pirarubicin and Osteosarcoma

The purpose of this study was to investigate the feasibility and efficacy of pirarubicin (THP)-cisplatin (DDP) chemotherapy for refractory and recurrent high-grade osteosarcoma. Between 2008 and 2010, 23 patients with refractory and recurrent high-grade osteosarcoma were included in this analysis. THP was given at a dose of 50 mg/m(2) i.v. d1 and DDP 100-120 mg/m(2) i.v. d2-3 every 3 weeks. Treatment was continued until evidence of disease progression or unacceptable toxicity. Tumor response was usually evaluated every two chemotherapy cycles by CT/MRI scan. The primary end point was overall response rate, secondary endpoint including progression-free survival (PFS), overall survival (OS), disease control rate, and toxicities. A total of 68 cycles were given, median 2 per patient (range 2-7). Overall response rate was 13% and disease control rate was 34.5%, with 3 partial responses and 5 stable diseases. Median time to progression and overall survival time were 2 (95%CI 2-11) and 10 months (95%CI 6-23), respectively. Major severe toxicities were grade 3 or 4 leucopenia occurred 12 times (17.7%) in total cycles; Mild toxicities included grade 1 or 2 nausea and vomiting (80.9%), leucopenia (61.8%), fatigue (50.0%), and alopecia (79.4%). THP-DDP regimen chemotherapy represents an active and well-tolerated treatment for Chinese refractory and recurrent high-grade osteosarcoma patients. Further assessment is necessary to confirm the safety and efficacy of this treatment.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Cisplatin; Disease-Free Survival; Doxorubicin; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Osteosarcoma; Young Adult

Although prognosis in patients with localized osteosarcoma has been dramatically improved by the introduction of multiple chemotherapy agents known as combination chemotherapy, there is growing concern about the development of secondary malignant neoplasms. We report the case of a 13-year-old girl in whom the diagnosis of Ewing sarcoma of bone localized on the shaft of left femur was made 2 years after successful treatment without radiotherapy for osteosarcoma of right proximal femur. EWS-FLI1 fusion gene was detected by reverse transcriptase-polymerase chain reaction. To our knowledge, this is the first case with Ewing sarcoma of the bone as a secondary malignant neoplasm developed in osteosarcoma survivor. We collected 15 cases, included this case, with secondary Ewing sarcoma family of tumor by utilizing the PubMed search and might consider the causes of this secondary cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Female; Femoral Neoplasms; Humans; Ifosfamide; Limb Salvage; Methotrexate; Neoplasms, Second Primary; Oncogene Proteins, Fusion; Osteosarcoma; Proto-Oncogene Protein c-fli-1; Remission Induction; RNA-Binding Protein EWS; Sarcoma, Ewing; Vincristine

Pirarubicin (THP), a novel anthracycline derivative of doxorubicin (ADM), is effective in treating patients with advanced, relapsed or recurrent high-grade osteosarcoma. But its role in neoadjuvant/adjuvant chemotherapy of osteosarcoma is still not defined. We conducted a retrospective evaluation of THP-containing chemotherapy for osteosarcoma in comparison with ADM-containing chemotherapy to determine differences in efficacy and toxicities between THP- and ADM-containing regimens. From January 2008 to May 2011, 112 stage IIB limb high-grade osteosarcoma patients were treated in our institute. Fifty-four patients received a median 6 cycles of neoadjuvant/adjuvant chemotherapy consisted of THP (pirarubicin), DDP (cisplatin), IFO (ifosfamide) and MTX (methotrexate), while 58 patients received a median 6 cycles of neoadjuvant/adjuvant chemotherapy consisted of ADM (doxorubicin), DDP (cisplatin), IFO (ifosfamide) and MTX (methotrexate). Efficacy and toxicity of the 2 anthracyclines given as combination chemotherapy were assessed in these patients. The limb salvage rate, histologic response rate, 2-year recurrence rate, 2-year metastasis rate, 2-year disease-free survival rate, 2-year overall survival rate, median disease-free survival time (DFS) and median overall survival time (OS) in THP-containing group were similar to that in ADM-containing group. Toxicities were well balanced in two groups. No death related to chemotherapy was observed. Left ventricular ejection fraction was unchanged 1 and 2 years after chemotherapy in two groups. Efficacy and toxicity of THP-containing combination are similar to those of ADM-containing combination in neoadjuvant/adjuvant chemotherapy for stage IIB limb high-grade osteosarcoma.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemotherapy, Adjuvant; Child; Cisplatin; Disease-Free Survival; Doxorubicin; Extremities; Female; Humans; Ifosfamide; Kaplan-Meier Estimate; Male; Methotrexate; Middle Aged; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Staging; Osteosarcoma; Retrospective Studies; Young Adult

Pirarubicin is frequently used in chemotherapy against tumors. However, clinical use is severely limited by the development of progressive dose-dependent cardiomyopathy and acquired drug resistance. LY294002 is a commonly used pharmacologic inhibitor, which selectively inhibits the phosphoinositide 3-kinase-AKT nexus. The aim of this study was to investigate the combined inhibitory effect of LY294002 and pirarubicin on human osteosarcoma (OS) cells in vitro. The inhibitory effect of LY294002 plus pirarubicin on U2-OS and MG-63 OS cell proliferation, apoptosis, migration and invasion was investigated by cell proliferation, wound healing and Transwell invasion assays. The results revealed that LY294002 and pirarubicin synergistically induced apoptosis, and inhibited the growth, migration and invasion of OS cells. This indicates that LY294002 enhanced the effects of pirarubicin on OS in vitro. LY294002 combined with pirarubicin may thus be a future therapeutic strategy in OS.

Topics: Antineoplastic Agents; Apoptosis; Bone Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromones; Doxorubicin; Humans; Morpholines; Osteosarcoma; Phenotype; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt

The prognoses for patients with relapsed and refractory osteosarcoma are poor and the optimal treatment strategy is still to be defined. We conducted this retrospective study to compare the feasibility and efficacy of pirarubicin-based chemotherapy with gemcitabine-docetaxel combination regimens for the salvage of these patients.. The clinical data of 75 patients who received pirarubicin-based (n = 52) or gemcitabine-docetaxel (n = 23) chemotherapy as a second-line treatment for relapsed and refractory osteosarcoma between January 2005 and September 2011were reviewed retrospectively. Tumor response was evaluated every two chemotherapy cycles by computed tomography/magnetic resonance imaging (CT/MRI) scans using the Response Evaluation Criteria in Solid Tumors. Progression-free survival and overall survival (OS) were evaluated by Kaplan-Meier analysis. Toxicity was examined according to the National Cancer Institute Toxicity Criteria grading system.. Patient characteristics were well balanced in the two groups. The response rate was 25.0 % in patients who received pirarubicin-based chemotherapy, while it was 13.0 % in the gemcitabine-docetaxel group. Moreover, the median OS was longer in the pirarubicin-based chemotherapy group (14.0 vs. 9.0 months, P < 0.05), especially in the pirarubicin-ifosfamide (14.0 months) and pirarubicin-cisplatin (15.0 months) subgroups. The incidence of grade 3-4 neutropenia was higher in the gemcitabine-docetaxel group (5.8 vs. 43.5 %, P < 0.05); other grade 3-4 toxicities were comparable in the two groups.. In our experience, pirarubicin-based chemotherapy was comparable with gemcitabine-docetaxel as a second-line treatment for relapsed and refractory osteosarcoma, and it even seemed to show greater efficacy, with milder toxicity. Further studies, especially prospective clinical trials, focusing on pirarubicin-based treatments for relapsed and refractory osteosarcoma patients should be strongly considered.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Deoxycytidine; Disease-Free Survival; Docetaxel; Doxorubicin; Drug-Related Side Effects and Adverse Reactions; Female; Gemcitabine; Humans; Ifosfamide; Kaplan-Meier Estimate; Male; Middle Aged; Osteosarcoma; Prospective Studies; Taxoids

Small cell osteosarcoma (SCO) is the most rare subtype of osteosarcoma and has a poor prognosis. An 11-year-old boy presented with 2-month history of painful tumefaction in the lower leg. Imaging analysis demonstrated a mixture of osteolytic and osteosclerotic lesions in the proximal tibia and extraskeletal area. Histology of the open biopsy showed small round cells producing mucous matrix. Based on these findings, SCO was suspected. The patient received three cycles of neoadjuvant chemotherapy using high-dose ifosfamide, high-dose methotrexate, pirarubicin and carboplatin. Wide-margin resection was performed followed by tibial lengthening using the Ilizarov method and two cycles of adjuvant chemotherapy with the same drugs as for neoadjuvant chemotherapy. Histology of the resected specimen showed that almost all tumor cells were necrotized. Neither recurrence nor metastasis was found after 4 years. Our experience suggests that neoadjuvant chemotherapy, such as the one used here, would be exceedingly effective for SCO without serious non-hematological toxicities.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carboplatin; Chemotherapy, Adjuvant; Child; Combined Modality Therapy; Doxorubicin; Humans; Ifosfamide; Male; Methotrexate; Osteosarcoma

Pirarubicin (THP) is recently found to be effective in treating patients with advanced, relapsed or recurrent high-grade osteosarcoma. In this study, the effects of THP on the multidrug-resistant (MDR) osteosarcoma cells were assessed, and the underlying mechanisms for the disruption of cell cycle kinetics by THP were explored.. Human osteosarcoma cell line MG63 and human MDR osteosarcoma cell line MG63/DOX were tested. The cytotoxicity of drugs was examined using a cell proliferation assay with the Cell Counting Kit-8 (CCK-8). The distribution of cells across the cell cycle was determined with flow cytometry. The expression of cell cycle-regulated genes cyclin B1 and Cdc2 (CDK1), and the phosphorylated Cdc2 and Cdc25C was examined using Western blot analyses.. MG63/DOX cells were highly resistant to doxorubicin (ADM) and gemcitabine (GEM), but were sensitive or lowly resistant to THP, methotrexate (MTX) and cisplatin (DDP). Treatment of MG63/DOX cells with THP (200-1000 ng/mL) inhibited the cell proliferation in time- and concentration-dependent manners. THP (50-500 ng/mL) induced MG63/DOX cell cycle arrest at the G(2)/M phase in time- and concentration-dependent manners. Furthermore, the treatment of MG63/DOX cells with THP (200-1000 ng/mL) downregulated cyclin B1 expression, and decreased the phosphorylated Cdc2 at Thr(161). Conversely, the treatment increased the phosphorylated Cdc2 at Thr(14)/Tyr(15) and Cdc25C at Ser(216), which led to a decrease in Cdc2-cyclin B1 activity.. The cytotoxicity of THP to MG63/DOX cells may be in part due to its ability to arrest cell cycle progression at the G(2)/M phase, which supports the use of THP for managing patients with MDR osteosarcoma.

Topics: Antineoplastic Agents; CDC2 Protein Kinase; cdc25 Phosphatases; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cyclin B1; Doxorubicin; G2 Phase; Gene Expression Regulation, Neoplastic; Humans; Osteosarcoma

Paclitaxel and pirarubicin exhibit cytotoxic and antitumor activities. However, little is known about the apoptosis-inducing effects of paclitaxel and pirarubicin on human osteosarcoma MG-63 cells.. The effects of paclitaxel and pirarubicin on cell cycle arrest and apoptosis were studied in MG-63 cells using flow cytometry. PCNA, Bcl-2, Bax, cyclin D1 and cyclin E expression was assessed by Western blotting.. Paclitaxel and pirarubicin caused G2/M and G0/G1 cell cycle arrest in MG-63 cells, respectively. Apoptosis of MG-63 cells mediated by paclitaxel was dependent on treatment duration. Interestingly, in cells treated with pirarubicin, apoptosis was related to treatment duration at concentrations of 10(2)-10(3) nM, whereas the effect of treatment duration was less marked at concentrations >10(4)-10(5) nM. Furthermore, paclitaxel and pirarubicin suppressed the expression of PCNA, cyclin D1, cyclin E and Bcl-2, and increased Bax expression.. These results suggest that the G2/M or G0/G1 cell cycle arrest and apoptosis induced by paclitaxel and pirarubicin are Bcl-2/Bax dependent, suggesting favorable effects of combination therapy with paclitaxel and pirarubicin in the treatment of osteosarcoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Cell Cycle; Cell Line, Tumor; Dose-Response Relationship, Drug; Doxorubicin; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Osteosarcoma; Paclitaxel; Proto-Oncogene Proteins c-bcl-2; Time Factors

This study assessed the therapeutic effect of and adverse reactions to pirarubicin (THP) chemotherapy in osteosarcoma patients with lung metastasis, and analyzed the relationship between THP therapeutic effect and expression of p-glycoprotein and topoisomerase-II. Osteosarcoma patients with lung metastases at relapse were given THP and then cisplatin (DDP) or ifosfamide (IFO). Overall survival in patients receiving THP was 31.00 +/- 7.98 months, progression-free survival was 13.00 +/- 2.46 months. Objective response and partial response rates were 46.88% and 40.63%, respectively. There were no differences in overall survival and progression-free survival between the THP+DDP and THP+IFO regimens. Adverse reactions to THP chemotherapy were mainly gastrointestinal and myelosuppression. The therapeutic effect of THP was correlated with the abrogated expression of pglycoprotein and/or topoisomerase-II positive expression. For osteosarcoma patients with secondary lung metastasis, THP-based chemotherapy regimens are safe and effective as a salvage chemotherapy option.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bone Neoplasms; Child; Cisplatin; Disease-Free Survival; DNA Topoisomerases, Type II; Doxorubicin; Female; Humans; Ifosfamide; Lung Neoplasms; Male; Middle Aged; Osteosarcoma; Young Adult

We report our experience with the use of intra-arterial chemotherapy and embolization before limb salvage surgery in patients with osteosarcoma of the lower extremity. We evaluated the effect of this procedure on the degree of tumor necrosis and on the amount of blood loss during surgery. We reviewed the medical records of all patients who received intra-arterial chemotherapy and embolization before undergoing limb salvage surgery for osteosarcoma of the lower extremity at our institution between January 2003 and April 2008. Patient demographic, tumor characteristics, treatment details, postembolization complications, and surgical and pathological findings were recorded for each patient. We evaluated the operative time, estimated blood loss (EBL), and volume of blood transfusion during surgery and in the postoperative period in all patients in the study group. The same parameters were recorded for 65 other patients with lower extremity osteosarcoma who underwent limb salvage operation at our institution without undergoing preoperative intervention. The study included 47 patients (25 males and 22 females). Angiography showed that the tumors were hypervascular. Intra-arterial chemotherapy and embolization were performed successfully, resulting in a substantial reduction or complete disappearance of tumor stain in all patients. No major complications were encountered. At the time of surgery, performed 3-7 days after embolization, a fibrous edematous band around the tumor was observed in 43 of the 47 patients, facilitating surgery. The goal of limb salvage was achieved successfully in all cases. Percentage tumor necrosis induced by treatment ranged from 70.2% to 94.2% (average, 82.9%). EBL during surgery, EBL from drains in the postoperative period, total EBL, and transfusion volumes were significantly lower in the 47 study patients compared to the 65 patients who underwent surgery without preoperative treatment with intra-arterial chemotherapy and embolization. The mean operative time was also significantly less in the intervention group compared to the nonintervention group (73.2 vs. 88.5 min; p < 0.05). In conclusion, intra-arterial chemotherapy and embolization performed 3 to 7 days before limb salvage surgery in patients with lower extremity osteosarcomas can cause substantial tumor necrosis, reduce the EBL and transfusion requirements during surgery, and induce formation of a false capsule around the tumor, thus facilitating surgical excision of the tum

Topics: Adolescent; Adult; Angiography; Antineoplastic Combined Chemotherapy Protocols; Blood Loss, Surgical; Blood Transfusion; Bone Neoplasms; Cisplatin; Combined Modality Therapy; Doxorubicin; Embolization, Therapeutic; Female; Humans; Infusions, Intra-Arterial; Limb Salvage; Lower Extremity; Male; Middle Aged; Osteosarcoma; Retrospective Studies; Treatment Outcome

To conduct a retrospective evaluation of tetrahydropyranyladriamycin (PIR)-based combination chemotherapy for osteosarcomas in comparison with doxorubicin (DOX)-based regimens to determine differences in response and toxicities between DOX- and PIR-containing regimens.. Toxicities and response rates of the 2 anthracyclines given as combination chemotherapy were assessed in patients with osteosarcoma, with 19 patients receiving PIR-based and 11 receiving DOX-based regimens.. The survival of osteosarcoma patients treated with PIR was significantly better than that with DOX (p = 0.023) based on 2-year follow-up. Adverse effects such as mucositis and diarrhea were also less pronounced in the PIR cohort.. PIR-based combination chemotherapy might be a useful and safe chemotherapeutic strategy for osteosarcomas compared with DOX regimens. Further assessment is necessary to confirm the safety and efficacy of this treatment.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Doxorubicin; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Osteosarcoma; Retrospective Studies; Survival Rate