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Background: The authors evaluated the efficacy and toxicity of cisplatin, ifosfamide, and doxorubicin with peripheral blood stem cell (PBSC) support in adult patients with osteosarcomas and variants with a poor prognosis., Methods: Between December 1994 and January 2001, 37 patients (20 males and 17 females) with a median age of 38 years (range, 18-63 years) entered the study. Ten patients had pelvic osteosarcomas (OS), 6 had malignant fibrous histiocytomas, 5 had metastatic OS, and 16 had miscellaneous histologies. The authors used doxorubicin (60-75 mg/m(2)) and ifosfamide (10 g/m(2)) followed by granulocyte-colony-stimulating factor (G-CSF) (5 microg/kg twice per day) for mobilization of PBSC, collected at a median of 12 days (range, 10-14 days). Three cycles with cisplatin (120 mg/m(2)), ifosfamide (10 g/m(2)), and doxorubicin (75 mg/m(2)), given 28 days apart, were planned followed by PBSC (2-4 x 10(6) CD34-positive cells/kg) infusion plus G-CSF., Results: Patients received a median of three cycles (range, one to three cycles) in addition to the mobilizing cycle. The median PBSC collection was 17.5 x 10(6)/kg (range, 13.2-90.8 x 10(6)/kg) with a median of 1 apheresis (range, 1-2 aphereses). Twenty-eight patients underwent surgery, 10 achieved 95-100% necrosis, and 4 achieved 90-94% necrosis. Six patients required early discontinuation of therapy due to toxicities, two patients developed progressive disease, and one patient was deemed unresectable. The median time to progression (TTP) and overall survival by Kaplan-Meier estimates for all 37 patients was 19 months and 49 months, respectively., Conclusions: The authors accomplished the objective of improving the rate of necrosis with intensification of preoperative therapy. However, TTP and survival rates remained poor. The toxicity profile of this regimen is prohibitive and alternative strategies need to be investigated., (Copyright 2004 American Cancer Society.)

Purpose: Recombinant human thrombopoietin (rhTPO) increases platelets, and the peak response of rhTPO is delayed and is, therefore, not uniformly effective when administered after chemotherapy. The purpose of this study was to identify an effective schedule of rhTPO to best attenuate early thrombocytopenia., Patients and Methods: Cohorts of six patients with sarcoma (66 assessable patients) were treated sequentially with doxorubicin and ifosfamide (AI), with rhTPO by a fixed dose and varying schedules being administered before and/or after chemotherapy in cycle 2 and subsequent cycles. Cycle 1 without rhTPO served as an internal control., Results: AI causes cumulative thrombocytopenia. The platelet nadir in cycle 2 was higher than in cycle 1 (mean nadir +/- SEM, 119 +/- 12 x 10(3)/microL v 80 +/- 7 x 10(3)/microL, respectively; P <.001) in 24 (80%) of the 30 patients (P <.001) in whom rhTPO (1.2 microg/kg) was administered starting from 5 days before chemotherapy (pre/postdoses, three/one or one/one) compared with only four (17%) of 24 patients given rhTPO by other schedules (pre/postdoses, two/two, one/three, zero/four, or four/zero) and none of 15 historical control patients. The need for platelet transfusions in four cycles was significantly lower (13 [11%] of 114 cycles, P <.001) in patients who received rhTPO from day -5 (pre/post doses, three/one or one/one) compared with patients who received rhTPO at later time points (28 [47%] of 60 cycles). Bone marrow megakaryocytes increased markedly (four-fold) before chemotherapy with predosing rhTPO and remained elevated (two-fold) after chemotherapy, which may explain the possible mechanism for response. One patient developed subclavian vein thrombosis, and no patients developed neutralizing antibodies to rhTPO., Conclusion: These results demonstrate the importance of timing of rhTPO in relation to chemotherapy and indicate that, by optimizing the timing, only two doses of rhTPO (one before and one after chemotherapy) were required to significantly reduce the severity of chemotherapy-related early thrombocytopenia.

The authors evaluate the efficacy and feasibility of dose-intensive doxorubicin and ifosfamide combination chemotherapy in patients with sarcomas. From January 1995 to April 1996, 33 evaluable patients with either metastatic sarcoma or primary sarcomas with a high-risk for metastases (all except one was previously untreated with chemotherapy) were treated on two consecutive protocols. The median age was 45 years (range, 15-68 years). The first protocol included doxorubicin at 75 mg/m2 given as a 72-hour infusion on days 1 to 3 along with ifosfamide at 2 g/m2/d over 2 hours x 5, days 1 to 5 (protocol AI 75/10). Granulocyte colony-stimulating factor (G-CSF) was used only if indicated according to American Society of Clinical Oncology guidelines. The second protocol included doxorubicin at 90 mg/m2 as a 72-hour continuous infusion and ifosfamide at 2.5 g/m2/d for 4 days (protocol AI 90/10) with prophylactic G-CSF. A median of four cycles were administered (range, 1-6). Three patients achieved a pathologic complete response (CR) and 18 patients achieved a partial response (PR) for a response rate (RR) of 64% (95% confidence interval (CI), 45-80%). Response rate for the subset of patients with soft-tissue sarcomas was 66% (95% CI, 46-82%). Only three patients progressed on therapy. Febrile neutropenia was noted in 31% of cycles at AI 75/10 and in 56% of cycles at AI 90/10. One patient developed reversible grade 3 central nervous system (CNS) toxicity. There was one treatment-related death on AI 90/10 secondary to doxorubicin cardiac toxicity at a cumulative dose of 435 mg/m2. Dose-intensive doxorubicin plus ifosfamide is feasible in appropriately selected patients and appears to be a very active regimen in patients with sarcomas. The authors are currently testing this regimen with G-CSF and thrombopoietin.