| IntroductionOsteosarcoma is the most common primary malignant tumor of bone with highest incidence which predominantly targets adolescent age group. In spite of great progress has been made in chemotherapy research of osteosarcoma because of scholars’unremitting efforts, primary or secondary resistance still exists among many patients with osteosarcoma in chemotherapy, and the prognosis is poor because that micro metastases have been found in many patients at the time of diagnosis. In recent years, the incidence of osteosarcoma in China has significantly increased. Therefore, find an effective program of osteosarcoma chemotherapy to improve the5-years survival rate of patients with osteosarcoma is an important issue related to the protection of adolescent health. In recent years, significant progress has been made in the research on anti-angiogenesis of tumors, studies suggest that angiogenesis is an important factor in disease, and its role is much more important in the development of malignant tumor.Endostatin is a C-terminal fragment of collagen XVIII and its relative molecular weight is20KD and its role in the inhibition of tumor angiogenesis has been confirmed. Endostar is a novel recombinant human endostatin developed by Chinese scholars and has through Phase I-III of clinical trials in2005In recent years, many scholars use Endostar for clinical study of treatment of malignant tumors especially non-small cell lung cancer and have improved the survival rate of patients. So we designed this research program in order to improve the prognosis of patients with malignant bone tumor by chemotherapy combined with Endostar.Objective1. To explore the short-term efficacy of chemotherapy combined with Endostar in osteosarcoma.2. To explore the safety of Endostar in the treatment of osteosarcoma.Materials and methods1. PatientsPatients with osteosarcoma were randomly divided into experimental group (Endostar group) and control group.63cases of osteosarcoma were included in this study, experimental group were treated with Endostar in combination with chemotherapy, control group were treated only with chemotherapy drugs. The clinical benefit response, quality of life scores and adverse reactions were observed.1.1Inclusion criteria1.1.1Patients with osteosarcoma diagnosed by pathologic and accessory examinations that have no distant metastasis and need chemotherapy.1.1.2Have a double diameter measurable focus at least. Lesions scanned by X-ray, CT and MRI≥20mm, Spiral CT and PET-CT≥10mm.1.1.3Physical condition is good, the ECOG physical condition score of0-2, expected survival>3months.1.1.4Aged10to60years old, male or female.1.1.5Match indications and basic requirements of chemotherapy, including normal peripheral hematological changes, normal cardiac, hepatic and renal function, normal ECG. Laboratory indicators have to meet the following requirements: WBC≥3.0×109/L, PLT≥75×109/L, Hb≥95g/L, Cr≤2.0×UNL, BUN≤2.5×UNL, BIL≤2.5×UNL, ALT/AST≤2.5×UNL.1.1.6Patients who have accepted other chemotherapy drugs must cost a4-week washout period before entering this clinical trial.1.1.7Have no allergic reaction to biological agents, especially E. coil genetically engineered products.1.1.8Voluntarily enrolled to participate in, good compliance with the experimental observation, and signed a written informed consent.1.2Exclusion criteria1.2.1Patients with other parts of the metastases.1.2.2Pregnant, lactating women or fertile female patients have not taken contraceptive measures.1.2.3Patients with severe acute infection uncontrolled, with purulent and chronic infections, or with severe bleeding tendency.1.2.4Patients with important organ dysfunction and severe heart disease, including congestive heart failure, uncontrollable high-risk arrhythmias, angina pectoris, cardiac value disease, myocardial infarction and resistant hypertension.1.2.5Patients with mental illness or mental disorders who can not cope with the treatment.1.2.6Patients who have participated in other clinical trials at the same time.1.2.7Patients who have been believed that should not participate in this trial.1.3Exit criteria1.3.1Patients can not continue to accept the treatment because of the adverse events.1.3.2Patients do not want to continue the treatment.1.3.3Researchers believe that patients are not suitable to continue the treatment because of other reasons. 1.4Elimination criteria1.4.1Patients who have serious violation of inclusion criteria.1.4.2Do not accept the treatment in the clinical trial.1.4.3Have no available inspection records for evaluation.1.4.4Patients who can not be evaluated because of taking the prohibited drugs for the trial.2. Major drugs2.1Source of drugs:Endostar (recombinant human endostatin injection), provided by the Simcere Bio-pharmaceutical Co. Ltd.(No. S20050088)2.2Administration of Endostar:Patients received Endostar7.5mg/m2in3to4hours once a day, and were administered continuously for14days starting from the first day of the first week and the fifth week of every chemotherapy cycle.2.3Administration of other chemotherapy drugs:2.3.1MTX:Patients received MTX8g/m2in4to6hours at the first day of the first week of every chemotherapy cycle. Blood concentration was monitored continuously and patients received CF at6hours after the end of the administration.2.3.2CDP:Patients received CDP100-200mg/m2totally at the first or second day of the third week of every chemotherapy cycle.2.3.3ADM/THP:60mg/m2, intravenous injection, at the first or second day of the third week of every chemotherapy cycle.2.3.4IFO:2g/day from the first day to the sixth day of the fifth week of every chemotherapy cycle with injection pump.3. Therapeutic schemesExperimental group were treated with Endostar in combination with chemotherapy, control group were treated only with chemotherapy drugs. Patients received one chemotherapy cycle and had a rest for one week before operation, and then received three chemotherapy cycles continuously.4. Therapeutic evaluation4.1Short-term efficacy evaluation criteria:taking into account the measurement of the longest diameter only for all target lesions:complete response(CR)-the disappearance of all target lesions; partial response(PR)-at least a30%decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter; progressive disease(PD)-at least a20%increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions; stable disease(SD)-neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started. Clinical benefit rate:[(CR+PR+SD)/total number of cases]*100%.4.2Evaluation of quality of life according to the physical condition (ECOG criteria and QOL criteria).4.3Adverse reactions divide into0-4degrees in accordance with the Common Toxicity Evaluation Criteria (CTC) developed by the U. S. National Cancer Institute (NCI)5. Statistical analysisSpss13.0statistical software was used to analyze the data. If the measurement data followed a normal distribution, they were described by mean±tandard deviation and the means would receive T test. If the measurement data did not follow a normal distribution, they were described by median (interquartile range) and the Mann-Whitney U test would be used between two groups. The count data would receive the Fisher’s exact test between two groups. p<0.05was considered statistically significant. 6. Results63patients were enrolled in this trial,32cases in the experimental group and the other31cases in the control group.10cases (3in experimental group and7cases in control group) failed to receive efficacy evaluation after the treatment, so53cases could receive the efficacy evaluation. Patients were balanced in various influencing factors between two groups. The CBR of experimental group was89.7%after the standardized treatment, including CR0case, PR0case, SD26cases and PD3cases. While the CBR of the control group was87.5%, including CR0case, PR1case, SD20cases and PD3cases. No significant differences in two groups by the Chi-square test (P>0.05). The quality of the life scores were upper after the treatment in both two groups, it mainly because that many patients in the trial were young and the dose of the drug were relative large which were different from other tumor chemotherapy. The main adverse reactions with grade3and4in two groups were leukocytopenia, neutropenia, hemoglobin decreased, thrombocytopenia, elevated AST and ALT and ECG changed. The incidence of adverse reactions was lower in the experimental group than in the control group, especially in hematological toxicity(p<0.05).7. Conclusion63cases of osteosarcoma were included in this study and53cases were evaluable for efficacy. The CBR in the experimental group was higher than that in the control group but there were no statistically different. It may be due to the number of the cases. The incidence of adverse reactions was lower in the experimental group than in the control group, especially in hematological toxicity(p<0.05), and the quality of life scores of the experimental group were higher than the control group, but there were no significant differences between two groups.In recent years, although many achievements had been got in the treatment of malignant tumors with Endostar in combination with chemotherapy, especially in the treatment of non-small cell lung cancer, there were few studies of Endostar combined with chemotherapy used in the treatment of osteosarcoma. In this trial, the clinical benefit response, quality of life scores and adverse reactions were observed. We found that Endostar may have anti-tumor activity with high clinical benefit response and is well tolerated in patients of osteosarcoma. It is worth further study. |
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