[The type of local treatment conditions the prognosis in patients with nonmetastatic Ewing's sarcoma of the extremities treated with adjuvant chemotherapy]. / Il tipo di trattamento locale condiziona la prognosi in pazienti con sarcoma di Ewing delle estremità non metastatico trattati con chemioterapia associata.

The results obtained in 172 cases of non metastatic Ewing's sarcoma of the extremities are reported. The patients were advised to undergo surgical treatment, followed by radiotherapy (40-45 Gy) in case of inadequate surgical margins. 48 patients who refused surgical treatment, were locally treated with radiotherapy alone (50-65 Gy). With a mean follow-up of 8 years (R. 3-15) 101 patients (58.7%) are free of disease and 68 relapsed with metastases and/or local recurrence. A radio-induced bone sarcoma developed in two patients, one patient died of ADM cardiomyopathy. No differences in terms of risk factors were observed between patients who were or were not treated with surgery. A better DFS was observed in the patients treated with surgery (66.9%) in comparison with those treated with radiotherapy alone. The higher percentage of local recurrences observed in patients treated with radiotherapy alone seems to be responsible for the worse prognosis observed in these patients. The authors' conclusion is that the local control in patients with non metastatic Ewing's sarcoma should always be achieved by means of surgery.

[A prospective study on nephrotoxicity induced by continuous infusion of high-dose ifosfamide (15/m2)]. / Studio prospettico della tossicità renale da alte dosi di ifosfamide (15/m2) in infusione continua endovenosa.

BACKGROUND: A good response rate to high-dose ifosfamide (HDIFO) has been reported in metastatic osteosarcoma and soft tissue tumors. As standard dose of IFO (< 12 g/m2) can give several renal complications and patients previously treated with nephrotoxic drugs are at high risk of nephrotoxicity, a prospective study to evaluate the pattern of nephrotoxicity induced by HDIFO was carried out. METHODS: Twelve patients (11 metastatic osteosarcoma, 1 synovial sarcoma; mean age 17, R 14-34) were treated with 4 courses of HDIFO/ MESNA (15 g/m2, IV 5 day continuous infusion with bicarbonate and K supplements). All but two were previously treated with cisplatin and methotrexate. Several parameters of renal function were measured before treatment, after each HDIFO course and two months after chemotherapy completion. RESULTS: Significant changes in the urinary excretion of beta 1-microglobulin, beta 2-microglobulin, Alanine Aminopeptidase, N-Acetil-beta, D-glucosaminidase and a significant reduction in phosphate tubular absorbtion according to the cumulative dose of IFO infused, were observed. Phosphaturia and hypophosphatemia occurred in all the patients studied. In 5 patients, CrCl fell below 70 ml/min with normal serum creatinine level after 45 g/m2 IFO. Plasma bicarbonate concentration less than 20 mmol/l was observed in 5 of 48 HDIFO courses. Glycosuria was detected in 4 patients. Two months after chemotherapy completion, mild glycosuria and slightly reduced CrCl persisted in two patients, whereas the other parameters of renal function studied were similar to the baseline values. An acute, usually reversible subclinical nephrotoxicity involving glomerule and renal tubule was demonstrated in all the patients treated with HDIFO. A persisting subclinical renal impairment was shown with mild glycosuria (2/12 patients) and slightly reduced CrCl (2/12 patients).

Methotrexate serum concentration and histological response to multiagent primary chemotherapy for osteosarcoma of the limbs.

The authors investigated the influence of methotrexate (MTX) serum concentration on (histologically evaluated) tumor necrosis, induced by a primary multiagent chemotherapy, including MTX, for osteosarcoma. MTX serum peaks in 151 patients, preoperatively treated with MTX (8-12g/m2), cisplatin (120mg/m2) and Adriamycin (60mg/m2), were analyzed. Significantly (p < 0.01) higher serum MTX mean peaks were observed in patients with complete tumor necrosis (MTX 773.8 mumol/l) compared to patients with 90-99% tumor necrosis (639.8 mumol/l), 50-89% tumor necrosis (649.1 mumol/l) or less than 50% tumor necrosis (610 mumol/l). Complete tumor necrosis was observed in 9% of patients with MTX peaks of less than 600 mumol/l, in 27% of patients with serum MTX peaks between 600 and 699 mumol/l and in 37% of those with MTX peaks ranging from 700 to 799 mumol/l. Higher MTX peaks (800-899, 900-999, > 1000 mumol/l) were not associated with a further increase of cases with complete tumor necrosis. 40% of patients with an MTX peak greater than 700 mumol/l had complete tumor necrosis, compared to 15.5% of patients who did not reach this value (p < 0.002). At a multivariant analysis including age, sex, tumor site and volume, pretreatment serum alkaline phosphatase and lactic dehydrogenase levels, MTX peaks of 700 mumol/l and, less significantly, the histologic type (telangiectatic osteosarcoma), were independent factors influencing tumor necrosis. The authors conclude that MTX serum peaks significantly influence chemotherapy-induced tumor necrosis in osteosarcoma. In a primary treatment consisting of cisplatin, Adriamycin and MTX, complete tumor necrosis can be obtained in 40% of patients with MTX peak concentrations > or = 700 mumol/l.

The role of corrected QT interval in the cardiologic follow-up of young patients treated with Adriamycin.

UNLABELLED: The behavior over time of the corrected QT interval (QTc) in patients treated with Adriamycin (ADM) was evaluated in order to detect any possible correlations between the modifications of the QTc duration and the cardiac function of patients treated with different cumulative doses of ADM (360, 390, 480 mg/m2). PATIENTS AND METHODS: Electrocardiograms (ECGs) performed 2 months (178 patients), 1 year (65) and 3 years (43) after the completion of chemotherapy, were examined. RESULTS: after 2 months a prolonged QTc interval (> or = 0.45 sec) was found in 50% of patients, after 1 year in 26% and after 3 years in 14%. The patients treated with the highest dose of the drug (480 mg/m2) showed the highest incidence of prolonged QTc intervals. No patients treated with 360 mg/m2 ADM showed prolonged QTc intervals after 3 years. No correlations between prolonged QTc and functional echocardiographic alterations were noticed. The QTc interval prolongation, easily observable after treatment with ADM, seems to be related to the quantity of the drug administered and is generally a reversible phenomenon. Nevertheless a prolonged QTc can persist after 3 years. The persistence of prolonged QTc intervals is not associated with a higher incidence of functional cardiac deficits which are echocardiographically detectable.

Neoadjuvant chemotherapy for malignant fibrous histiocytoma of bone and for osteosarcoma of the limbs: a comparison between the results obtained for 21 and 144 patients, respectively, treated during the same period with the same chemotherapy protocol.

Twenty-one patients affected with malignant fibrous histiocytoma localized in the limbs were treated by pre- and postoperative chemotherapy (neoadjuvant). Preoperatively methotrexate (i.v.), cisplatinum (i.a.), and adriamycin (i.v.) were administered. Postoperatively the same drugs (in patients who responded well) or with the addition of ifosfamide and VP 16 (in those who responded poorly) were administered. Twenty resections and 1 amputation followed. The response to chemotherapy was good in 7 patients, and poor in 14. At a mean follow-up of 6.3 years 15 patients were disease-free and 6 had relapses. These results appear to be comparable to those for 144 patients affected with osteosarcoma of the limbs treated at the same time with the same protocol. The percentage of good responses and pulmonary metastases was higher in cases of osteosarcoma. Pre- and postoperative chemotherapy increases the percentage of healing in malignant fibrous histiocytoma. The lower percentage of good responses and the different type of relapse as compared to osteosarcoma indicate that preoperatively chemotherapy different from that used for osteosarcoma should be conducted.

[Neoadjuvant chemotherapy in malignant fibrous histiocytoma of the limbs: 10 years of experience (1983-1992) at the Rizzoli Orthopedic Institute]. / Chemioterapia neoadjuvante dell'istiocitoma fibroso maligno delle estremità: 10 anni di esperienze (1983-1992) all'Istituto Ortopedico Rizzoli.

During the period September 1983 to December 1991, 47 patients with nonmetastatic malignant fibrous histiocytoma (MFH) of the limbs were treated using 3 different protocols of neoadjuvant chemotherapy activated at successive intervals. Surgery consisted of limb salvage in 41 cases and amputation in 6. After a mean follow-up of 6.5 years 33 patients (70%) had been continuously disease-free and 14 had undergone relapses. In the latter group the first sign of recurrence was metastasis in 12 cases and local recurrence in 2 cases. These results are distinctly better than those obtained in 20 patients treated during the same period using surgery alone (24% of disease-free survival and 30% local recurrence), and compared to those obtained in an earlier study in which surgery was associated with postoperative chemotherapy alone (59% of disease-free survival and 25% of local recidivation). The authors conclude that, as already observed in the case of osteosarcoma, neoadjuvant chemotherapy can significantly improve prognosis even in patients with bone MFH localised in the limbs. Moreover, given that, contrary to adjuvant chemotherapy, associated chemotherapy is effective not only in controlling the microscopic disease but also reducing the incidence of local recurrence, it enables amputation to be avoided in the majority of patients.

[Non-metastatic osteosarcoma of the extremities: the pattern of relapse as a function of the type of treatment and of the modulation of the radiological follow-up of the thorax]. / Osteosarcoma non metastatico delle estremità: pattern di ricaduta in funzione del tipo di trattamento e modulazione del follow-up radiologico del torace.

The authors analysed the patterns of recurrence of osteosarcoma of the extremities treated between 1959 and 1989 either with surgery alone (1959-71) or with combined surgery and adjuvant (1972-82) or neoadjuvant chemotherapy (1983-89). In a total of 452 patients with recurrent osteosarcoma, the initial site of metastasis was the lung in 88% of cases independently of the type of treatment received. The mean period of onset of pulmonary metastasis differed according to the type of treatment performed: 8 months for patients treated with surgery alone; 15.9 months for those treated with adjuvant chemotherapy and 20.3 months for patients treated with neoadjuvant chemotherapy. The incidence of metastases appearing within 12 months of FU was 87%, 56% and 21% respectively. In a most recent and effective neoadjuvant protocol (66% DFS), the incidence of recurrence owing to pulmonary metastasis during the first year of FU was 2% and as much as 75% of all recurrences were concentrated in the following 18 months. Surgery for pulmonary metastasis in patients undergoing chemotherapy was performed in 54 cases with secondary healing in 14 (26%). On the basis of these results the authors suggest a scheme of radiological follow-up for patients with osteosarcoma of the extremities treated with neoadjuvant chemotherapy with intensified controls (every 2 months) during the period with the highest risk of recurrence (13-20 months) and four-monthly controls during the first year and after 31 months of FU. In order to increase the efficacy of FU controls during the high-risk period, the a. propose using CT controls instead of chest X-rays at months 14, 20 and 26.

[Neoadjuvant treatment of Ewing's sarcoma: results obtained in 122 patients treated with a 6-drug chemotherapeutic protocol (vincristine, adriamycin, cyclophosphamide, dactinomycin, ifosfamide and etoposide)]. / Trattamento neoadjuvante del sarcoma di Ewing: risultati ottenuti in 112 pazienti trattati con un protocollo chemioterapico a 6 farmaci (vincristina, adriamicina, ciclofosfamide, deactinomicina, ifosfamide ed etoposide).

From January 1988 to October 1991, one hundred and twelve patients with non metastatic Ewing's sarcoma of bone were treated with a 6 drugs neoadjuvant chemotherapy protocol (IOR/Ew2) in which, to the four drugs usually used in the treatment of this tumor (vincristine, adriamycin, cyclophosphamide and dactinomycin), Ifosfamide and VP-16 were added. The local treatment consisted of radiation therapy in 52 cases, a surgical treatment was performed in 27 cases and in the remaining 33 cases both the previous treatments were used. At a mean follow-up of 4.5 years (3-6.5), 62 patients (55.3%) remained continuously free of disease and 50 relapsed: 41 with metastases, 8 with mestastases and local recurrence and 1 with local recurrence alone. These results do not differ from the ones obtained in our Institution in 98 patients treated between 1983 and 1988 with a neoadjuvant protocol (IOR/Ew1) in which only VCR, ADM, CTX and actD were used (3 year CDFS: IOR/Ew2 = 60.7%-IOR/Ew1 = 55.1%). In IOR/Ew2 a higher DFS rate was observed in the patients with tumor located in the axile bones in comparison with that obtained in the previous study (IOR/Ew2 = 48.6%, IOR Ew1 = 25.6%). Despite the fact that these results came from a not-randomized study, the authors conclude that the addition of Ifosfamide and VP-16 to the four drugs standard regimen do not improve the outcome of patients with Ewing's sarcoma of bone, with the possible exception of the patients with tumor located in the axile bones. This data should be confirmed in further and larger studies.

Changing pattern of relapse in osteosarcoma of the extremities treated with adjuvant and neoadjuvant chemotherapy.

In 551 patients with osteosarcoma of the extremities treated between 1980 and 1991 in our Institution with surgery only (35 cases), surgery combined with adjuvant chemotherapy (147 cases) or neoadjuvant chemotherapy (369 cases) the relapse patterns were analyzed. Adjuvant chemotherapy was performed according to 2 different protocols and neoadjuvant chemotherapy according to 3 different protocols successively activated. In the 252 patients who relapsed, the interval between initial treatment and first relapse was significantly longer in the group treated with adjuvant and neoadjuvant chemotherapy (18.1 and 21.3 mo) than in the group treated with surgery only (5.4 mo). For patients treated with neoadjuvant chemotherapy, a longer interval was seen in the most effective regimen of neoadjuvant chemotherapy (25 mo). No significant differences were seen among the 3 groups, according to the site of first metastasis, although in patients treated with the most effective neoadjuvant regimen there was a higher incidence of bone metastasis. In patients who relapsed with pulmonary metastases the average number of nodules seen by standard X-rays, as well as CT scans, was significantly higher in patients treated with surgery only (3.6) than in patients treated with adjuvant or neoadjuvant chemotherapy (2.5 and 2.6 nodules). We conclude that these changes in metastatic pattern in patients treated with adjuvant and neoadjuvant chemotherapy are important, because they may encourage the use of salvage therapy with thoracotomy in a larger number of patients. Prolongation of time relapsed after more effective regimens of adjuvant and neoadjuvant chemotherapy should be considered when evaluating the preliminary results of new chemotherapy protocols.

[Nonmetastatic osteosarcoma of the limbs treated with neoadjuvant chemotherapy: correlation of tumor volume evaluated by CT and prognosis]. / Osteosarcoma non-metastatico delle estremità trattato con chemioterapia neoadjuvante: correlazione fra volume del tumore valutato mediante TC e prognosi.

A relationship between tumor volume and prognosis has been demonstrated in extraosseaous solid tumors, soft tissue tumors and Ewing's sarcoma. Fifty-five osteosarcoma patients, treated according to IOR-OS/NEO 3 protocol, have been studied in an attempt to verify if tumor volume is also a significant prognostic factor for the osteosarcoma of the extremities. Tumor volume was measured by CT-Scan. A trend towards a better prognosis for smaller tumors was observed, but no statistically significant differences were demonstrated according to the tumor size in the population studied. The authors conclude that for patients with osteosarcoma of the extremities, tumor volume can not be considered an adequate prognostic factor on the basis of which to tailor the chemotherapy treatment, as been recently proposed by other authors.

Prognostic significance of serum lactate dehydrogenase in patients with osteosarcoma of the extremities.

Six hundred and fifty-six patients with osteosarcoma of the extremities (107 metastatic and 549 with localized disease) were followed from 2.5 to 20 years (average: 10 years) to evaluate whether their pretreatment serum lactate dehydrogenase (LDH) enzyme levels had a clinical value in predicting the course of the disease. The percentage of patients who had an elevated serum LDH at the time of diagnosis was significantly higher in those patients with metastatic disease than those who had localized disease (64% versus 33%, p < 0.0001). For those who presented with localized disease and had an increased serum LDH level, far more ultimately developed a relapse of disease (60% versus 38%, p < 0.0001) than those patients with a normal pre-treatment value. The prognostic significance of the serum LDH was more pronounced for the 247 patients treated with adjuvant chemotherapy (relapse rate of 72% versus 48%; p < 0.0002) than the 271 patients treated with neoadjuvant chemotherapy (relapse rate: 46% versus 28%, p < 0.005). Following treatment, serum LDH levels almost uniformly returned to normal and no correlation between postoperative levels and relapse of disease could be identified. We have demonstrated that in patients with osteosarcoma of the extremities, pretreatment serum LDH levels have a definite prognostic value which should be considered when comparing the results achieved with different therapeutic protocols and in planning new randomized clinical trials.