Primary metastatic Ewing's family tumors: results of the Italian Sarcoma Group and Scandinavian Sarcoma Group ISG/SSG IV Study including myeloablative chemotherapy and total-lung irradiation.

BACKGROUND: The Italian Sarcoma Group and the Scandinavian Sarcoma Group designed a joint study to improve the prognosis for patients with Ewing's family tumors and synchronous metastatic disease limited to the lungs, or the pleura, or a single bone. PATIENTS AND METHODS: The study was opened in 1999 and closed to the enrollment in 2008. The program consisted of intensive five-drug combination chemotherapy, surgery and/or radiotherapy as local treatment, and consolidation treatment with high-dose busulfan/melphalan plus autologous stem cell rescue and total-lung irradiation. RESULTS: During the study period, 102 consecutive patients were enrolled. The median follow-up was 62 months (range 24-124). The 5-year event-free survival probability was 0.43 [standard deviation (SD) = 0.05] and the 5-year overall survival probability was 0.52 (SD = 0.052). Unfavorable prognostic factors emerging on multivariate analysis were a poor histological/radiological response at the site of the primary tumor [relative risk (RR) = 3.4], and incomplete radiological remission of lung metastases after primary chemotherapy (RR = 2.6). One toxic death and one secondary leukemia were recorded. CONCLUSIONS: This intensive approach is feasible and long-term survival is achievable in ∼50% of patients. New treatment approaches are warranted for patients responding poorly to primary chemotherapy.

Nonmetastatic Ewing family tumors: high-dose chemotherapy with stem cell rescue in poor responder patients. Results of the Italian Sarcoma Group/Scandinavian Sarcoma Group III protocol.

BACKGROUND: High-dose chemotherapy (HDT) was added to conventional chemotherapy in Ewing sarcoma family tumor (EFT) patients, poor responders (PRs) to induction chemotherapy in order to improve their survival. PATIENTS AND METHODS: Patients aged ≤40 years with nonmetastatic Ewing sarcoma (ES) received vincristine (V), doxorubicin (A), cyclofosfamide (C), actinomycin (Ac), ifosfamide (I) and etoposide (E) (VACAc-IE regimen) as induction chemotherapy. As maintenance treatment, good responders (GR) received nine cycles of VACAc-IE regimen. PRs received three cycles of VAC-IE, mobilizing cycle with CE and HDT with Busulfan and Melphalan with stem cell support. RESULTS: Three hundred patients [median age 15 years (3-40 years)] entered the study. One patient refused local treatment, 242 (81%) underwent surgery [with radiotherapy (RT) in 80] and 57 (19%) RT alone. No toxic deaths were recorded. Overall GR were 146 (49%). Twenty-eight PR did not receive HDT. At a median follow-up of 64 months (21-116 months), 5-year overall and event-free survival (EFS) were 75% and 69%, respectively. Five-year EFS was 75% for GR, 72% for PR treated with HDT and 33% for PR who did not receive HDT. CONCLUSIONS: High-dose therapy added to the VACA-IE regimen in PR patients is feasible and effective. Selected groups of patients with ES can benefit from HDT.

Response to melphalan in up-front investigational window therapy for patients with metastatic Ewing's family tumours.

The aim of the study was to determine the activity and toxicity of melphalan as a single agent given in up-front therapy for patients with newly-diagnosed Ewing's family tumours with bone/bone marrow metastases. Nineteen patients were enrolled from 2001 to 2004. The treatment consisted of up-front therapy with melphalan (two courses of 50 mg/m2, 3 weeks apart). The overall rate of response to melphalan (complete response+partial response, according to the RECIST criteria) was 78%. Transient grade 3-4 neutropenia, thrombocytopenia and anaemia were recorded in 97%, 81% and 28% of melphalan courses, respectively. No other relevant toxicities were recorded. Melphalan proved to be active in up-front treatment at non-myeloablative doses, and its toxicity was predictable and manageable. The schedule adopted did not interfere with any further intensive chemotherapy or myeloablative treatment in the majority of cases.

A randomized study comparing filgrastim versus lenograstim versus molgramostim plus chemotherapy for peripheral blood progenitor cell mobilization.

We conducted a prospective randomized clinical trial to assess the mobilizing efficacy of filgrastim, lenograstim and molgramostim following a disease-specific chemotherapy regimen. Mobilization consisted of high-dose cyclophosphamide in 45 cases (44%), and cisplatin/ifosfamide/etoposide or vinblastine in 22 (21%), followed by randomization to either filgrastim or lenograstim or molgramostim at 5 microg/kg/day. One hundred and three patients were randomized, and 82 (79%) performed apheresis. Forty-four (43%) patients were chemonaive, whereas 59 (57%) were pretreated. A median number of one apheresis per patient (range, 1-3) was performed. The median number of CD34+ cells obtained after mobilization was 8.4 x 10(6)/kg in the filgrastim arm versus 5.8 x 10(6)/kg in the lenograstim arm versus 4.0 x 10(6)/kg in the molgramostim arm (P=0.1). A statistically significant difference was observed for the median number of days of growth factor administration in favor of lenograstim (12 days) versus filgrastim (13 days) and molgramostim (14 days) (P<0.0001) and for the subgroup of chemonaive patients (12 days) versus pretreated patients (14 days) (P<0.001). In conclusion, all three growth factors were efficacious in mobilizing peripheral blood progenitor cells with no statistically significant difference between CD34+ cell yield and the different regimens, and the time to apheresis is likely confounded by the different mobilization regimens.

Osteosarcoma of the pelvis.

AIMS: To describe the outcomes of a large number of patients with pelvic osteosarcoma, and to define the guidelines for appropriate treatment. METHODS: We reviewed 60 consecutive patients with primary pelvic high-grade osteosarcoma. The tumour involved the whole hemipelvis in 15 cases, while the most common location was the iliac wing in 29 cases (48.3%): 25 of these adjacent to or passing the sacroiliac joint. RESULTS: Thirty patients underwent surgery; there were 16 hindquarter amputations and 14 internal hemipelvectomies. All the patients who presented with metastasis died of their disease. In 18 cases wide margins were achieved, however, eight patients experienced local recurrence. Of the series, only eight patients are still alive. CONCLUSION: The use of intense chemotherapy and surgical wide margin, hardly seems to achieve local control, however, tumour necrosis was correlated with positive prognosis. When internal hemipelvectomy it is not safe enough, amputation must be considered, particularly for cases with sacrifice of the sciatic nerve roots or for older patients where a shorter surgical procedure can be less risky.

Prophylaxis with GM-CSF mouthwashes does not reduce frequency and duration of severe oral mucositis in patients with solid tumors undergoing high-dose chemotherapy with autologous peripheral blood stem cell transplantation rescue: a double blind, randomized, placebo-controlled study.

BACKGROUND: The aim of this study was to evaluate the effectiveness of granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwashes in the prevention of severe mucositis induced by high doses of chemotherapy. PATIENTS AND METHODS: Ninety consecutive patients affected by solid tumors and undergoing high-dose chemotherapy with autologous peripheral blood stem cell transplantation rescue were randomized to receive placebo versus GM-CSF mouthwash 150 micro g/day. Patients were stratified on the basis of the conditioning treatment and the consequent different risk of severe oral mucositis. Treatment was administered from the day after the end of chemotherapy until the resolution of stomatitis and/or neutrophil recovery. RESULTS: The statistical analyses were intention-to-treat and involved all patients who entered the study. The severity of stomatitis was evaluated daily by the physicians according to National Cancer Institute Common Toxicity Criteria. Both study and control groups were compared with respect to the frequency [30% versus 36%, chi(2) exact test, not significant (NS)] and mean duration (4.8 +/- 4.7 versus 4.4 +/- 2.7 days, t-test, NS) of severe stomatitis (grade > or =3). Oral pain was evaluated daily by patients themselves by means of a 10 cm analog visual scale: the mean (+/- standard error of the mean) maximum mucositis scores were 4.8 +/- 3.5 versus 4.2 +/- 3.5 cm (t-test, NS). Furthermore, 15/46 patients in the study group (33%) and 19/44 patients in the control group experienced pain requiring opioids (chi(2) exact test, NS). CONCLUSION: We did not find any evidence to indicate that prophylaxis with GM-CSF mouthwash can help to reduce the severity of mucositis in the setting of the patients we studied.

High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study.

PURPOSE: To study the feasibility and activity of two courses of high-dose chemotherapy (HDCT) in patients with osteosarcoma in metastatic relapse. PATIENTS AND METHODS: Patients with high-grade osteosarcoma in metastatic relapse (multiple metastases or solitary metastasis at intervals of less than 30 months) were eligible for study. High-dose chemotherapy consisted of carboplatin and etoposide followed by stem-cell rescue. A second course was planned 4 to 6 weeks after the first. Surgery was performed before or after HDCT. RESULTS: Thirty-two patients were enrolled onto the study. At the end of the treatment, 25 patients were in complete remission (CR), six were alive with disease progression, and one died of toxicity. At present, 14 patients are alive with a median survival time of 23 months from study entry: four are in first CR, three are in second CR, and one is in fourth CR. Six patients are alive with disease. Eighteen patients (56%) died: 17 of disease and one of toxicity. Transplantation-related mortality was 3.1%. The relapse or progression disease rate was 84.4%. The 3-year overall survival rate is 20% and the 3-year disease-free survival rate is 12%. CONCLUSION: HDCT combined with surgery is feasible and can induce CR in a large portion of patients. Two points, however, need to be considered: only patients who are chemosensitive to induction treatment can obtain CR after HDCT, and the length of remission is short, because most patients relapse. Thus novel strategies are needed to maintain the remission status or to treat patients who do not respond to induction treatment.

Neoadjuvant high dose chemotherapy plus peripheral blood progenitor cells in inflammatory breast cancer: a multicenter phase II pilot study.

BACKGROUND AND OBJECTIVES: With the introduction of combined modality therapy, approximately 30% of patients with inflammatory breast cancer (IBC) are alive and free of disease at 5 years, but the lack of control of systemic disease continues to be the main reason for treatment failure. The importance of the response to primary chemotherapy and, in particular, complete tumor regression after primary chemotherapy have previously been described to be among the most reliable prognostic factors along with the dose intensity of doxorubicin. DESIGN AND METHODS: To evaluate pathologic response rate and toxicity of neoadjuvant high dose chemotherapy (HDCT) with autologous peripheral blood progenitor cell (PBPC) support in patients affected by IBC, 21 patients were enrolled in a study in which it was planned that they would receive 4 courses of epirubicin 150 mg/m(2) plus granulocyte colony-stimulating factor (G-CSF) as induction and mobilizing chemotherapy. Patients with non-progressive disease were intended to receive 2 consecutive courses of a combination of high doses of mitoxantrone 40 mg/m(2) , thiotepa 500 mg/m(2) and cyclophosphamide 200 mg/kg as a conditioning regimen. RESULTS: PBPC collection was successful in 20/21 patients. Twelve patients received a single course of HDCT, whereas 7/20 patients underwent a double procedure. At a median follow up of 48 months, 20/21 patients were evaluable for toxicity and 19/21 for response. At surgery 4/19 patients (21%) had no evidence of viable tumor cells in the breast and in axillary nodes, while 4 (21%) and 11 patients (58%) had microscopic and macroscopic disease, respectively. Eight patients have relapsed (35%) so far at a median of 16 months (9-54) from diagnosis. Eleven patients remain alive without evidence of disease. Five out of 20 patients experienced severe cardiotoxicity with congestive heart failure (CHF) which was responsible for the only treatment-related death. INTERPRETATION AND CONCLUSIONS: This neoadjuvant HDCT regimen seems to be very effective in terms of objective responses, but we observed a high rate of cardiotoxicity and only a few patients were able to receive the two planned courses of high dose chemotherapy.

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

AIM: 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 > or = 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.

Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with node-negative, rapidly proliferating breast cancer: a randomized multicenter study.

PURPOSE: According to one of the most recent key scientific questions concerning the use of biomarkers in clinical trials, we investigated whether node-negative breast cancer patients, defined as high-risk cases on the basis of tumor cell proliferation, could benefit from cyclophosphamide, methotrexate, and fluorouracil (CMF) adjuvant therapy. PATIENTS AND METHODS: Two hundred eighty-one patients with negative nodes and rapidly proliferating tumors, defined according to thymidine labeling index (TLI), were randomized to receive six cycles of CMF or no further treatment after surgery +/- radiotherapy. RESULTS: The 5-year disease-free survival (DFS) was 83% for patients treated with CMF compared with 72% in the control group (P: =.028). Adjuvant treatment reduced both locoregional and distant metastases. When clinical outcome was analyzed in cell kinetic subgroups characterized according to tertile criteria, compared with patients in the control arm, 5-year DFS was significantly higher after adjuvant CMF in patients with TLI values in the second (78% v 88%, respectively; P: =.037) and third tertiles (58% v 78%, respectively; P: =.024). CONCLUSION: The results from this randomized clinical study indicate that patients with node-negative, rapidly proliferating tumors significantly benefit from adjuvant CMF.

A sequential chemo-radiotherapeutic treatment for patients with malignant gliomas: a phase II pilot study.

BACKGROUND: The purpose of our study was to evaluate the activity and toxicity of a sequential chemo-radiotherapeutic treatment on the basis of an earlier report by The Johns Hopkins Oncology Center. MATERIALS AND METHODS: Eighteen patients with histologically diagnosed malignant gliomas entered the study. Fifteen patients had glioblastoma multiforme (83%). BCNU (40 mg/sqm/die) and Cisplatin (40 mg/sqm/die) were administered concurrently for 3 days every 3-4 weeks. Radiotherapy consisted of 45 Gy whole cranial irradiation plus a 15 Gy boost on the preoperative volume. RESULTS: Thirteen patients had measurable disease and were evaluable for response. After chemotherapy we obtained 3 CRs (complete remission) and 4 PRs (partial remission) (RR (response rate 54%). Three PRs were converted to CRs after radiotherapy, for a complete remission rate of 46% (6/13). The median duration of response was 10 months. The median survival of the entire patients population was 9 months with 33% survival rates at 1 year. Hematological toxicity grade 4 in one patient and grade 3 in two patients were the major complications due to chemotherapy. CONCLUSIONS: Our sequential chemo-radiotherapeutic regimen appears to have significant activity in adults with newly diagnosed high-grade gliomas.

Peripheral blood progenitor cell (PBPC) mobilization in heavily pretreated patients with germ cell tumors: a report of 34 cases.

The aim of the study was to evaluate peripheral blood progenitor cell mobilization by disease-specific chemotherapy in heavily pretreated patients with germ cell tumor (GCT), scheduled for high-dose chemotherapy. Thirty-four consecutive patients, 29 males and five females, with advanced GCT referred to our department for high-dose chemotherapy were evaluated retrospectively. Sixteen patients were mobilized by vinblastine 0.11 mg/kg on days 1 and 2, ifosfamide 1200 mg/m2 days 1-5 and cisplatin 20 mg/m2 days 1-5 (VeIP). In 10 patients, etoposide 75 mg/m2 days 1-5 was used instead of vinblastine (VIP), while in eight patients the mobilization was attempted by administering 7 g/m2 of cyclophosphamide. The choice of either etoposide or vinblastine was predicated upon which of these two drugs was associated with best results during premobilization chemotherapy. Cyclophosphamide was selected in patients refractory to previous cisplatin-based salvage chemotherapy. Twenty-five out of 34 patients underwent a successful PBPC collection. In 17 of them one leukapheresis procedure was sufficient to collect the target number of CD34+ cells, while in eight patients a double procedure was necessary. Altogether 33 aphereses were performed in 25 patients. In nine patients leukapheresis was not attempted. This was due to the fact that the chemotherapy failed to mobilize the target number of CD34+ cells in eight of them, treated with the VeIP mobilizing regimen, while one patient treated with high-dose cyclophosphamide rapidly progressed during therapy and for this reason leukapheresis was not undertaken. In conclusion, in heavily pretreated patients with GCT, PBPC mobilization is feasible by a further course of salvage chemotherapy. The choice of either etoposide (VIP) or vinblastine (VeIP) can be predicated upon which of these two drugs was associated with best results during premobilization chemotherapy. In our hands, VeIP seems to be less satisfactory as mobilizing treatment than VIP, possibly due to a superior number of premobilization courses of chemo therapy in some patients. Moreover, high-dose cyclophosphamide remains a good alternative for mobilizing patients refractory to salvage chemotherapy.

Nonmetastatic osteosarcoma of the extremity: results of a neoadjuvant chemotherapy protocol (IOR/OS-3) with high-dose methotrexate, intraarterial or intravenous cisplatin, doxorubicin, and salvage chemotherapy based on histologic tumor response.

AIMS AND BACKGROUND: From 1986 to 1989, a study for the treatment of nonmetastatic osteosarcoma of the extremity (IOR/OS-2) was carried out at the Rizzoli Institute. The cumulative dose of doxorubicin delivered was 480 mg/m2, and severe heart failure developed in 5 (3%) of the 164 treated patients. The specific aim of the subsequent study was to assess the efficacy of a protocol, similar to IOR/OS-2, but with a reduced cumulative dose of doxorubicin (390 mg/m2). Additional aims were to assess the role of the route of infusion (intraarterial or intravenous) of cisplatin on histologic response of the primary tumor and the use of ifosfamide as salvage chemotherapy in poor responders. METHODS: The new chemotherapy regimen (IOR/OS-3) was comprised of a preoperative phase with methotrexate (10 g/m2), cisplatin (120 mg/m2 intraarterially or intravenously), and doxorubicin (60 mg/m2). After surgery, the same drugs were administered, with the addition of ifosfamide (10 g/m2) in patients who had a poor histologic response to primary chemotherapy. RESULTS: Ninety-five patients entered the study. The rate of good histologic response was 64% with intraarterial cisplatin and 43% with intravenous cisplatin (P = 0.05). The 8-year event-free survival and overall survival were 54% and 61%, respectively, with no significant difference according to the histologic response. No cases of clinical doxorubicin-induced cardiopathy were recorded. Event-free and overall survival did not significantly differ from those achieved with IOR/OS-2 (8-year disease-free and overall survival, respectively 63% and 72%). CONCLUSIONS: The reduction in the doxorubicin cumulative dose avoided episodes of cardiotoxicity, without consequences on the efficacy of treatment. The addition of ifosfamide was an effective "salvage" therapy for poor responders. A better histologic response with intraarterial cisplatin was observed, but owing to the availability of an effective salvage therapy for poor responders, the advantages in terms of histologic response did not compensate for the cost and discomfort for the patients of this modality of infusion of cisplatin.

Neoadjuvant chemotherapy for extremity osteosarcoma--preliminary results of the Rizzoli's 4th study.

A neoadjuvant chemotherapy protocol (1/93-1/95) for extremity osteosarcoma preoperatively using high-dose methotrexate (HDMTX) as single agent per cycle and three different combinations of other drugs (CDP/IFO,CDP/ADM,IFO/ADM) is reported. The four drugs were used postoperatively as single agents. Treatment was uniform, but suspended earlier if total necrosis was attained. An improvement was found in the results of the previous study using only IFO postoperatively, with 16/119 patients (97%) avoiding amputation, and 38 (32%) attaining complete necrosis. At a 3-year (2-4 years) mean follow-up, 92 patients (76%) remained continuously disease-free, 2 died of chemotherapy-related toxicity and 25 suffered relapse. Projected 3-year DFS also improved (75% vs. 60%; p = 0.04). Despite limb salvage, local recurrences (6.3%) and infections were few, although postoperative chemotherapy was restarted within a week. Therefore, until new effective drugs are found, expertise in using the four known drugs may improve cure rate and help to avoid amputation in almost all patients.

Neoadjuvant chemotherapy for Ewing's sarcoma of bone: no benefit observed after adding ifosfamide and etoposide to vincristine, actinomycin, cyclophosphamide, and doxorubicin in the maintenance phase--results of two sequential studies.

BACKGROUND: Ifosfamide (IF) alone or combined with etoposide (ET) was reported to be effective in the treatment of patients with Ewing's sarcoma who relapsed after treatment with the VACA regimen, which consisted of vincristine (VC), actinomycin (AC), cyclophosphamide (CP), and doxorubicin (AD). The purpose of this article is to report the results achieved in a new neoadjuvant protocol in which IF and ET were added to the conventional VACA regimen and administered to patients with localized disease. METHODS: In this study, eighty-two patients were treated between May 1988 and October 1991. Chemotherapy consisted of two induction cycles of VC/CP/AD followed by alternating cycles of VC/AD/CP, VC/IF/AC, IF/ET, and VC/CP/AC after local treatment. Twenty-two patients (27%) were treated with surgery only, 22 (27%) underwent surgery followed by radiation therapy, and 38 (46%) received radiotherapy only. RESULTS: At a median follow-up of 6.7 years (range, 4-9 years), 43 patients (52%) remained continuously disease free, and 39 relapsed (34 with metastases, 4 with local recurrence and metastases, and 1 with a local recurrence). These results were similar to those obtained at the same institute in a previous neoadjuvant study (March 1983 and April 1988) that included 108 patients treated with the conventional 4-drug regimen. The 5-year disease free and overall survival in the current study were 54% and 59%, respectively, and in the first study were 50% and 56%, respectively. CONCLUSIONS: The comparison of these two sequential studies, although not randomized, referred to homogeneous groups of patients observed at the same institution who were treated by the same medical team. No advantage was observed when IF and ET were added to the VACA regimen.

Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated with high-dose methotrexate, doxorubicin, and cisplatin.

PURPOSE: In osteosarcoma of the extremity, a strong correlation between chemotherapy-induced necrosis and prognosis has been reported. The aim of this study was to investigate the possible factors that influence histologic response to primary chemotherapy. PATIENTS AND METHODS: In 272 patients with high-grade osteosarcoma of the extremity preoperatively treated with high-dose methotrexate (HDMTX), cisplatin (CDP), and doxorubicin (ADM), the histologic response to chemotherapy was evaluated and graded as complete (no viable tumor cells) or incomplete (persistence of viable tumor cells). Several factors, such as metastatic disease to the lung at diagnosis, sex, age, site and tumor volume, histologic subtype, serum alkaline phosphatase, lactate dehydrogenase (LDH), and methotrexate (MTX) pharmacokinetics were investigated to test their predictive significance on histologic response. RESULTS: Fifty-one patients with localized disease (20.6%) and none of the 25 patients with metastatic disease at presentation had a complete histologic response (P = .006). After multivariate analysis, performed on patients with localized disease only, MTX serum peak (> or = 700 micromol/L) and histologic subtype were proven to be significant predictive factors of histologic response. A complete response was seen in 28.8% of patients with 700 micromol/L or greater MTX serum levels and in 9.9% of those patients with lower levels (P = .001). The chondroblastic subtype was less responsive (6.1% of complete response), compared with the osteoblastic (16.3%), fibroblastic (33.3%), and telangiectatic (42.3%). CONCLUSION: Patients with metastatic osteosarcoma and localized chondroblastic osteosarcoma have a reduced chemosensitivity to primary chemotherapy with MTX, CDP, and ADM. MTX serum peak significantly influences tumor necrosis. A dose adaptation of MTX is recommended to obtain a serum peak of 700 micromol/L or greater when MTX is infused in 6 hours.

Paclitaxel plus doxorubicin in breast cancer: an Italian experience.

Based on preclinical data, phase I/II clinical trials were performed at Istituto Oncologico Romagnolo (IOR) Operative Units (Medical Oncology Departments of Forlì, Rimini, and Ravenna, Italy) to determine the efficacy and toxicity of sequential administration of doxorubicin followed by paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with advanced breast cancer that either had been previously untreated or that had relapsed after adjuvant therapy. In the phase I trial, 19 patients received bolus doxorubicin (50 mg/m2) followed after a 16-hour interval by paclitaxel (given at dose levels ranging from 130 to 250 mg/m2) by 3-hour infusion every 3 weeks, for a maximum of eight cycles. Paclitaxel doses were escalated in 30-mg/m2 increments if the maximum tolerated dose had not been reached in the previous dose level. Analysis of the 128 cycles assessable for toxicity demonstrated neutropenia (<500/microL) in 26 courses (20.3%), with no significant clinical events. No relevant clinical cardiotoxicity was observed. The paclitaxel maximum tolerated dose was not reached at the 250-mg/m2 dose level (no grade 3 or 4 extramedullary toxicity). In the IOR phase II trial, 13 patients were treated with fixed doses of both drugs (doxorubicin 50 mg/m2 and paclitaxel 220 mg/m2). Grade 4 neutropenia occurred in 39 of the 95 cycles, but was complicated by fever in only eight cycles (8.4%); three cycles required granulocyte colony-stimulating factor support. Peripheral neurotoxicity was the most common extramedullary side effect noted. Overall clinical responses in the IOR trials included 10 complete responses (31.3%) and 15 partial responses (46.9%), with an objective response rate of 78.1%. Comparison of these results with those obtained from a phase I trial using the opposite drug sequence showed comparable overall response rates, but IOR's sequence was associated with a higher complete response rate, as well as less frequent and less severe nonhematologic toxicity.

Neoadjuvant chemotherapy for osseous malignant fibrous histiocytoma of the extremity: results in 18 cases and comparison with 112 contemporary osteosarcoma patients treated with the same chemotherapy regimen.

Eighteen patients with high grade malignant fibrous histiocytoma (MFH) of bone and 112 patients with high grade osteosarcoma (OS) of the extremity were treated with neoadjuvant chemotherapy comprised of methotrexate, cisplatinum, doxorubicin and ifosfamide. For the 18 patients with MFH, surgery involved amputation in 2 cases and limb salvage in 16 (89%); the 112 osteosarcoma patients had amputation in 8 cases and limb salvage procedure in 104 cases (93%). The rate of good histologic response to preoperative chemotherapy (90% or more tumor necrosis) was significantly higher in patients with osteosarcoma than in patients with MFH (74% vs 28%; p < 0.003). However, at a median follow-up of 38 months (range 25-61), the 3-year event-free survival (EFS) did not differ in the two groups (MFH 77.8%, OS 70.5%; p = ns). In patients with MFH, no local recurrences were registered, whereas in the osteosarcoma group there were 6 local relapses (5.%). The effectiveness of neoadjuvant chemotherapy in the treatment of osteosarcoma has been assessed during the last 15 years. The results of the present study seem to indicate that, in spite of a usually poor histologic response to preoperative treatment, neoadjuvant chemotherapy is very effective also in MFH of bone.

Long-term follow-up and post-relapse survival in patients with non-metastatic osteosarcoma of the extremity treated with neoadjuvant chemotherapy.

BACKGROUND: Most of the studies of the treatment of non-metastatic osteosarcoma of the extremity have reported results in terms of probability of survival up to five years with a minimum follow-up of less than two to three years. Definition of reliable indicators of prognosis and predictive factors for survival require mature data derived from a long-term survival analysis. PATIENTS AND METHODS: A review of 127 patients with non-metastatic osteosarcoma of the extremity, treated between March 1983 and June 1986, was performed. The treatment protocol consisted of primary chemotherapy with MTX (randomization to high vs. moderate dosages) and CDP followed by surgery. Postoperatively, patients with < 60% tumor necrosis received ADM and BCD; those with tumor necrosis > or = 60% < 90% (Fair Responders FR) were given MTX, CDP and ADM. Up to January 1984, patients with tumor necrosis > 90% received MTX and CDP only, and after then they were given the same treatment as for FR. A multivariate analysis to test predictive factors for survival was performed. RESULTS: With a median follow-up of 134 months (range 114-153), the 12-year DFS was 46%. A good histologic response, an LDH baseline value within the normal range, and the use of high-dose MTX were positive predictive factors for DFS. With a median time of observation for survivors of 130 months, the 12-year overall survival was 53%. None of the patients who relapsed with local or distant recurrences other than lung metastasis are now alive. Patients with a relapse-free interval longer than 24 months had a significantly better post-relapse survival than those with a shorter relapse-free interval (40% vs. 7%; P = 0.0159). All of the patients who were not surgically treated had disease progression and died within 40 months after the first recurrence. The surgically-treated patients had a 30% post-relapse survival probability. CONCLUSIONS: In non-metastatic osteosarcoma of the extremity, chemotherapy-induced tumor necrosis, the baseline LDH serum value and the use of HDMTX are significant predictive factors for DFS. The relapse-free interval and the possibility of metastasectomy are significant factors conditioning the post-relapse survival.

Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing's sarcoma of the extremities.

PURPOSE: This study was performed to assess the prognostic value of the proposed histopathologic method to evaluate the response of the primary tumor to preoperative chemotherapy in Ewing's sarcoma. PATIENTS AND METHODS: The response to chemotherapy was evaluated from the specimens of 118 Ewing's sarcoma patients, who were preoperatively treated by chemotherapy alone. Responses were graded I to III (macroscopic viable tumor, microscopic viable tumor, and no viable tumor cells, respectively). Follow-up data were available for all patients, with a mean follow-up duration of 86 months (range, 30 to 158). RESULTS: A statistically highly significant difference was observed in outcome among the three groups of patients. For patients with total necrosis (grade III response), the estimated 5-year disease-free survival rate was 95%, in contrast to 68% for grade II responders and 34% for grade III responders (P < .0001). This difference was also confirmed when any single group was compared with the other groups. Among the parameters tested, patient age and the size of tumor had some prognostic value. CONCLUSION: The proposed histopathologic grading, to evaluate the effect of chemotherapy on the primary tumor, had the strongest correlation to clinical outcome. This method could therefore be used to identify patients with a high risk of recurrent disease. These patients could be randomized to receive alternative postoperative treatments to investigate whether more aggressive therapies will improve outcome.