoperative patients. Initial field margins were < 5 cm in 12 patients, 5-9.9 cm in 32 and > or = 10 cm in 6. Patients with negative pathological margins were initially treated with traditional postoperative doses (64-66 Gy); however, in later years the postoperative dose was reduced to 60 Gy. Thirteen cell lines were established prior to definite therapy, and radiobiological parameters (multitarget and linear-quadratic) were obtained and correlated with outcome. RESULTS : Postoperative patients treated with an initial field margin of < 5 cm had a 5-year local control of 30.4% vs. 93.2% in patients treated with an initial margin of > or = 5 cm (p=0.0003). Five-year local control rates were similar in patients treated with initial field margins of 5-9.9 cm (91.6%) compared with those treated with > or = 10 cm margins (100%) (p=0.49). While postoperative patients receiving < 60 Gy had a worse local control than those receiving > or = 60 Gy (p=0.08), no difference was seen in local control between patients receiving less than traditional postoperative doses (60-63.9 Gy) (74.4% vs. those receiving 64-66 Gy (87.0%) (p=0.5). The local control of patients treated in the later years of the study, with strict attention to surgical and radiotherapeutic technique, was 87.6%. Severe late sequelae were more frequent in patients treated with doses > or = 63 Gy compared to patients treated with lower doses (23.1% vs. 0%) (p<0.05). Mean values for Do, alpha, beta, D, n and SF2 obtained from the 13 cell lines were 115.7, 0.66, 0.029, 2.15, 0.262, respectively. Four of the 13 cell lines established prior to therapy ultimately failed locally. The radiobiological parameters of these cell lines were similar to the other nine cell lines in terms of radiosensitivity. CONCLUSIONS: Our data confirm the importance of maintaining an initial field margin of at least 5cm around the tumor bed/scar in the postoperative setting. No benefit was seen with the use of margins > or = 10 cm. In addition, patients undergoing wide local excision with negative margins can be treated with lower than traditional postoperative doses (60 Gy) without compromising local control and with fewer chronic sequelae. Finally, it does not appear that inherent tumor cell sensitivity is a major determinant of local failure following radiation therapy and conservative surgery in soft tissue sarcoma.

RADIOTHERAPY DOSE

Management of extremity soft tissue sarcomas with limb-sparing surgery and postoperative irradiation: do total dose, overall treatment time, and the surgery-radiotherapy interval impact on local control?
Fein DA, Lee WR, Lanciano RM et al.
Int J Radiat Oncol Biol Phys. 1995 Jul 15;32(4):969-76.

PURPOSE : To evaluate potential prognostic factors in the treatment of extremity soft tissue sarcomas that may influence local control, distant metastases, and overall survival. METHODS AND MATERIALS : Sixty-seven patients with extremity soft tissue sarcomas were treated with curative intent by limb-sparing surgery and postoperative radiation therapy at the Fox Chase Cancer Center or the Hospital of the University of Pennsylvania, between October 1970 and March 1991. Follow-up ranged from 4-218 months. The median external beam dose was 60.4 Gy. In 13 patients, interstitial brachytherapy was used as a component of treatment. RESULTS : The 5-year local control rate for all patients was 87%. The 5-year local control rate for patients who received < or = 62.5 Gy was 78% compared to 95% for patients who received > 62.5 Gy had larger tumors (p=0.008) and a higher percentage of Grade 3 tumors and positive margins than patients who received < or = 62.5 Gy. The 5-year local control rate for patients with negative or close margins was 100% vs. 56% in patients with positive margins (p=0.002). Cox proportional hazards regression analysis was performed using the following variables as covariates: tumor dose, overall treatment time, interval from surgery to initiation of radiation therapy, margin status, grade, and tumor size. Total dose (p=0.04) and margin status (p=0.02) were found to significantly influence local control. Only tumor size significantly influenced distant metastasis (p=0.01) or survival (p=0.03). CONCLUSION : Postoperative radiation therapy doses > 62.5 Gy were noted to significantly improve local control in patients with extremity soft tissue sarcomas. This is the first analysis in the literature to demonstrate the independent influence of total dose on local control of extremity soft tissue sarcomas treated with adjuvant postoperative irradiation.