Alessandra Longhi - Academia.edu (original) (raw)

Papers by Alessandra Longhi

Research paper thumbnail of Neoadjuvant Chemotherapy With High-Dose Ifosfamide, High-Dose Methotrexate, Cisplatin, and Doxorubicin for Patients With Localized Osteosarcoma of the Extremity: A Joint Study by the Italian and Scandinavian Sarcoma Groups

Journal of Clinical Oncology, 2005

Purpose To explore the effect of high-dose ifosfamide in first-line treatment for patients ≤ 40 y... more Purpose To explore the effect of high-dose ifosfamide in first-line treatment for patients ≤ 40 years of age with nonmetastatic osteosarcoma of the extremity. Patients and Methods From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m2), methotrexate (12 g/m2), cisplatin (120 mg/m2), and doxorubicin (75 mg/m2). Postoperatively, patients received two cycles of doxorubicin (90 mg/m2), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m2). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination. Results No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result ...

Research paper thumbnail of Ifosfamide and Actinomycin-D, Added in the Induction Phase to Vincristine, Cyclophosphamide and Doxorubicin, Improve Histologic Response and Prognosis in Patients with Non Metastatic Ewing's Sarcoma of the Extremity

Journal of Chemotherapy, 1998

The role of ifosfamide as first-line chemotherapy treatment of non metastatic Ewing's sar... more The role of ifosfamide as first-line chemotherapy treatment of non metastatic Ewing's sarcoma of the extremity is still under discussion. The purpose of this paper is to report the results achieved in a neoadjuvant protocol (REN-3) in which ifosfamide, added to the conventional VACA regimen, was employed since the induction phase. Induction chemotherapy consisted of vincristine, cyclophosphamide, doxorubicin, actinomycin-D and ifosfamide. After local treatment, patients received the drugs used in the induction phase and etoposide. Between November 1991 and November 1994, 61 patients with non metastatic Ewing's sarcoma of the extremity were treated. Forty-nine patients underwent surgery and 73.5% of them had a good histologic response. At a median follow-up of 60 months (range 32-76), 48 patients (79%) remained continuously disease-free. The 5-year event-free and overall survival were 77% and 87%, respectively. These results were significantly better both in terms of histologic response or event-free and overall survival than those obtained in 58 patients with non metastatic Ewing's sarcoma of the extremity treated in a previous protocol (REN-2) in which the same drugs were used, but ifosfamide was employed only in the maintenance phase. The present study suggests the importance of early use of ifosfamide in the treatment of patients with non metastatic Ewing's sarcoma of the extremity.

Research paper thumbnail of Osteosarcoma of the limb

The Journal of Bone and Joint Surgery, 2002

ABSTRACT We have studied 560 patients with osteosarcoma of a limb, who had been treated by neoadj... more 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 local and systemic recurrence according to the type of surgery undertaken. Of these, 465 patients 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 60.7% and 68.5%, respectively, with no significant difference between patients undergoing amputation and those 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 a local recurrence was significantly worse than for those who had recurrent disease with metastases only. We conclude that limb-salvage procedures are relatively safe in osteosarcoma treated by neoadjuvant 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.

Research paper thumbnail of The role of surgical margins in treatment of Ewing’s sarcoma family tumors: Experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy

International Journal of Radiation Oncology*Biology*Physics, 2006

To evaluate the importance of surgical margins for local and systemic control of Ewing&am... more To evaluate the importance of surgical margins for local and systemic control of Ewing's sarcoma family tumors (ESFT). Between 1979 and 1999, 512 patients with ESFTs entered 4 different adjuvant and neoadjuvant studies performed at a single institution. Of these patients, 335 were treated with surgery alone (196) or surgery followed by radiotherapy at doses of 44.8 Gy (139). We compared their outcome with that of the 177 patients who were locally treated by radiotherapy at 60 Gy. Local control (88.8% vs. 80.2%, p < 0.009) and 5-year disease-free survival (63.8% vs. 47.6%, p < 0.0007) were significantly better in patients treated with surgery and, among them, in those with adequate surgical margins (96.6% vs. 71,7%, p < 0.0008, and 69.6% vs. 46.3%, p < 0.0002). Nonetheless, better results were observed only in extremity tumors. Surgery is better than radiotherapy in cases of extremity ESFT with achievable adequate surgical margins, and in cases of inadequate surgical margins, adjuvant reduced-dose radiotherapy is ineffective. Therefore, when inadequate margins are expected, patients are better treated with full-dose radiotherapy from the start.

Research paper thumbnail of Treatment of nonmetastatic Ewing’s sarcoma family tumors of the spine and sacrum: the experience from a single institution

European Spine Journal, 2009

The objective of this study is to determine the best local treatment combined with neoadjuvant ch... more The objective of this study is to determine the best local treatment combined with neoadjuvant chemotherapy for ESFT of the spine and sacrum, for the best local treatment for Ewing sarcoma family tumors (ESFT) according to the primary site is still unclear. Nowadays surgery is used in local treatment of ESFT, but literature is scarce on the best local treatment in sites where surgery is problematic, such as the spine. This study evaluates the outcome and the rate of local recurrence of ESFT in the spine and sacrum when treated with neoadjuvant chemotherapy, and locally by radiotherapy alone or surgery, followed by reduced doses of radiotherapy. Forty-three patients with nonmetastatic ESFT located in the spine and sacrum were treated at our institution between 1983 and 2000 with neoadjuvant chemotherapy, and locally by radiotherapy alone in 26 cases, and surgery followed by radiotherapy at reduced doses in 17. The 5-and 10-year

Research paper thumbnail of A comparison of methods of loco-regional chemotherapy combined with systemic chemotherapy as neo-adjuvant treatment of osteosarcoma of the extremity

European Journal of Surgical Oncology (EJSO), 2001

Our experience of pre-operative intraarterial (i.a.) vs intravenous (i.v.) infusion of cisplatinu... more Our experience of pre-operative intraarterial (i.a.) vs intravenous (i.v.) infusion of cisplatinum (CDP) in a multiagent neo-adjuvant chemotherapy for osteosarcoma of the extremity is reported. Methods: Two successive randomized studies were performed. In the first, pre-operatively, CDP i.a. vs CDP i.v. was applied in combination with high-dose methotrexate (HDMTX) and adriamycin (ADM) within a three-drug regimen. In the second, a combination of HDMTX, ADM and IFO, within a four-drug regimen was tested. Results: The rate of responses to chemotherapy (tumour necrosis [90%) was significantly higher (P<0.04) for the 142 patients treated with the four-drug regimen than in the 79 patients treated with a three-drug regimen (76% vs 62%). According to the route of CDP infusion, in the three-drug regimen the rate of responses was significantly higher (P=0.004) in patients treated with i.a. CDP (77%) than in patients treated i.v. (46%); with the four-drug regimen the rate of response was not significantly different in patients treated i.a. (81%) and in patients treated i.v. (71%). No significant differences in the rates of limb salvages, local recurrence and event-free survival (EFS) were seen between the i.a. and the i.v. groups. Conclusion: In the treatment of osteosarcoma of the extremity, the i.a. infusion of CDP does not offer any significant advantage when this drug is used within an aggressive, multiagent, pre-operative four-drug regimen.

Research paper thumbnail of Pattern of relapse in 290 patients with nonmetastatic Ewing's sarcoma family tumors treated at a single institution with adjuvant and neoadjuvant chemotherapy between 1972 and 1999

European Journal of Surgical Oncology (EJSO), 2006

Aims: Evaluation of pattern of recurrences of 290 patients with an Ewing's sarcoma family tumor (... more Aims: Evaluation of pattern of recurrences of 290 patients with an Ewing's sarcoma family tumor (ESFT), who relapsed after adjuvant or neoadjuvant chemotherapy. Methods: Retrospective analysis at a median follow-up of 16.6 years (range: 5e32) from the primary therapy. Results: There were 378 recurrences, treated by surgery, and/or chemotherapy, radiotherapy, or only palliative treatments. At the last control 18 patients were alive and free of disease 2.5 to 20 years (median 12.1 year) from the last treatment, 4 were alive with uncontrolled disease, 2 died of second line chemotherapy-related toxicity, and 266 died of the tumor 4 months to 20.5 years from the first relapse (median 3.2 years). The 5-year event free survival after the last relapse and overall survival were 5.1 and 7.9%, respectively, and resulted significantly correlated with the time of first relapse, the site of first metastases, the treatment performed after relapse (all patients presently free of disease had been treated by surgery alone or combined with a second line chemotherapy) and for patients treated with neoadjuvant chemotherapy and locally by surgery, with the histologic response to preoperative chemotherapy. Conclusions: We confirm that the post-relapse outcome of patients with ESFT who relapse after conventional treatment is very poor. Nonetheless specific subgroups of patients may be cured even after 2 or 3 relapses: patients who relapse 2 or more years after primary treatment, patients who relapse with only lung metastases, and patients whose recurrences can be surgically treated.

Research paper thumbnail of A comment and update on “Does the histological subtype of high-grade central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the European Osteosarcoma Intergroup”

European Journal of Cancer, 2003

Research paper thumbnail of Neoadjuvant chemotherapy for Ewing's tumour of bone: recent experience at the Rizzoli Orthopaedic Institute

European Journal of Cancer, 2002

The results achieved in 157 patients with non-metastatic Ewing's sarcoma of the bone treated at a... more The results achieved in 157 patients with non-metastatic Ewing's sarcoma of the bone treated at a single institution between 1991 and 1997 according to a new protocol (REN-3) are reported. Induction chemotherapy consisted of two cycles of 'VAC': vincristine (V), doxorubicin (A), cyclophosphamide (C) alternated with one cycle of 'VIAc': V, ifosfamide (I), actinomycin (Ac). After local treatment, patients received three more cycles of VAC, two of VIAc, three cycles of I plus etoposide (E) and two cycles with V, C and Ac. Local treatment was surgery in 53% of patients, surgery+radiotherapy in 25% and radiotherapy only in 22%. With a follow-up ranging between 4 and 10 years (mean: 7 years), 110 patients (70%) remained continuously event-free, 2 patients died of toxicity and 45 patients relapsed: 33 due to metastases and 12 due to local recurrence always associated with metastases. The 5-year event-free survival (EFS) and overall survival (OS) were 71.0 and 76.5% respectively. These results are significantly better that the ones achieved in our previous three studies in which a three-drug VAC regimen (REA-1), and 4-drug VACAc regimen (REA-2 and REN-1) was used, and in our most recent study (REN-2) which was based on a six-drug regimen as in the present study, but where I and Ac were used only after the local treatment. However, since REN-3 surgery was used in a significantly larger number of patients, we cannot say whether the better outcome of this study was due to the use of a six-drug regimen with an early delivery of ifosfamide and actinomycin, or to the wider use of surgery as local treatment or both. #

Research paper thumbnail of Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution

European Journal of Cancer, 2005

To determine whether necrosis induced by pre-operative chemotherapy correlates with the rate of s... more To determine whether necrosis induced by pre-operative chemotherapy correlates with the rate of systemic and local relapse, may change the pattern of relapse and/or may modify the chance of success of post-relapse treatments, we evaluated 881 patients with non-metastatic osteosarcoma of the extremities treated with five different protocols of neoadjuvant chemotherapy and surgery at the same institution between 1983 and 1999. The 5-year disease-free survival (DFS) and overall survival (OS) correlated significantly with the histological response to chemotherapy. Five-year DFS and OS in good and poor responders were 67.9% versus 51.3% (P < 0.0001) and 78.4% versus 63.7% (P < 0.0001), respectively. The prognostic value of the histological response was valid only for osteoblastic and telangiectatic osteosarcoma subtypes. Nonetheless, since they represent more than 70% of all osteosarcomas, we conclude that chemotherapy-induced necrosis has a significant prognostic value, regardless of the type of chemotherapy performed after surgery.

Research paper thumbnail of A comment on “Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders”

European Journal of Cancer, 2003

We read with interest the paper of Smeland and colleagues [1] about prognostic factors in 113 pat... more We read with interest the paper of Smeland and colleagues [1] about prognostic factors in 113 patients with osteosarcoma of the extremities treated in the last neoadjuvant study of the SSG. In their paper, the authors reported that only three factors appeared to influence the prognosis of these patients: gender, tumour volume at a cut-off of 190 ml, and the mean serum level of methotrexate (MTX) at the 24th hour.

Research paper thumbnail of Histologic Response of High-Grade Nonmetastatic Osteosarcoma of the Extremity to Chemotherapy

Clinical Orthopaedics and Related Research, 2001

In 510 patients with osteosarcoma of the extremity treated at the authors&amp;amp;amp;amp;#39... more In 510 patients with osteosarcoma of the extremity treated at the authors&amp;amp;amp;amp;#39; institute between March 1983 and June 1995 with different regimens of neoadjuvant chemotherapy, factors that influenced the histologic response were investigated. The rate of total necrosis was not related to the patients&amp;amp;amp;amp;#39; gender, age, site, size of tumor, serum of alkaline phosphatase values, or route of cisplatin administration. The histologic response significantly and independently correlated with the number of drugs administered before surgery and with the histologic subtype of the tumor. According to the number of drugs used, the percentage of total necrosis was 31% for a four-drug regimen, 18% for a three-drug regimen, and only 1.5% for a two-drug regimen. According to the histologic type, the rates of total necrosis were 41% for telangiectatic tumors, 36% for fibroblastic tumors, 15% for osteoblastic tumors, and 3% for chondroblastic tumors. The authors concluded that in neoadjuvant therapy of osteosarcoma, the histologic response to preoperative treatment, which correlates with prognosis, depends on the effectiveness of the chemotherapy regimen and on some features intrinsically inherent to the tumor. These data should be considered when selecting the type of treatment (adjuvant or neoadjuvant) and the combinations of drugs to be used in preoperative treatment of patients with osteosarcoma.

Research paper thumbnail of Insulin Receptor Isoform A and Insulin-like Growth Factor II as Additional Treatment Targets in Human Osteosarcoma

Cancer Research, 2009

Despite the frequent presence of an insulin-like growth factor I receptor (IGFIR)-mediated autocr... more Despite the frequent presence of an insulin-like growth factor I receptor (IGFIR)-mediated autocrine loop in osteosarcoma (OS), interfering with this target was only moderately effective in preclinical studies. Here, we considered other members of the IGF system that might be involved in the molecular pathology of OS. We found that, among 45 patients with OS, IGF-I and IGFBP-3 serum levels were significantly lower, and IGF-II serum levels significantly higher, than healthy controls. Increased IGF-II values were associated with a decreased disease-free survival. After tumor removal, both IGF-I and IGF-II levels returned to normal values. In 23 of 45 patients, we obtained tissue specimens and found that all expressed high mRNA level of IGF-II and >IGF-I. Also, isoform A of the insulin receptor (IR-A) was expressed at high level in addition to IGFIR and IR-A/IGFIR hybrids receptors (HR A ). These receptors were also expressed in OS cell lines, and simultaneous impairment of IGFIR, IR, and Hybrid-Rs by monoclonal antibodies, siRNA, or the tyrosine kinase inhibitor BMS-536924, which blocks both IGFIR and IR, was more effective than selective anti-IGFIR strategies. Also, anti-IGF-II-siRNA treatment in low-serum conditions significantly inhibited MG-63 OS cells that have an autocrine circuit for IGF-II. In summary, IGF-II rather than IGF-I is the predominant growth factor produced by OS cells, and three different receptors (IR-A, HR A , and IGFIR) act complementarily for an IGF-IImediated constitutive autocrine loop, in addition to the previously shown IGFIR/IGF-I circuit. Cotargeting IGFIR and IR-A is more effective than targeting IGF-IR alone in inhibiting OS growth. [Cancer Res 2009;69(6):2443-52]

Research paper thumbnail of Reproductive functions in female patients treated with adjuvant and neoadjuvant chemotherapy for localized osteosarcoma of the extremity

Cancer, 2000

The side effects of chemotherapy on ovarian and reproductive functions in female patients who rec... more The side effects of chemotherapy on ovarian and reproductive functions in female patients who received adjuvant and/or neoadjuvant treatment for localized osteosarcoma of the extremities at our institution in the last 21 years (1974-1995) were assessed. Ninety-two patients with a mean actual age of 26 (14-51) were interviewed. They had been followed 3 to 16 years after treatment (mean: 9.6 yrs). Twenty-four of them had received chemotherapy before puberty and 68 after puberty. Amenorrhea during chemotherapy occurred in 69% of postpuberal patients but only in 2 patients aged 39 and 43, respectively, was permanent. After the end of treatment, the patients&amp;amp;#39; menstrual activity started again, and only a slight number of cases showed increases of menstrual irregularities. Twenty-two patients married after treatment; 20 patients started a pregnancy at a mean age of 27. Of these 20 patients, 3 had voluntary abortions and 17 succeeded. At the time of article submission, three were pregnant, 14 had 19 full term pregnancies, and no birth defects nor congenital anomalies were registered in their 19 full term newborns. In this group of female patients, chemotherapy seemed to alter neither their reproductive function nor the health of their newborns.

Research paper thumbnail of Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity

Cancer, 2003

In primary central high-grade osteosarcoma, a number of distinct subtypes have been identified, b... more In primary central high-grade osteosarcoma, a number of distinct subtypes have been identified, but little is known about the response to chemotherapy.

Research paper thumbnail of Influence of local recurrence on survival in patients with extremity osteosarcoma treated with neoadjuvant chemotherapy

Cancer, 2006

BACKGROUND. Risk factors for local recurrence (LR) after osteosarcoma, such as surgical margins a... more BACKGROUND. Risk factors for local recurrence (LR) after osteosarcoma, such as surgical margins and histologic response to preoperative treatment, have been well documented, whereas the outcome for patients who locally recur has not been well established yet.

Research paper thumbnail of Prognostic significance of serum alkaline phosphatase measurements in patients with osteosarcoma treated with adjuvant or neoadjuvant chemotherapy

Cancer, 1993

tic protocols and in planning new randomized clinical trials. Cancer 1993; 71:1224-30.

Research paper thumbnail of No correlation between methotrexate serum level and histologic response in the pre-operative treatment of extremity osteosarcoma

Anti-Cancer Drugs, 2006

Our objectives were to evaluate the behavior of different doses of pre-operative methotrexate (MT... more Our objectives were to evaluate the behavior of different doses of pre-operative methotrexate (MTX) pharmacokinetics, and assess correlations between the osteosarcoma histologic response and MTX serum peak concentrations. In total, 336 patients with osteosarcoma of the extremities were treated with three neoadjuvant protocols of chemotherapy including high-dose MTX (different doses for each protocol), cisplatin and doxorubicin (same doses in all protocols). The doses of MTX were 8 g/m2 in 124 patients, 10 g/m2 in 110 patients and 12 g/m2 in 102 patients. The mean value of peak serum MTX was 801 micromol/l (range 298-1831) with significant intra- and inter-patient variability. For patients treated with 8, 10 and 12 g/m2 it was 587, 735 and 1114 micromol/l, respectively (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). The histologic response to pre-operative chemotherapy was 90% or above tumor necrosis in 62.8% of patients and less than 90% in 37.2%. The grade of histologic response significantly correlated with the histologic subtype of the tumor, whereas no significant association was found between the mean peak of serum MTX and the histologic response. Thus, increasing the dose of MTX increases the MTX serum peaks, but does not correlate with the histologic response of the tumor.

Research paper thumbnail of Adjuvant and neo-adjuvant chemotherapy for Ewing's sarcoma family tumors and osteosarcoma of the extremity: further outcome for patients event-free survivors 5 years from the beginning of treatment

Annals of Oncology, 2007

Background: In 326 patients with Ewing's sarcoma family tumor (ESFT) and 628 extremity osteosarco... more Background: In 326 patients with Ewing's sarcoma family tumor (ESFT) and 628 extremity osteosarcoma (OS) treated with adjuvant and neo-adjuvant chemotherapy and event-free survivors 5 years from the beginning of treatment we evaluated outcome in the following years. Post 5-year follow-up for these patients was 9.7 years (5.5-29 years).

Research paper thumbnail of Neoadjuvant chemotherapy for osteosarcoma of the extremities in patients aged 41–60 years

Research paper thumbnail of Neoadjuvant Chemotherapy With High-Dose Ifosfamide, High-Dose Methotrexate, Cisplatin, and Doxorubicin for Patients With Localized Osteosarcoma of the Extremity: A Joint Study by the Italian and Scandinavian Sarcoma Groups

Journal of Clinical Oncology, 2005

Purpose To explore the effect of high-dose ifosfamide in first-line treatment for patients ≤ 40 y... more Purpose To explore the effect of high-dose ifosfamide in first-line treatment for patients ≤ 40 years of age with nonmetastatic osteosarcoma of the extremity. Patients and Methods From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m2), methotrexate (12 g/m2), cisplatin (120 mg/m2), and doxorubicin (75 mg/m2). Postoperatively, patients received two cycles of doxorubicin (90 mg/m2), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m2). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination. Results No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result ...

Research paper thumbnail of Ifosfamide and Actinomycin-D, Added in the Induction Phase to Vincristine, Cyclophosphamide and Doxorubicin, Improve Histologic Response and Prognosis in Patients with Non Metastatic Ewing's Sarcoma of the Extremity

Journal of Chemotherapy, 1998

The role of ifosfamide as first-line chemotherapy treatment of non metastatic Ewing&#39;s sar... more The role of ifosfamide as first-line chemotherapy treatment of non metastatic Ewing&#39;s sarcoma of the extremity is still under discussion. The purpose of this paper is to report the results achieved in a neoadjuvant protocol (REN-3) in which ifosfamide, added to the conventional VACA regimen, was employed since the induction phase. Induction chemotherapy consisted of vincristine, cyclophosphamide, doxorubicin, actinomycin-D and ifosfamide. After local treatment, patients received the drugs used in the induction phase and etoposide. Between November 1991 and November 1994, 61 patients with non metastatic Ewing&#39;s sarcoma of the extremity were treated. Forty-nine patients underwent surgery and 73.5% of them had a good histologic response. At a median follow-up of 60 months (range 32-76), 48 patients (79%) remained continuously disease-free. The 5-year event-free and overall survival were 77% and 87%, respectively. These results were significantly better both in terms of histologic response or event-free and overall survival than those obtained in 58 patients with non metastatic Ewing&#39;s sarcoma of the extremity treated in a previous protocol (REN-2) in which the same drugs were used, but ifosfamide was employed only in the maintenance phase. The present study suggests the importance of early use of ifosfamide in the treatment of patients with non metastatic Ewing&#39;s sarcoma of the extremity.

Research paper thumbnail of Osteosarcoma of the limb

The Journal of Bone and Joint Surgery, 2002

ABSTRACT We have studied 560 patients with osteosarcoma of a limb, who had been treated by neoadj... more 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 local and systemic recurrence according to the type of surgery undertaken. Of these, 465 patients 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 60.7% and 68.5%, respectively, with no significant difference between patients undergoing amputation and those 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 a local recurrence was significantly worse than for those who had recurrent disease with metastases only. We conclude that limb-salvage procedures are relatively safe in osteosarcoma treated by neoadjuvant 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.

Research paper thumbnail of The role of surgical margins in treatment of Ewing’s sarcoma family tumors: Experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy

International Journal of Radiation Oncology*Biology*Physics, 2006

To evaluate the importance of surgical margins for local and systemic control of Ewing&amp;am... more To evaluate the importance of surgical margins for local and systemic control of Ewing&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s sarcoma family tumors (ESFT). Between 1979 and 1999, 512 patients with ESFTs entered 4 different adjuvant and neoadjuvant studies performed at a single institution. Of these patients, 335 were treated with surgery alone (196) or surgery followed by radiotherapy at doses of 44.8 Gy (139). We compared their outcome with that of the 177 patients who were locally treated by radiotherapy at 60 Gy. Local control (88.8% vs. 80.2%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.009) and 5-year disease-free survival (63.8% vs. 47.6%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0007) were significantly better in patients treated with surgery and, among them, in those with adequate surgical margins (96.6% vs. 71,7%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0008, and 69.6% vs. 46.3%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0002). Nonetheless, better results were observed only in extremity tumors. Surgery is better than radiotherapy in cases of extremity ESFT with achievable adequate surgical margins, and in cases of inadequate surgical margins, adjuvant reduced-dose radiotherapy is ineffective. Therefore, when inadequate margins are expected, patients are better treated with full-dose radiotherapy from the start.

Research paper thumbnail of Treatment of nonmetastatic Ewing’s sarcoma family tumors of the spine and sacrum: the experience from a single institution

European Spine Journal, 2009

The objective of this study is to determine the best local treatment combined with neoadjuvant ch... more The objective of this study is to determine the best local treatment combined with neoadjuvant chemotherapy for ESFT of the spine and sacrum, for the best local treatment for Ewing sarcoma family tumors (ESFT) according to the primary site is still unclear. Nowadays surgery is used in local treatment of ESFT, but literature is scarce on the best local treatment in sites where surgery is problematic, such as the spine. This study evaluates the outcome and the rate of local recurrence of ESFT in the spine and sacrum when treated with neoadjuvant chemotherapy, and locally by radiotherapy alone or surgery, followed by reduced doses of radiotherapy. Forty-three patients with nonmetastatic ESFT located in the spine and sacrum were treated at our institution between 1983 and 2000 with neoadjuvant chemotherapy, and locally by radiotherapy alone in 26 cases, and surgery followed by radiotherapy at reduced doses in 17. The 5-and 10-year

Research paper thumbnail of A comparison of methods of loco-regional chemotherapy combined with systemic chemotherapy as neo-adjuvant treatment of osteosarcoma of the extremity

European Journal of Surgical Oncology (EJSO), 2001

Our experience of pre-operative intraarterial (i.a.) vs intravenous (i.v.) infusion of cisplatinu... more Our experience of pre-operative intraarterial (i.a.) vs intravenous (i.v.) infusion of cisplatinum (CDP) in a multiagent neo-adjuvant chemotherapy for osteosarcoma of the extremity is reported. Methods: Two successive randomized studies were performed. In the first, pre-operatively, CDP i.a. vs CDP i.v. was applied in combination with high-dose methotrexate (HDMTX) and adriamycin (ADM) within a three-drug regimen. In the second, a combination of HDMTX, ADM and IFO, within a four-drug regimen was tested. Results: The rate of responses to chemotherapy (tumour necrosis [90%) was significantly higher (P<0.04) for the 142 patients treated with the four-drug regimen than in the 79 patients treated with a three-drug regimen (76% vs 62%). According to the route of CDP infusion, in the three-drug regimen the rate of responses was significantly higher (P=0.004) in patients treated with i.a. CDP (77%) than in patients treated i.v. (46%); with the four-drug regimen the rate of response was not significantly different in patients treated i.a. (81%) and in patients treated i.v. (71%). No significant differences in the rates of limb salvages, local recurrence and event-free survival (EFS) were seen between the i.a. and the i.v. groups. Conclusion: In the treatment of osteosarcoma of the extremity, the i.a. infusion of CDP does not offer any significant advantage when this drug is used within an aggressive, multiagent, pre-operative four-drug regimen.

Research paper thumbnail of Pattern of relapse in 290 patients with nonmetastatic Ewing's sarcoma family tumors treated at a single institution with adjuvant and neoadjuvant chemotherapy between 1972 and 1999

European Journal of Surgical Oncology (EJSO), 2006

Aims: Evaluation of pattern of recurrences of 290 patients with an Ewing's sarcoma family tumor (... more Aims: Evaluation of pattern of recurrences of 290 patients with an Ewing's sarcoma family tumor (ESFT), who relapsed after adjuvant or neoadjuvant chemotherapy. Methods: Retrospective analysis at a median follow-up of 16.6 years (range: 5e32) from the primary therapy. Results: There were 378 recurrences, treated by surgery, and/or chemotherapy, radiotherapy, or only palliative treatments. At the last control 18 patients were alive and free of disease 2.5 to 20 years (median 12.1 year) from the last treatment, 4 were alive with uncontrolled disease, 2 died of second line chemotherapy-related toxicity, and 266 died of the tumor 4 months to 20.5 years from the first relapse (median 3.2 years). The 5-year event free survival after the last relapse and overall survival were 5.1 and 7.9%, respectively, and resulted significantly correlated with the time of first relapse, the site of first metastases, the treatment performed after relapse (all patients presently free of disease had been treated by surgery alone or combined with a second line chemotherapy) and for patients treated with neoadjuvant chemotherapy and locally by surgery, with the histologic response to preoperative chemotherapy. Conclusions: We confirm that the post-relapse outcome of patients with ESFT who relapse after conventional treatment is very poor. Nonetheless specific subgroups of patients may be cured even after 2 or 3 relapses: patients who relapse 2 or more years after primary treatment, patients who relapse with only lung metastases, and patients whose recurrences can be surgically treated.

Research paper thumbnail of A comment and update on “Does the histological subtype of high-grade central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the European Osteosarcoma Intergroup”

European Journal of Cancer, 2003

Research paper thumbnail of Neoadjuvant chemotherapy for Ewing's tumour of bone: recent experience at the Rizzoli Orthopaedic Institute

European Journal of Cancer, 2002

The results achieved in 157 patients with non-metastatic Ewing's sarcoma of the bone treated at a... more The results achieved in 157 patients with non-metastatic Ewing's sarcoma of the bone treated at a single institution between 1991 and 1997 according to a new protocol (REN-3) are reported. Induction chemotherapy consisted of two cycles of 'VAC': vincristine (V), doxorubicin (A), cyclophosphamide (C) alternated with one cycle of 'VIAc': V, ifosfamide (I), actinomycin (Ac). After local treatment, patients received three more cycles of VAC, two of VIAc, three cycles of I plus etoposide (E) and two cycles with V, C and Ac. Local treatment was surgery in 53% of patients, surgery+radiotherapy in 25% and radiotherapy only in 22%. With a follow-up ranging between 4 and 10 years (mean: 7 years), 110 patients (70%) remained continuously event-free, 2 patients died of toxicity and 45 patients relapsed: 33 due to metastases and 12 due to local recurrence always associated with metastases. The 5-year event-free survival (EFS) and overall survival (OS) were 71.0 and 76.5% respectively. These results are significantly better that the ones achieved in our previous three studies in which a three-drug VAC regimen (REA-1), and 4-drug VACAc regimen (REA-2 and REN-1) was used, and in our most recent study (REN-2) which was based on a six-drug regimen as in the present study, but where I and Ac were used only after the local treatment. However, since REN-3 surgery was used in a significantly larger number of patients, we cannot say whether the better outcome of this study was due to the use of a six-drug regimen with an early delivery of ifosfamide and actinomycin, or to the wider use of surgery as local treatment or both. #

Research paper thumbnail of Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution

European Journal of Cancer, 2005

To determine whether necrosis induced by pre-operative chemotherapy correlates with the rate of s... more To determine whether necrosis induced by pre-operative chemotherapy correlates with the rate of systemic and local relapse, may change the pattern of relapse and/or may modify the chance of success of post-relapse treatments, we evaluated 881 patients with non-metastatic osteosarcoma of the extremities treated with five different protocols of neoadjuvant chemotherapy and surgery at the same institution between 1983 and 1999. The 5-year disease-free survival (DFS) and overall survival (OS) correlated significantly with the histological response to chemotherapy. Five-year DFS and OS in good and poor responders were 67.9% versus 51.3% (P < 0.0001) and 78.4% versus 63.7% (P < 0.0001), respectively. The prognostic value of the histological response was valid only for osteoblastic and telangiectatic osteosarcoma subtypes. Nonetheless, since they represent more than 70% of all osteosarcomas, we conclude that chemotherapy-induced necrosis has a significant prognostic value, regardless of the type of chemotherapy performed after surgery.

Research paper thumbnail of A comment on “Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders”

European Journal of Cancer, 2003

We read with interest the paper of Smeland and colleagues [1] about prognostic factors in 113 pat... more We read with interest the paper of Smeland and colleagues [1] about prognostic factors in 113 patients with osteosarcoma of the extremities treated in the last neoadjuvant study of the SSG. In their paper, the authors reported that only three factors appeared to influence the prognosis of these patients: gender, tumour volume at a cut-off of 190 ml, and the mean serum level of methotrexate (MTX) at the 24th hour.

Research paper thumbnail of Histologic Response of High-Grade Nonmetastatic Osteosarcoma of the Extremity to Chemotherapy

Clinical Orthopaedics and Related Research, 2001

In 510 patients with osteosarcoma of the extremity treated at the authors&amp;amp;amp;amp;#39... more In 510 patients with osteosarcoma of the extremity treated at the authors&amp;amp;amp;amp;#39; institute between March 1983 and June 1995 with different regimens of neoadjuvant chemotherapy, factors that influenced the histologic response were investigated. The rate of total necrosis was not related to the patients&amp;amp;amp;amp;#39; gender, age, site, size of tumor, serum of alkaline phosphatase values, or route of cisplatin administration. The histologic response significantly and independently correlated with the number of drugs administered before surgery and with the histologic subtype of the tumor. According to the number of drugs used, the percentage of total necrosis was 31% for a four-drug regimen, 18% for a three-drug regimen, and only 1.5% for a two-drug regimen. According to the histologic type, the rates of total necrosis were 41% for telangiectatic tumors, 36% for fibroblastic tumors, 15% for osteoblastic tumors, and 3% for chondroblastic tumors. The authors concluded that in neoadjuvant therapy of osteosarcoma, the histologic response to preoperative treatment, which correlates with prognosis, depends on the effectiveness of the chemotherapy regimen and on some features intrinsically inherent to the tumor. These data should be considered when selecting the type of treatment (adjuvant or neoadjuvant) and the combinations of drugs to be used in preoperative treatment of patients with osteosarcoma.

Research paper thumbnail of Insulin Receptor Isoform A and Insulin-like Growth Factor II as Additional Treatment Targets in Human Osteosarcoma

Cancer Research, 2009

Despite the frequent presence of an insulin-like growth factor I receptor (IGFIR)-mediated autocr... more Despite the frequent presence of an insulin-like growth factor I receptor (IGFIR)-mediated autocrine loop in osteosarcoma (OS), interfering with this target was only moderately effective in preclinical studies. Here, we considered other members of the IGF system that might be involved in the molecular pathology of OS. We found that, among 45 patients with OS, IGF-I and IGFBP-3 serum levels were significantly lower, and IGF-II serum levels significantly higher, than healthy controls. Increased IGF-II values were associated with a decreased disease-free survival. After tumor removal, both IGF-I and IGF-II levels returned to normal values. In 23 of 45 patients, we obtained tissue specimens and found that all expressed high mRNA level of IGF-II and >IGF-I. Also, isoform A of the insulin receptor (IR-A) was expressed at high level in addition to IGFIR and IR-A/IGFIR hybrids receptors (HR A ). These receptors were also expressed in OS cell lines, and simultaneous impairment of IGFIR, IR, and Hybrid-Rs by monoclonal antibodies, siRNA, or the tyrosine kinase inhibitor BMS-536924, which blocks both IGFIR and IR, was more effective than selective anti-IGFIR strategies. Also, anti-IGF-II-siRNA treatment in low-serum conditions significantly inhibited MG-63 OS cells that have an autocrine circuit for IGF-II. In summary, IGF-II rather than IGF-I is the predominant growth factor produced by OS cells, and three different receptors (IR-A, HR A , and IGFIR) act complementarily for an IGF-IImediated constitutive autocrine loop, in addition to the previously shown IGFIR/IGF-I circuit. Cotargeting IGFIR and IR-A is more effective than targeting IGF-IR alone in inhibiting OS growth. [Cancer Res 2009;69(6):2443-52]

Research paper thumbnail of Reproductive functions in female patients treated with adjuvant and neoadjuvant chemotherapy for localized osteosarcoma of the extremity

Cancer, 2000

The side effects of chemotherapy on ovarian and reproductive functions in female patients who rec... more The side effects of chemotherapy on ovarian and reproductive functions in female patients who received adjuvant and/or neoadjuvant treatment for localized osteosarcoma of the extremities at our institution in the last 21 years (1974-1995) were assessed. Ninety-two patients with a mean actual age of 26 (14-51) were interviewed. They had been followed 3 to 16 years after treatment (mean: 9.6 yrs). Twenty-four of them had received chemotherapy before puberty and 68 after puberty. Amenorrhea during chemotherapy occurred in 69% of postpuberal patients but only in 2 patients aged 39 and 43, respectively, was permanent. After the end of treatment, the patients&amp;amp;#39; menstrual activity started again, and only a slight number of cases showed increases of menstrual irregularities. Twenty-two patients married after treatment; 20 patients started a pregnancy at a mean age of 27. Of these 20 patients, 3 had voluntary abortions and 17 succeeded. At the time of article submission, three were pregnant, 14 had 19 full term pregnancies, and no birth defects nor congenital anomalies were registered in their 19 full term newborns. In this group of female patients, chemotherapy seemed to alter neither their reproductive function nor the health of their newborns.

Research paper thumbnail of Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity

Cancer, 2003

In primary central high-grade osteosarcoma, a number of distinct subtypes have been identified, b... more In primary central high-grade osteosarcoma, a number of distinct subtypes have been identified, but little is known about the response to chemotherapy.

Research paper thumbnail of Influence of local recurrence on survival in patients with extremity osteosarcoma treated with neoadjuvant chemotherapy

Cancer, 2006

BACKGROUND. Risk factors for local recurrence (LR) after osteosarcoma, such as surgical margins a... more BACKGROUND. Risk factors for local recurrence (LR) after osteosarcoma, such as surgical margins and histologic response to preoperative treatment, have been well documented, whereas the outcome for patients who locally recur has not been well established yet.

Research paper thumbnail of Prognostic significance of serum alkaline phosphatase measurements in patients with osteosarcoma treated with adjuvant or neoadjuvant chemotherapy

Cancer, 1993

tic protocols and in planning new randomized clinical trials. Cancer 1993; 71:1224-30.

Research paper thumbnail of No correlation between methotrexate serum level and histologic response in the pre-operative treatment of extremity osteosarcoma

Anti-Cancer Drugs, 2006

Our objectives were to evaluate the behavior of different doses of pre-operative methotrexate (MT... more Our objectives were to evaluate the behavior of different doses of pre-operative methotrexate (MTX) pharmacokinetics, and assess correlations between the osteosarcoma histologic response and MTX serum peak concentrations. In total, 336 patients with osteosarcoma of the extremities were treated with three neoadjuvant protocols of chemotherapy including high-dose MTX (different doses for each protocol), cisplatin and doxorubicin (same doses in all protocols). The doses of MTX were 8 g/m2 in 124 patients, 10 g/m2 in 110 patients and 12 g/m2 in 102 patients. The mean value of peak serum MTX was 801 micromol/l (range 298-1831) with significant intra- and inter-patient variability. For patients treated with 8, 10 and 12 g/m2 it was 587, 735 and 1114 micromol/l, respectively (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). The histologic response to pre-operative chemotherapy was 90% or above tumor necrosis in 62.8% of patients and less than 90% in 37.2%. The grade of histologic response significantly correlated with the histologic subtype of the tumor, whereas no significant association was found between the mean peak of serum MTX and the histologic response. Thus, increasing the dose of MTX increases the MTX serum peaks, but does not correlate with the histologic response of the tumor.

Research paper thumbnail of Adjuvant and neo-adjuvant chemotherapy for Ewing's sarcoma family tumors and osteosarcoma of the extremity: further outcome for patients event-free survivors 5 years from the beginning of treatment

Annals of Oncology, 2007

Background: In 326 patients with Ewing's sarcoma family tumor (ESFT) and 628 extremity osteosarco... more Background: In 326 patients with Ewing's sarcoma family tumor (ESFT) and 628 extremity osteosarcoma (OS) treated with adjuvant and neo-adjuvant chemotherapy and event-free survivors 5 years from the beginning of treatment we evaluated outcome in the following years. Post 5-year follow-up for these patients was 9.7 years (5.5-29 years).

Research paper thumbnail of Neoadjuvant chemotherapy for osteosarcoma of the extremities in patients aged 41–60 years