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A report on the long-term follow up of the first cooperative Scandinavian Sarcoma Group study in Ewing's sarcoma of bone is presented. Fifty-two previously untreated patients entered the study between 1984 and 1990. Half of the tumors were located in the extremities and one quarter in the pelvis. The combined modality treatment consisted of 5 cycles of chemotherapy--including vincristine, methotrexate, doxorubicin, cyclophosphamide, bleomycin and dactinomycin. The first two cycles were followed by local resection or amputation in 35 patients and by radiotherapy alone in 17 patients. When surgery was not performed, was incomplete or yielded poor margins radiotherapy was given at a dose of 40-60 Gy. Local tumor relapses developed in 10 patients and in all but one patient were accompanied by metastatic disease. Five patients had metastasis at diagnosis and distant metastases developed after primary treatment in 27 patients after a median of 14 months. The median follow-up time for the 20 surviving patients is 10 years. At 5 years the tumor-related survival was 46% and the metastasis-free survival 43%. Late tumor relapses occurred in 4 patients, which reduced the 10-year tumor related survival to 41% and the metastasis-free survival to 38%. Histopathological tumour response correlated with survival with 5-year metastasis-free survival rates of 73% for the good responders and 35% for the poor responders.

(1997). Chemotherapy for osteosarcoma and Ewing's sarcoma. Acta Orthopaedica Scandinavica: Vol. 68, The Scandinavian—Australian Symposium on the Management of Bone and Soft Tissue Sarcomas, pp. 120-125.

Based on a literature review and the SSG experience, the most important prognostic factors in high-grade osteosarcoma appear to be the presence of detectable metastases at diagnosis, tumour volume, old age, sex, histologic response, and possibly tumoral P-glycoprotein expression. However, for an adolescent patient with non-metastatic extremity disease, there is no consensus regarding prognostic factors at initial presentation, and currently there is thus no established method for dividing them into high- and low risk groups for the purpose of treatment differentiation. It should also be remembered that available prognostic factors have been identified only in a retrospective manner, following aggressive treatment of all patients. Thus patients in "favourable" prognostic groups may simply be patients who have had a good effect from aggressive treatment, and how they would have done with reduced treatment remains to be shown. Obviously the best method for prognostication would be the direct demonstration of micrometastatic disease in the lungs or in peripheral blood. In the relatively near future, this may become possible with immunoscintigrapy or immunohistochemistry utilizing monoclonal antibodies [29-31]. In Ewing's sarcoma, the most powerful factors indicating poor prognosis are metastases at diagnosis, poor histologic response, large tumour size and possibly pelvic localisation. There appears to be a somewhat better international consensus regarding prognostic factors in Ewing's sarcoma than in osteosarcoma. Although several studies have implemented intensified treatment for poor prognostic groups [8, 32], the role (if any) of high-dose treatment with stem cell rescue remains to be proven. The same factors are prognostic both for the development of metastases and local recurrence, but in addition, surgical treatment as opposed to radiotherapy appears to reduce local failure rate [12, 17, 33, 34]. As in osteosarcoma, the near future offers promise regarding the detection and quantification of micrometastatses and minimal residual disease, by means of PCR techniques recognizing specific genetic changes in the Ewing family of tumors [35].

The local and systemic invasiveness of soft-tissue sarcomas may depend upon an interaction between the primary tumour and the extracellular matrix in which the proteolytic enzyme, urokinase plasminogen activator (uPA), may have an important role. We analyzed the expression of uPA in soft-tissue sarcoma using a luminescent immunoassay technique, and examined the relationships between different uPA levels and tumour characteristics and behaviour. We evaluated 69 adult patients with surgically treated soft-tissue sarcomas (MFH 43, leiomyosarcoma 8, liposarcoma 5, synovial sarcoma 4, others 9) of the extremities and trunk wall. Sixteen developed local recurrences, 26 developed metastases, and 5 had both. The median follow-up for survivors was 55 (30-80) months. The median uPA level was 1.4 (0.04-10.6) ng/mg protein. Increasing uPA levels correlated with increasing grade, malignant fibrous histiocytomas, leiomyosarcomas, DNA non-diploidy, tumour necrosis, local recurrence, and metastasis. Storiform-pleomorphic MFH had higher uPA levels than the myxoid variant. A cut-off value of 0.25 ng/mg protein was identified, above which local recurrence and metastasis occurred more frequently. High uPA levels appear to reflect the malignant phenotype in soft-tissue sarcoma, thus supporting the role of uPA as a prognostic indicator.

This synthesis of the literature on radiotherapy related to bone marrow transplantation is based on 59 scientific articles, including 5 randomized studies and 20 retrospective studies. These studies involve 2563 patients. Bone marrow transplantation is a rapidly expanding treatment method where whole-body irradiation can play an important role. The literature review reveals that treatment methods for whole-body irradiation are highly heterogeneous. Standardization would be desirable. Fractionated and single-dose, whole-body irradiation are probably of equal value when the dose and technique are optimal. Cataracts seem to be more common following a single dose. Fractionated treatment is more resource intensive, but less burdensome for patients. For advanced-stage leukemia and some other diseases, eg, myeloma, international experience has shown that a combined treatment strategy (high-dose cyclophosphamide and whole-body irradiation) is probably superior to chemotherapy (cyclophosphamide and busulfan) alone. For many other hematological malignancies at less advanced stages, conditioning methods are probably of equal value.

This synthesis of the literature on radiotherapy for sarcomas originating in the body's soft, supportive tissues, ie, muscle, connective tissue, and fatty tissue is based on 71 scientific articles, including 4 randomized studies, 5 prospective studies, and 26 retrospective studies. These studies involve 3,444 patients. Over 90% of patients with soft tissue sarcomas in the arms and legs can be treated in a way that preserves the extremities. Subcutaneous and intramuscular sarcomas can be treated surgically with little functional loss or risk for local recurrence without adjuvant radiotherapy. To avoid amputation, surgery is often combined with radiotherapy for treatment of local relapse. Adequate surgical margins are usually difficult to achieve for head/neck tumors and retroperitoneal tumors, and therefore surgery is often combined with radiotherapy to reduce the risk for local relapse. Pre- and postoperative radiotherapy are similar. A disadvantage of preoperative radiotherapy is that it reduces the opportunity for exact diagnosis and determining morphobiologic sarcoma parameters. To further improve treatment results for advanced sarcomas, it is necessary to introduce other fractionation schedules, mainly hyperfractionation. This places greater demands on radiotherapy, mainly for staff resources. Combining radiotherapy and local intraarterial chemotherapy involves greater risks for complications and has not shown better treatment results than pre- or postoperative radiotherapy alone, and it is not recommended as standard treatment for soft tissue sarcomas. Intraoperative treatment methods should be targeted for further study and development.

Abnormal patterns of proliferation characterize the behavior of many tumors. Proliferating cell nuclear antigen (PCNA) and Ki‐67 are two cell cycle antigens which are expressed in proliferative states. Our study examines the prognostic value of these cell‐cycle antigens in soft tissue sarcoma (STS). Paraffin‐embedded primary tumor tissues from 185 patients (1980–92) were stained with the anti‐PCNA antibody PC‐10; 182 of these were stained with the antibody MIB‐1 for Ki‐67. Using PCNA (≤50; >50%) and Ki‐67 (≤10; >10%) indices, we examined and compared metastasis‐free survival (MFS) in a mixed‐histotype group, as well as after subdivision into MFH and non‐MFH groups. Fifty‐seven patients developed metastases. The median follow‐up for survivors was 6 (2–13) years. In the mixed series, the 2‐year MFS for a PCNA index ≤50 was 76%, and for an index >50 56%. Survival predicted by Ki‐67 index was comparable. PCNA index (but not Ki‐67) strongly correlated with the incidence of metastasis in MFH tumors and predicted 2‐year MFS of 81 vs 48%. In contrast, Ki‐67 index (but not PCNA) strongly correlated with metastasis in non‐MFH tumors and predicted 2‐year MFS survival of 90 vs 45%. No correlation existed between PCNA and Ki‐67 indices in the mixed histotype, MFH or non‐MFH groups. In combination, a high PCNA and Ki‐67 index correlated with poor survival, a high PCNA and lower Ki‐67 index (or vice versa) with an intermediate survival, and low PCNA and Ki‐67 indices with the best survival. The pattern of PCNA and Ki‐67 expression raises the possibility of histotype specificity. (Less)

Soft tissue sarcomas (STS) are characterized by deregulated proliferation. Ki-67 is a cell cycle antigen which may be elevated in proliferative states. We analysed Ki-67 expression in fixed and embedded tissues from STS in order to examine associations between proliferation, primary tumour characteristics, and metastasis. One hundred and eighty-two adult patients with trunk wall or extremity STS were treated at our institution between 1980 and 1992 (35 developed local recurrence and 56 developed metastases). Median follow-up time for survivors was 6 years (1-13). We used a semiquantitative score to the assess percentage of Ki-67-positive cells:or = 10% (n = 86),10-25% (n = 57),25-50% (n = 30),50-75% (n = 7),75-100% (n = 2). Increasing Ki-67 expression correlated positively with tumour size, malignancy grade, necrosis, vascular invasion, S-phase fraction, and metastasis. A Ki-67 index Ki-Dor = 10% (n = 86) and10% (n = 96) defined two groups who had 84% and 56% 3-year metastasis-free survival (p = 0.0001), respectively. Tumours with Ki-D10 were typically large, high grade, necrotic, DNA aneuploid, and had intravascular invasion and a higher S-phase fraction. Ki-67 expression may be helpful in predicting survival of patients with soft tissue sarcomas.

LBA1 Background: Adjuvant IM administered for 12 months (mos) after surgery improves recurrence-free survival (RFS) of patients (pts) diagnosed with operable GIST. We compared 12 vs 36 mos of adjuvant IM as treatment of pts with a high risk for GIST recurrence after surgery. Methods: Pts with histologically diagnosed KIT-positive GIST were entered to this prospective, open-label, multicenter, randomized Phase III study (identifier NCT00116935 ). The risk of recurrence was estimated according to the modified Consensus Criteria. The primary objective was RFS. The secondary objectives included survival (OS) and treatment safety. The key exclusion criteria were ECOG PS >2, metastatic or inoperable GIST, and >12 wks from surgery to the study entry. IM was administered orally 400 mg/d. The sample size (n =200 in each group to obtain ≥110 events) was estimated by simulating log-rank tests assuming an overall hazard ratio (HR) of 0.44, a 20% drop-out rate, 2-sided type-I error rate of .05 and power 0.80. Analysis was based on the intention-to-treat population (ITT). Tumor histology was centrally reviewed. Results: 400 pts were entered to the study from Feb 2004 to Sep 2008. Three pts were excluded due to lack of consent from the ITT, which includes 15 pts who did not have GIST at a central review. The median FU time was 54 mos. RFS was longer in the 36-mo group compared to the 12-mo group (HR 0.46, 95% CI 0.32-0.65; p

From 1980 through 1986, 119 patients with soft tissue sarcomas of the extremities were referred to our tumor center either before surgery (n = 78) or immediately after incisional biopsy or marginal excision (n = 41). The tumors were classified according to anatomic location at admittance as subcutaneous (n = 40), intramuscular (n = 30), and extramuscular tumors (n = 49). Open biopsy was omitted in 75 of the 78 patients referred before surgery; the preoperative diagnosis was based on physical and radiographic findings and fine-needle aspiration cytology. The surgical intention for subcutaneous tumor was to obtain a wide margin, which required a cuff of fat tissue around the tumor and inclusion of the deep fascia beneath the tumor. A wide margin for an intramuscular tumor implied no open biopsy and an unbroken muscle fascia or thick muscle cuff around the tumor (primary myectomy). The 70 patients with subcutaneous and intramuscular tumors were all treated by local surgery. A wide margin was obtained in 56 patients who were not given radiotherapy. During a median follow-up of 5 years (range, 3.5 to 10 years), four of these 56 patients--47 of whom had high-grade malignant tumors--had a local recurrence. We conclude that routine combination of limb-sparing surgery with adjuvant radiotherapy is not necessary in patients with soft tissue sarcoma. Two thirds of soft tissue sarcomas of the extremities are primarily subcutaneous or intramuscular tumors, the majority of which can be treated by local surgery without local adjuvant therapy with a local recurrence rate of less than 10%, irrespective of malignancy grade.

From 1982 to 1989, 97 patients with extremity-localized, high-grade osteosarcoma were treated according to the T-10 protocol. Two thirds of the patients consisted of the near-complete national patient materials from Norway and Finland. Eighty patients (82%) received four courses of high-dose methotrexate (HD MTX, 8 to 12 g/m2) at weekly intervals as their only preoperative treatment, and 77 patients (79%) were assessable for histologic response grading according to Rosen et al (Cancer 49:1221-1230, 1991). Observed histologic response was no certain chemotherapy effect (grade I) in 21%, grade II effect in 62%, and grade III or IV effect in 17%. Nonresponders had significantly lower serum MTX concentrations after 24 and 48 hours than responders; the significance of the difference at 48 hours was maintained in a multivariate analysis. After a median follow-up of 45 months, projected 5-year overall and relapse-free survival for all patients were 64% and 54%, respectively. Patients with a good response to preoperative chemotherapy (grade III/IV) had a significantly better survival than grade I/II responders, despite a switch to postoperative cisplatin/doxorubicin chemotherapy in the latter group. These results were obtained in a largely nonselected group of patients. We conclude that a good initial chemotherapy effect is important for the final outcome in osteosarcoma, and that HD MTX alone is insufficient preoperative treatment for the majority of patients. The individual MTX excretion rate is of importance for tumor response, suggesting a dose-response relationship for HD MTX treatment.

Epidemiology and prognosis were analyzed in a consecutive, population‐based series of 137 patients with malignant fibrous histiocytoma of soft tissue in the extremities and trunk wall, with a complete follow‐up of minimum 3 years. All but one patient were treated by surgery in 28 cases combined with adjuvant radiotherapy or chemotherapy. The annual incidence was 0.42/105. The ratio men to women was 1.1. The median age was 64 years (range, 22 to 87 years). The thigh was the most common location. The median size was 6 cm. Superficial tumors constituted 43% and were smaller than deep‐seated tumors. Eighty‐three tumors were storiform‐pleomorphic, 53 were myxoid, and one was of inflammatory type. The myxoid tumors were smaller and more often superficial. The cumulative 5‐year survival rate for all patients was 0.7, but differed markedly between the histologic types; it was 1.0 in patients with myxoid tumors and 0.5 in patients with storiform‐pleomorphic tumors. In the 77 patients with storiform‐pleomorphic tumors without metastases at presentation, only tumor size larger than 10 cm and tumor necrosis independently impaired survival. The 23 patients who had none of these risk factors had a 5‐year survival rate of 0.8. (Less)

A method which is simple, reliable, and rapid to use in clinical routine for basic dose calculation in total body irradiation (TBI) has been tested with 8 MV x-rays. The dosimetry follows, as far as possible, national and international recommendations for conventional radiotherapy. The dose rate at different locations and depths is calculated from the absorbed dose rate at dose maximum for a phantom size of 30 x 30 x 30 cm in the TBI field (Dc), an inverse square law factor (SAD2/SPD2), the tissue-maximum ratio (TMR), an equivalent phantom and patient size correction factor (A), a factor for lack of back-scattering material (B), an off-axis output correction factor (O), and a factor that corrects for off-axis variations in effective photon beam energy and for oblique beam penetration of the patient (R). The collimator opening is constant for all patient sizes. It is shown that TMR, A, B and R can be measured in conventional geometry in ordinary phantoms but at an extended distance, while Dc, O and SAD2/SPD2 must be measured in TBI geometry. Tests in Humanoid phantoms showed an agreement in measured and planned AP/2 doses of 2% or better. If the calculation method is used for lower photon energies or in other TBI geometries it may be necessary to correct for the elliptical shape of the patient and for back-scattered radiation from the walls or floor.

10014 Background: Poor response to induction chemotherapy negatively affects prognosis for Ewing's sarcoma (ES) patients. To improve outcome, high-dose chemotherapy (HDCT) with stem cell rescue was added to conventional chemotherapy in patients poor responders after induction treatment. Methods: Non-metastatic ES patients aged 2-cyclofosfamide 1,200 mg/m2) weeks 0 and 6, IVAc (ifosfamide 9g/m2-vincristin 2 mg-actinomycin 2 mg) week 3 and IE (ifosfamide 9g/m2-etoposide 450 mg/m2) week 9 as induction therapy. Poor response was histologically defined as persistence of microfoci of viable tumor cells and radiologically as persistence of soft tissue mass. As maintenance treatment good responders (GR) received three cycles of VAC-IVAc-IE. Poor responders (PR) received VAC (weeks 13,19), IE (week 22), CE (mobilizing cycle, cyclophoshamide 4g/m2, etoposide 600 mg/m2, week 16) and HDCT with BuMel (busulfan 4 mg/kg × 4 days orally and melphalan 140 mg/m2 with stem cell support week 25). Results: Starting from 1999, 296 patients were enrolled with a median age of 15 years (3–40). 54 % of the tumors were located to the extremities and 46% in the axial skeleton. 274 patients underwent local treatment: surgery in 222 (81%) patients (with post operative Rxt in 70), RxT alone in 52 (19%). 10 patients progressed during treatment. No toxic deaths were recorded. Response evalutation was available for 262 patients: 135 (52%) were PR. 116 of them completed protocol treatment and 19 did not receive HDCT (5 poor harvest, 5 medical contraindication, 9 refusal).With a median follow-up of 37 months (1–89) 5-year overall and event-free survival were 74 % and 65.5% respectively. 5-year event-free survival was 71% (95% CI 62–81%) for GR, 68% (95% CI 58–78%) for PR treated with HDCT and 35% (95% CI 10–60%) for PR who did not receive HDCT. Conclusions: The preliminary survival data show for PR similar outcome as for GR. The treatment including HDCT is feasible with no toxic death recorded. Longer follow-up will confirm its efficacy. No significant financial relationships to disclose.

9002 Background: The ISG-SSG II study was undertaken to explore the effect of adding high-dose chemotherapy (HDCT) with peripheral blood stem cells support (PBSC) to conventional chemotherapy (CT) ...

9004 Background: Metastates at diagnosis are the worst prognostic factor in Ewing’s sarcoma. To ameliorate the prognosis of patients (pts) with lung-pleural and/or solitary bone metastases, ISG-SSG...

Two-hundred and forty adult patients with a high-grade soft tissue sarcoma were treated surgically in 18 hospitals participating in the Scandinavian Sarcoma Group Protocol I. The patients were randomized to either postoperative doxorubicin or control; patients whose surgical margin was judged marginal also received radiotherapy. The outcome after different surgical margins was analyzed in 185 tumors of Grades III or IV in the extremities. The total cumulative local tumor control was 91 percent (168 of 185) after a median of 47 months. The cumulative local control rates in the surgical groups were: compartmental or wide amputation--37/37 (100 percent), compartmental local excision--23/24 (96 percent), wide local excision--77/84 (92 percent), marginal excision and radiotherapy--19/21 (90 percent), and marginal excision alone (reevaluated margin)--12/19 (63 percent, significantly lower than others). The risk of local recurrence was 13 times higher after marginal than after compartmental surgery (P = 0.02) and 3 times higher if the tumor was larger than 10 cm (P = 0.05). The treatment with doxorubicin did not influence the risk of local recurrence. The survival rates did not differ significantly in the groups.

The growth rate of pulmonary metastases was analyzed in eleven patients with soft tissue sarcoma. In cases where more than two examinations were available the growth rate seemed to be exponential. In all but one case microscopic pulmonary spread was calculated to be present when the primary tumor was diagnosed. Tumor doubling time varied between 8 and 198 days in different patients. The variation in growth rate between various nodules in the same patient was much less pronounced but nevertheless considerable, which might, at least partly, be explained by tumor cell polyclonality. Computed tomography of the chest may detect pulmonary metastases earlier than conventional radiography and is therefore recommended in the preoperative work-up in soft tissue sarcoma.

From January 1981 to February 1986, a total of 240 patients with primary, malignancy-grade III or IV soft tissue sarcoma were entered into an adjuvant chemotherapy multicenter trial conducted by the Scandinavian Sarcoma Group (SSG). Of these patients, 181 were evaluable. The tumor was located in the extremities in 155 patients. After radical surgery (wide and compartmental) the patients were randomized to treatment with single-agent doxorubicin 60 mg/m2 administered as an intravenous (IV) bolus once a month for 9 months (group 1, n = 77) or to control (group 2, n = 77). If the surgical procedure was marginal, the patients initially received postoperative radiotherapy, followed by doxorubicin (group 3, n = 16) or control (group 4, n = 11). The control groups did not receive any adjuvant chemotherapy. Adjuvant therapy was initiated within 6 weeks of surgery (group 1) or within 10 weeks of surgery for patients receiving postoperative radiotherapy (group 3). With a median follow-up of 40 months, there was no significant difference between the four treatment groups in overall survival (group 1, 75%; group 2, 70%; group 3, 69%; group 4, 73%), disease-free survival (group 1, 62%; group 2, 56%; group 3, 62%; group 4, 64%), or local tumor control (group 1, 92%; group 2, 92%; group 3, 87%; group 4, 90%). The conclusions were the same whether the total group or evaluable patients only were included in the analysis. The local recurrence rate for patients undergoing radical surgery was 8% and for patients undergoing marginal surgery followed by radiotherapy was 12%. This study indicates that the use of single-agent doxorubicin as postoperative adjuvant chemotherapy has no significant clinical benefit in patients with high-grade soft tissue sarcoma.

Over a period of 3 years in Southern Sweden 35 patients were seen with deep-seated limb sarcomas without metastases, 30 of whom were referred before any operation had been carried out. Thirty seven patients with deep-seated benign lesions were referred during the same period because of suspected malignancy. A preoperative diagnosis considered sufficient for a definitive operation was made from the clinical findings, aspiration cytology and radiographic examination, but without open biopsy, in 59 of these 67 cases. The differentiation between a benign and a malignant tumour was correct in all but one. The extent of excision necessary to achieve adequate margins for a soft-tissue sarcoma can often be reduced if open biopsy is avoided, with preservation of function. We conclude that treatment without open biopsy is possible in the great majority of patients with soft-tissue sarcoma.

From 1981 to 1986, 240 patients with primary, malignancy grade III or IV soft-tissue sarcoma were entered into a randomized adjuvant chemotherapy multicenter trial, conducted by the Scandinavian Sarcoma Group. After a median follow-up time of 46 (2-97) months, a multivariate analysis of risk factors for metastases was performed in 138 radically operated on patients with tumors of the extremities. Adjuvant single-agent doxorubicin did not improve the metastasis-free survival. Histologic malignancy grade IV, tumor size greater than 10 cm, vascular invasion by tumor, and male sex were identified as risk factors. Patients with no or one risk factor had a 5-year metastasis-free survival of 0.7, with two risk factors 0.5, and with three or four risk factors 0.2. The combination of different risk factors provides a prognostic model for soft tissue sarcomas, which could be a basis for therapeutic trials.

From 1981 to 1986, a total of 240 patients with a primary soft tissue sarcoma with malignancy grade III or IV were entered into an adjuvant chemotherapy multicenter trial conducted by the Scandinavian Sarcoma Group (SSG). Histopathologic peer review of all the specimens was performed by an expert pathology committee. The most common soft tissue sarcoma after review was malignant fibrous histiocytoma (MFH) (40%), followed by synovial sarcoma (15%), leiomyosarcoma (9%), liposarcoma (8%), and malignant Schwannoma (6%). In 25% of the cases the histologic type of sarcoma was reclassified, and in 40% of the cases the malignancy grade was changed. By survival analyses, the reclassification of malignancy grade seemed to be valid. Also, grading highly malignant soft tissue sarcoma in two grades (III and IV) increased the prognostic information. Of 164 tumors from the centers with the most reported cases (five centers with 25 to 51 tumors each), eight tumors were found to be ineligible for the adjuvant study (5%); of 76 tumors from 13 centers with few tumors (one to 16 tumors per center), 12 tumors were ineligible (16%). We conclude that histologic peer review is important in studies of soft tissue sarcoma.

We analyzed the management of all the patients with soft tissue sarcoma located in the trunk and extremities in Sweden in 1982. The total fraction of patients referred to musculoskeletal tumor centers for definitive treatment was 0.6. In more than four fifths of the patients operated on at the centers, surgery was performed with a wide or radical margin compared with one fifth of the patients treated at other hospitals. In our center specifically, 10 patients with soft tissue lesions that turned out to be benign were referred per every unoperated on sarcoma patient. The treatment of soft tissue sarcomas outside tumor centers is less than optimal, and centralization is associated with substantially increased referral of patients with benign tumors to catch the majority of soft tissue sarcomas in the virgin state. Information to peripheral hospitals about indications for referral of patients with soft tissue lesions has been effective in our region.

A Ewing's sarcoma of the thigh in a 9-year-old boy was diagnosed by light microscopy, electron microscopy, and chromosomal analysis performed on fine needle aspirates.

With the intention of starting an international protocol between Italy and Scandinavia on neoadjuvant treatment of extremity osteosarcoma using the four active drugs at maximum doses (doxorubicin 75 mg/m2 pre-operatively, and 90 mg/m2 post-operatively, cisplatin 120 mg/m2, methotrexate 12 g/m2, and ifosfamide 15 g/m2), a single center (the Rizzoli institute) performed a pilot study to closely monitor toxicity, safety, and tumor necrosis. Only 7 patients (10%) had a reduced number of the scheduled cycles. A total of 1,050 of the expected 1,076 cycles (98%) were administered. Delays and dose reduction were minimal, leading to a mean received dose intensity of 89%. Limb salvage surgery was performed in 59 cases (87%), with 6 amputations and 3 rotation plasties. Chemotherapy-induced necrosis higher than 95% was observed in 38 patients (56%). Eleven patients had total necrosis (16%). At a median follow-up of 60 months (range 50-65 months), 53 patients (73%) were continuously disease-free. Six of the relapsed patients were rescued with further treatments leading to an overall survival of 87%. Hematological toxicity was remarkable despite the use of G-CSF and hospitalization due to febrile neutropenia occurred in 25 patients (37%). Platelet transfusions were required in 77 of the 194 episodes of grade 4 thrombocytopenia, but no case of major bleeding was observed. Red blood cell transfusions were necessary in all patients (in 15 cases perioperatively only). Non-hematological toxicity comprised grade 1-2 nephrotoxicity in 3 cases, CNS toxicity in 2 cases, and dilata- tive cardiopathy leading to heart transplantation in 1 case. In conclusion, the pilot study was feasible in the vast majority of cases with toxicity not superior to that of the previous protocols where chemotherapy was given in lower doses. The rate of limb salvage procedures, event-free survival and overall survival seemed to be higher than in previous protocols. On the basis of this study, in March 1997 the Italian and Scandinavian Sarcoma Groups started a new protocol for osteosarcoma of the extremities.

The nuclear DNA content of 148 high-grade soft tissue sarcomas of the extremities and trunk was determined by flow cytometry, using tumor material from paraffin-embedded tissue. The patients were part of a prospective randomized clinical trial on the efficacy of adjuvant single-agent chemotherapy with doxorubicin. Chemotherapy did not improve the metastasis-free survival (MFS). After a median follow-up time of 48 months (range, 2 to 97), a multivariate analysis of prognostic factors for developing metastatic disease was performed. DNA aneuploidy was found to be an independent prognostic risk factor in addition to histologic malignancy grade IV, intratumoral vascular invasion, tumor size over 10 cm, and male sex. Patients with none or one risk factor had a 5-year MFS of 79%, with two risk factors 65%, with three risk factors 43%, and with four and five risk factors 0%. About one half (78 of 148) of the patients with three factors or less belonged to a group with a MFS over 60%. The combination of different risk factors, including DNA aneuploidy, seems to be a useful prognostic model for soft tissue sarcomas, which could be of value to select high-risk patients for further trials with adjunctive therapy.

Adjuvant imatinib administered for 12 months after surgery has improved recurrence-free survival (RFS) of patients with operable gastrointestinal stromal tumor (GIST) compared with placebo.To investigate the role of imatinib administration duration as adjuvant treatment of patients who have a high estimated risk for GIST recurrence after surgery.Patients with KIT-positive GIST removed at surgery were entered between February 2004 and September 2008 to this randomized, open-label phase 3 study conducted in 24 hospitals in Finland, Germany, Norway, and Sweden. The risk of GIST recurrence was estimated using the modified National Institutes of Health Consensus Criteria.Imatinib, 400 mg per day, orally for either 12 months or 36 months, started within 12 weeks of surgery.The primary end point was RFS; the secondary end points included overall survival and treatment safety.Two hundred patients were allocated to each group. The median follow-up time after randomization was 54 months in December 2010. Diagnosis of GIST was confirmed in 382 of 397 patients (96%) in the intention-to-treat population at a central pathology review. KIT or PDGFRA mutation was detected in 333 of 366 tumors (91%) available for testing. Patients assigned for 36 months of imatinib had longer RFS compared with those assigned for 12 months (hazard ratio [HR], 0.46; 95% CI, 0.32-0.65; P.001; 5-year RFS, 65.6% vs 47.9%, respectively) and longer overall survival (HR, 0.45; 95% CI, 0.22-0.89; P = .02; 5-year survival, 92.0% vs 81.7%). Imatinib was generally well tolerated, but 12.6% and 25.8% of patients assigned to the 12- and 36-month groups, respectively, discontinued imatinib for a reason other than GIST recurrence.Compared with 12 months of adjuvant imatinib, 36 months of imatinib improved RFS and overall survival of GIST patients with a high risk of GIST recurrence.clinicaltrials.gov Identifier: NCT00116935.