Late effects of chemotherapy and radiotherapy in osteosarcoma and Ewing sarcoma patients: the Italian Sarcoma Group Experience (1983-2006).

BACKGROUND: Patients with osteosarcoma and Ewing sarcoma have achieved longer survival over the past decades, but late side effects of chemotherapy and radiotherapy have become important concerns. METHODS: The authors reviewed all patients with localized osteosarcoma or Ewing sarcoma who had been enrolled in the Italian Sarcoma Group neoadjuvant protocols from 1983 through 2006. Data were updated in December 2010 to determine 3 endpoints: the incidence of a secondary primary cancer (designated as "second malignant neoplasm" [SMN]), infertility, and cardiotoxicity. RESULTS: Data were available on 883 patients with osteosarcoma and 543 patients with Ewing sarcoma. In the osteosarcoma group, there were 39 SMNs (4.4%) in 36 patients; in the Ewing sarcoma group, 15 patients (2.8%) experienced a single SMN each. The cumulative 10-year and 20-year incidence of an SMN (±standard error) was 4.9% ± 0.9% and 6.1% ± 1.2%, respectively, in the osteosarcoma group and 3.4% ± 0.9% and 4.7% ± 1.6%, respectively, in the Ewing sarcoma group. The most common SMN in the osteosarcoma group was breast cancer (n = 11), and the most common SMN in the Ewing sarcoma group was radiotherapy-induced osteosarcoma (n = 6). After 20 years, the risk of developing an SMN increased, whereas the risk of a recurrence of the primary tumor decreased. Permanent sterility was more common in males than in females. Doxorubicin cardiotoxicity occurred in 18 patients with osteosarcoma (2%) and in 7 patients with Ewing sarcoma (1.3%). CONCLUSIONS: The awareness of late side effects in long-term survivors of primary bone cancers should encourage longer follow-up.

Non-metastatic osteosarcoma of the extremities in children aged 5 years or younger.

BACKGROUND: The occurrence of high-grade osteosarcoma is rare in children aged 5 years or younger and only limited series or case reports have been described. METHODS: The records of patients aged 5 years or younger with non-metastatic high-grade osteosarcoma of the extremities treated with surgery and adjuvant or neo-adjuvant chemotherapy at Rizzoli Institute between 1972 and 1999 were retrospectively evaluated in relation to gender, primary tumor site, histological subtype, surgical treatment, chemotherapy-induced tumor necrosis, 5- and 10-year event-free survival (EFS), and rate of local recurrence. Data were compared to patients aged 6-40 years entered with the same diagnosis and over the same time interval. RESULTS: Data from 20 patients were collected. Comparing these data with those from 1,106 patients 6-40 years of age only two main differences resulted: the younger group showed a higher rate for fibroblastic subtype (P < 0.01) and for amputation surgery (P < 0.01). Among the two groups, no statistical difference was observed for the 5-year EFS (60% vs. 53.8%; P = 0.6) and 10-year EFS (60% vs. 52.1%; P = 0.5). The rate of local recurrence was 5.0% and 5.4%. CONCLUSIONS: These findings suggest that in non-metastatic osteosarcoma of the extremities outcome and clinical characteristics are similar among children 5 years of age or younger and older patients. However, in the younger group we have observed a significant higher rate of fibroblastic subtype as well as a significant higher rate of mutilating surgery. Pediatr Blood Cancer.

Vincristine, doxorubicin, cyclophosfamide, actinomycin D, ifosfamide, and etoposide in adult and pediatric patients with nonmetastatic Ewing sarcoma. Final results of a monoinstitutional study.

AIMS AND BACKGROUND: To investigate a six-drug combination in patients with nonmetastatic Ewing sarcoma, focusing on chemotherapy-induced necrosis and chemotherapy toxicity in adult and pediatric patients. METHODS AND STUDY DESIGN: Alternating cycles of vincristine (1.5 mg/m2), doxorubicin (80 mg/m2) and cyclophosfamide (1200 mg/m2) (weeks 0, 6, 13, 22 and 31), ifosfamide (9 g/m2), vincristine (1.5 mg/m2), and actinomycin D (1.5 mg/m2) (weeks 3, 16, 25 and 34), and ifosfamide (9 g/m2) and etoposide (450 mg/m2) (weeks 9, 19, 28 and 37) were administered. Primary chemotherapy-induced necrosis was graded: G3 (complete necrosis), G2 (microfoci of tumor cells) and G1 (macrofoci of tumor cells). RESULTS: From 1996 to 1999, 50 patients with Ewing sarcoma were enrolled. The median age was 23.5 years (range, 4-56). Chemotherapy-induced necrosis (in 28 patients) was G3 in 36%, G2 in 21% and G1 in 43%. At a median follow-up of 110 months (range, 36-129), 5-year overall survival and event-free survival were 72% and 66%, respectively. According to histologic response, 5-year event-free survival was 90% in G3, 83% in G2, and 42% in G1 (P = 0.02). In adult and pediatric (<18 years) patients, the incidence of G4 leukopenia was 62% and 74%, respectively, with febrile neutropenia in 13% and 21%, respectively. G4 thrombocytopenia occurred in 3% of cycles in adults and in 7% in pediatric patients. Platelet and red blood cell transfusions were required respectively in 1% and 11% of cycles in adults and in 6% and 24% of cycles in pediatric patients. CONCLUSIONS: The six-drug combination can be administered safely in adult and pediatric populations. About 40% of patients have a poor chemotherapy-induced tumor necrosis, leading to poor probability of survival. New strategies are recommended to improve survival of poor responders to the six-drug combination.

The treatment of nonmetastatic high grade osteosarcoma of the extremity: review of the Italian Rizzoli experience. Impact on the future.

The Bone Tumor Center of the "Istituto Ortopedico Rizzoli" was established in 1955 with the aim of studying and treating the musculoskeletal tumors. Between 1959 and 2006, 1245 patients with high grade nonmetastatic osteosarcoma of the extremity were treated at our Institute. Most of them were enrolled in study protocols. In the "prechemotherapy era", the cure rate was 11%, with an amputation rate of 90%. Our first experience with adjuvant chemotherapy was in 1972. A total of 223 patients received adjuvant chemotherapy, with a disease-free survival (DFS) ranging from 45% to 53%, according to the chemotherapy protocol used. With the introduction of neoadjuvant chemotherapy, the resection rate increased and reached 94%, when high dose fosfamide was added to standard doses of methotrexate, cisplatin, and adriamycin. In the last few years, the results of treatment of nonmetastatic osteosarcoma of the extremity have reached a plateau (64% five-year DFS), and strategies of dose intensification are not able to improve the prognosis. Not only new active drugs, but also different approaches to the disease, are needed. In this regard, we are now investigating tumor microenvironment-targeted agents and chemotherapy protocols based on prospective biological stratification of patients. Collaborative projects with international groups and institutions are crucial for this rare disease.

Local and systemic control of Ewing's bone sarcoma family tumors of the ribs.

BACKGROUND: A retrospective analysis of the results and relapse pattern was evaluated in 34 patients with Ewing's family bone tumors (EFBT) treated at Rizzoli Institute with neoadjuvant chemotherapy between 1983 and 2003. OBJECTIVES: The aim of the study was to evaluate treatment strategy and compare our results with those obtained in other studies. METHODS: Local treatment in these patients was radiotherapy alone in 4 cases, surgery alone in 13 and surgery followed by radiotherapy in 17. RESULTS: Five-year event-free survival (EFS) was 44%, no different from that observed in another 558 patients with EFBT located in other sites treated in the same period with neoadjuvant chemotherapy protocols. Eighteen patients had a systemic relapse, followed by local relapse in two and one patient had a local relapse alone. EFS was significantly correlated to the time interval between onset symptoms and beginning of treatment and, in operated patients to histologic response to preoperative treatment. CONCLUSIONS: We conclude that EFBT of the ribs, when treated with neoadjuvant chemotherapy, have an outcome similar to that of patients with EFBT located in other sites.

Treatment of nonmetastatic Ewing's sarcoma family tumors of the spine and sacrum: the experience from a single institution.

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 event-free survival (EFS) was 37 and 30%, and the 5- and 10-year overall survival was (OS) 42 and 32%. The prognosis was unrelated to gender and age, tumor volume, chemotherapy protocol, and local treatment. The outcome seemed worse for patients with primary tumors located in the sacrum than for patients with tumors located in the rest of the spine (5-year EFS = 23 vs. 46%). For these patients the results were significantly worse than for those we achieved with neoadjuvant treatment for ESFT located in other sites. However, no differences were observed between patients locally treated with radiotherapy alone and those treated by radiotherapy followed by surgery. We concluded that regardless of the type of local treatment even when associated with neoadjuvant therapy, ESFT in the spine and sacrum has a poor outcome and prognosis is significantly worse than that of primary ESFT in other sites.

High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions.

BACKGROUND AND METHODS: Between 1986 and 2001, 162 patients with extremity osteosarcoma and lung metastases at presentation, were treated by neoadjuvant chemotherapy, simultaneous resection of primary and, when feasible, secondary lesions followed by chemotherapy. RESULTS: After neoadjuvant chemotherapy, metastases disappeared in 14 patients, 16 were judged unresectable by both our thoracic surgeons, 132 had primary tumors and lung metastases removed simultaneously. Removal of lung metastases was complete in 123 and incomplete in 9. Histologically lesions were benign in 32 patients. For the 100 patients simultaneously operated with histologically proven lung metastases, 5-year event-free survival (EFS) was 18.9%; 27.4% for the 91 who had a complete resection of pulmonary lesions and entered remission as opposed to none for 9 patients who had incomplete removal of lung nodules. Among these 91, 5-year EFS was significantly higher for patients with monolateral compared to bilateral lesions (27.1% vs. 7.9%, P < 0.02) and when only one to three metastatic nodules were present (40.0% vs. 13.3%, P < 0.0001). CONCLUSIONS: These different results, demonstrate that our treatment had a reasonable survival outcome whereas other groups continue to have dismal prognosis. More efforts should be made to improve survival by identifying new active agents or novel approaches with cellular molecular targets.

Neoadjuvant chemotherapy for osteosarcoma of the extremities in preadolescent patients: the Rizzoli Institute experience.

Medical records of 133 patients, 10 years old or younger with primary high-grade nonmetastatic osteosarcoma of the extremities treated at the Rizzoli Institute between 1983 and 1999 with neoadjuvant chemotherapy were reviewed and compared with those of 782 patients aged 11 to 40 years treated in the same period with the same chemotherapy protocols. In comparison to the older group, the younger group had more females, more patients with normal lactic dehydrogenase levels, and more non-limb-salvage procedures (amputation or rotationplasty). Five-year event-free and overall survivals were essentially the same in the two groups (63% and 71% vs. 60% and 70%) as were the patients rescued after relapse and presently event-free (18% vs. 20%). The authors conclude that there does not seem to be any indication to treat preadolescent primary high-grade nonmetastatic osteosarcoma patients by alternative and/or more aggressive therapies.

Neoadjuvant chemotherapy for radioinduced osteosarcoma of the extremity: The Rizzoli experience in 20 cases.

PURPOSE: Evaluate treatment and outcome of 20 patients with radioinduced osteosarcoma (RIO). Because of previous primary tumor treatment, RIO protocols were different from others we used for non-RIO. PATIENTS AND METHODS: Between 1983 and 1998, we treated 20 RIO patients, ages 4-36 years (mean 16 years), with chemotherapy (two cycles before surgery, three postoperatively). The first preoperative cycle consisted of high-dose Methotrexate (HDMTX)/Cisplatinum (CDP)/Adriamycin (ADM) and the second of HDMTX/CDP/Ifosfamide (IFO). The three postoperative treatments were performed with cycles of MTX/CDP; IFO was used as single agent per cycle repeated three times. RESULTS: Two patients received palliative treatment because their osteosarcoma remained unresectable after preoperative chemotherapy. The remaining 18 patients had surgery (7 amputations, 11 resections); histologic response to preoperative chemotherapy was good in 8 patients, poor in 10. At a mean follow-up of 11 years (range, 7-22 years), 9 patients remained continuously disease-free, 10 died from osteosarcoma and 1 died from a third neoplasm (myeloid acute leukemia). These results are not significantly different from those achieved in 754 patients with conventional osteosarcoma treated in the same period with protocols used for conventional treatment. However, this later group had an 18% 3-year event-free survival after treatment of relapse vs. 0% in the RIO group. CONCLUSION: Treated with neoadjuvant chemotherapy RIO seem to have an outcome that is not significantly different from that of comparable patients with conventional primary high grade osteosarcoma (5-year event-free survival: 40% vs. 60%, p = NS; 5-year overall survival 40% vs. 67%, p < 0.01).

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.

PURPOSE: To explore the effect of high-dose ifosfamide in first-line treatment for patients < or = 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 of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI, 57% to 71%) and overall survival was 77% (95% CI, 67% to 81%), whereas seven patients (4%) experienced local recurrence. CONCLUSION: The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.

Primary bone osteosarcoma in the pediatric age: state of the art.

The current combination treatment, chemotherapy and surgery, has significantly improved the cure rate and the survival rate of primary bone osteosarcoma. The 5-year survival rate has increased in the last 30 years from 10% to 70%. Even in patients with poor prognosis, such as those with metastases at diagnosis, the 5-year survival rate has reached 20-30% due to chemotherapy and the surgical removal of metastases and primary tumor. However, the most effective drugs are still the same as those employed over the last 20 years as front line neoadjuvant or adjuvant chemotherapy: Doxorubicin, Cisplatin, Methotrexate, Ifosfamide. No standard, second line therapy exists for those who relapse. At relapse, due to the lack of new non-cross-resistant drugs, surgery is still the main option when feasible. Other drugs have been employed in relapsed patients with poor results. This article reviews the state of the art of treatment for bone osteosarcoma in the pediatric age.

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.

PURPOSE: To evaluate the importance of surgical margins for local and systemic control of Ewing's sarcoma family tumors (ESFT). METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.

May P-glycoprotein status be used to stratify high-grade osteosarcoma patients? Results from the Italian/Scandinavian Sarcoma Group 1 treatment protocol.

The aim was to evaluate the clinical impact of P-glycoprotein in primary non-metastatic high-grade osteosarcoma patients, treated with neoadjuvant chemotherapy protocols. P-glycoprotein was assessed by immunohistochemistry on paraffin-embedded tissue samples collected at time of diagnosis from 94 osteosarcoma patients, treated with the Italian Sarcoma Group/Scandinavian Sarcoma Group 1 (ISG/SSG 1) protocol. P-glycoprotein-positivity at diagnosis was found in 53/94 ISG/SSG 1 cases (56%) and emerged as the single factor significantly associated with an unfavourable outcome from survival and multivariate analyses. A comparative analysis of the subgroup of 94 patients considered for P-glycoprotein evaluation and the whole series of ISG/SSG 1 patients showed that this marker retained its prognostic value also in the latter group. In osteosarcoma patients treated with doxorubicin-based chemotherapy protocols, P-glycoprotein overexpression at diagnosis is an important adverse prognostic factor for outcome. P-glycoprotein evaluation can therefore constitute the basis for stratifying, at diagnosis, osteosarcoma patients for whom alternative treatments may be considered.

Postrelapse survival in osteosarcoma of the extremities: prognostic factors for long-term survival.

PURPOSE: To identify factors that influence postrelapse survival (PRS) in patients with nonmetastatic osteosarcoma of the extremity. PATIENTS AND METHODS: One hundred sixty-two patients with recurrent osteosarcoma of the extremity were retrospectively reviewed. The first-line treatment included surgery of the primary lesion and chemotherapy with methotrexate, doxorubicin, cisplatin, and ifosfamide. RESULTS: The projected 5-year PRS rate was 28%. Patients who had complete surgery of recurrence had a 5-year PRS of 39%, whereas for those who did not have complete surgery, PRS was 0% at 3 years (P <.0001). In the latter group, PRS was not influenced by site of recurrence and relapse-free interval (RFI), although it was influenced (P =.006) by the use of second-line chemotherapy (PRS, 53% at 12 months for patients who received chemotherapy v 12% for those who did not). In patients who had complete surgery, PRS was influenced by site of relapse (5-year PRS, lung 44%, other 19%; P <.06), RFI (5-year PRS at < or = 24 months, 20%; at > 24 months, 60%; P <.0001), and number of lung metastases (5-year PRS, two or fewer nodules, 59%; more than two nodules, 14%; P <.0001) but not by the use of a second-line chemotherapy treatment. CONCLUSION: RFI, site of metastases, and number of pulmonary nodules are the main prognostic factors for PRS in osteosarcoma. Complete surgery of recurrence is pivotal in the strategy of treatment. Patients with unresectable recurrence benefit from second-line chemotherapy, whereas our data do not support a generalized use of chemotherapy after complete surgery of first recurrence.

Value of P-glycoprotein and clinicopathologic factors as the basis for new treatment strategies in high-grade osteosarcoma of the extremities.

PURPOSE: To evaluate the prognostic value of P-glycoprotein and clinicopathologic parameters in a large series of high-grade osteosarcoma (OS) patients treated at the Rizzoli Institute. PATIENTS AND METHODS: With the use of immunohistochemistry, P-glycoprotein was assessed in 149 patients with primary, nonmetastatic, high-grade OS who were homogeneously treated with chemotherapy protocols based on doxorubicin, high-dose methotrexate, and cisplatin and the addition of ifosfamide in the postoperative phase. RESULTS: P-glycoprotein positivity was found in 47 of 149 cases (32%) and was significantly associated with a higher incidence of relapse and a worse outcome, as was age younger than 12 years and tumor volume greater then 150 mL at diagnosis. Multivariate analysis further confirmed the prognostic value of these parameters, which all were independent adverse prognostic factors. Event-free survival and proportional hazards regression analyses confirmed that overexpression of P-glycoprotein at clinical onset is the most important adverse prognostic factor for high-grade OS patients treated with these chemotherapy protocols. CONCLUSION: Increased P-glycoprotein levels, together with tumor volume and age, should be taken into consideration to identify, at time of diagnosis, subgroups of OS patients with a higher risk of recurrence. This subgroup identification will constitute the basis for drawing individualized treatment protocols on the basis of risk evaluation, with the aim of using more aggressive chemotherapy, or combination chemotherapy with other adjuvants, only in those patients for which more aggressive regimens are strictly necessary and warranted.

Adjuvant and neoadjuvant chemotherapy for osteosarcoma of the extremities: 27 year experience at Rizzoli Institute, Italy.

Around 1148 patients with non-metastatic osteosarcoma of the extremity were treated in a single institution between 1972 and 1999 with 4 different protocol of adjuvant and 7 different protocols of neoadjuvant chemotherapy. The rate of limb salvage increased from 20% to 71%. The 5-year event-free survival (EFS) and overall survival (OS) were 57% and 66%, respectively. The 10-year EFS and OS were 52% and 57%, respectively, and the results significantly correlated with serum alkaline phosphatase levels; the type of chemotherapy (adjuvant vs neoadjuvant); and with histologic response to pre-operative treatment. Aggressive chemotherapy and surgery could cure about the 60% of patients with osteosarcoma of the extremity. However, since local or systemic relapses, myocardiopathies and a second malignancy are possible even 5 or more years since the beginning of treatment, a long-term follow-up is recommended.

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.

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.

Prognostic and therapeutic relevance of HER2 expression in osteosarcoma and Ewing's sarcoma.

Expression of HER2 was evaluated by immunohistochemical techniques in 84 osteosarcoma (OS) and 113 Ewing's sarcoma (ES) paraffin-embedded tumour biopsies. HER2 gene status was also assessed in a panel of cell lines as well as in vitro efficacy of trastuzumab (a humanised antibody directed against HER2) as single agent or in combination with the insulin-like growth factor I receptor (IGF-IR) IR3 antibody. Overexpression of HER2 was present in 32% of OS and 16% of ES and was significantly associated with the increased expression of P-glycoprotein, a surface molecule responsible for multidrug resistance. Event-free survival analyses revealed a prognostic value for HER2 and/or P-glycoprotein expression in OS, but not in ES. However, despite its prognostic relevance, no therapeutic effectiveness was observed pre-clinically for trastuzumab-driven therapy, in both OS or ES cell lines, unless the antibody was associated with anti-IGF-IR targeting strategies. Therefore, the therapeutic potential of trastuzumab in these neoplasms may be better exploited in combined treatments with anti-IGF-IR approaches.

Primary non-Hodgkin's lymphoma of the bone: treatment and analysis of prognostic factors for Stage I and Stage II.

PURPOSE: Primary non-Hodgkin's lymphomas of the bone (PLB) are very rare diseases accounting for 3%-5% of primary bone tumors. The best treatment for PLB has not been found yet. We report on the experience of the Radiation Oncology Department of Bologna University, Italy, relative to the diagnosis and treatment of this disease. METHODS AND MATERIAL: Seventy-seven patients with newly diagnosed PLB were treated from June 1983 to October 2001. Fifty-six were male (72.7%) and 21 were female (27.3%); the median age was 41.8 years, with a range of 16-84 years. The majority of patients had B-cell high-grade histology. The median follow-up was 149 months. Forty-four patients had a solitary bone lesion (Stage I); and in 33 patients, the tumor was spread to locoregional lymphatic area (Stage II). All patients were treated with radiotherapy (RT) with a median dose of 40 Gy (range, 36-54 Gy), and 67 received an additional anthracycline-based regimen of chemotherapy (combined modality therapy [CMT]). RESULTS: After therapy 73 of 77 patients (94.8%) reached a complete remission. At a median time of 23 months, 14 of 77 patients (18.2%) had a disease relapse. Four of them were treated with RT alone (in these cases tumor lesions were <3 cm and located at sites different from mandible); 10 patients were treated with combined RT and CMT. Actuarial disease-free survival (DFS) and overall survival (OS) at 15 years were, respectively, 76.6% and 88.3%. No local failures were seen. Prognostic factors such as age, sex, stage, and bulky lesions were analyzed. Age (<40 vs. >40 years) was the only significant factor for DFS (85.3% vs. 66.6%, p = 0.03). Bulky lesions apparently did not affect OS (90.9% vs. 72.7%). However, the difference has no statistical significance (p = 0.05). Acute and late toxicity related to the treatment was moderate. CONCLUSIONS: In PLB the CMT seems to produce a better outcome than RT alone; that still remains the best treatment for local disease control. Radiation therapy alone should be reserved for mandibular tumors, which are usually very small and earlier diagnosed.

Effect of oral contraceptive on ovarian function in young females undergoing neoadjuvant chemotherapy treatment for osteosarcoma.

We compared the residual ovarian function and the fertility of two groups of female patients treated at different times at the authors' institution by neoadjuvant chemotherapy for localized osteosarcoma of the extremities. From 1997 to 2000, one group of 31 females received neoadjuvant treatment according to the IOR 6 protocol, which included high-dose ifosfamide, high-dose methotrexate, adryamycin, and cis-platinum. In this group of patients an oral contraceptive (OC) was given in an attempt to prevent post-chemotherapy ovarian failure. Another group of 90 patients was treated between 1974 to 1995 with the same antiblastic drugs according to similar protocols (IOR 1-IOR 5). These patients did not receive OC or other treatment to protect ovarian function. There were no significant differences between the two groups of patients. Early chemotherapy-induced menopause occurred in 3 out of 19 postpubertal patients who received the OC and in 3 out of 71 postpubertal patients in the control group. In the OC group there were 2 cases of thrombophlebitis. No delay in menarche was seen in prepubertal patients. From statistical evaluation we underline that age and alkylant doses are the most important predictive factors for early menopause and that oral contraceptives during chemotherapy do not protect ovarian function in patients receiving high-dose alkylant based chemotherapy.