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The efficacy and safety comparison of first-line chemotherapeutic agents (high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide) for osteosarcoma: a network meta-analysis.

ABSTRACT: BACKGROUND:Osteosarcoma, a primary malignant bone tumor derived from mesenchymal tissue, is the most common type of pleomorphic tumor that occurs in children and adolescents. The aim of this study was to compare the efficacy and safety of high-dose methotrexate (M), doxorubicin (D), cisplatin (C), and ifosfamide (I) in the management of osteosarcoma. METHODS:Electronic databases including PubMed, Cochrane Library, and Embase database were searched for studies published from when the databases were established to July 13, 2019. The network meta-analysis was performed using software R 3.3.2 and STATA version 41.0 after demographic and outcome data extraction. The ranks based on probabilities of interventions for each outcome were performed. In addition, the consistency of direct and indirect evidence was assessed by node splitting. RESULTS:The network meta-analysis results revealed that MDCI had a significant lower hazard risk of overall survival [MDCI vs MDC: HR?=?0.74, 95% CrI (0.23, 0.87); MDCI vs DC: HR?=?0.60, 95% CrI (0.16, 0.92)]. In addition, MDCI had a clearly longer progression-free survival time than that of DC [MDCI: HR?=?0.88, 95% CrI (0.46, 0.98)]. No significant difference was detected in MDC and DC in OS, PFS, and AEs. The probabilities of rank plot showed that MDCI ranked first in OS (73.12%) and PFS (52.43%). DC was the best treatment in safety, ranked first (75.43%). CONCLUSIONS:MDCI showed its superiority among all chemotherapeutic agents in relation to efficacy and safety, followed by MDC. In addition, MDCI was associated with an increased risk of AEs. According to our analysis, DC was less effective but safer for MDC and MDCI.

SUBMITTER: Zhang B

PROVIDER: S-EPMC7020590 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The efficacy and safety comparison of first-line chemotherapeutic agents (high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide) for osteosarcoma: a network meta-analysis.

Zhang Bin B Zhang Yan Y Li Rongzhen R Li Jiazhen J Lu Xinchang X Zhang Yi Y

Journal of orthopaedic surgery and research 20200213 1

<h4>Background</h4>Osteosarcoma, a primary malignant bone tumor derived from mesenchymal tissue, is the most common type of pleomorphic tumor that occurs in children and adolescents. The aim of this study was to compare the efficacy and safety of high-dose methotrexate (M), doxorubicin (D), cisplatin (C), and ifosfamide (I) in the management of osteosarcoma.<h4>Methods</h4>Electronic databases including PubMed, Cochrane Library, and Embase database were searched for studies published from when t ...[more]

PMID: 32054494

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Project description:BackgroundThe effectiveness of second-line palliative chemotherapy in patients with recurrent/metastatic osteosarcoma is not well defined. Several small studies (6-19 patients) have reported on ifosfamide as second-line treatment. In this study we report our single-center experience with second-line ifosfamide monotherapy in patients treated for recurrent/metastatic osteosarcoma.MethodsA chart review was conducted of all patients with osteosarcoma treated with ifosfamide from 1978 until 2017. Until 1997 a 5 g/m2 regimen was used, and from 1997 onwards a 9 g/m2 regimen was used. Overall survival (OS) from start of ifosfamide was the primary endpoint. Progression-free survival (PFS) from start of treatment was also studied. To assess difference in survival between groups the log rank test was applied. To investigate the effect of ifosfamide dose and World Health Organization performance status (PS) a Cox proportional hazard regression model was estimated.ResultsSixty-two patients were selected with recurrent/metastatic osteosarcoma treated with second-line ifosfamide monotherapy (dose of 5 g/m2 , n = 26; 9 g/m2 , n = 36). OS was significantly better in univariate analysis for 9 g/m2 compared with 5 g/m2 (10.9 months [95% confidence interval (CI), 9.3-12.6] vs. 6.7 months [95% CI, 5.9-7.6], respectively) and for PS (median OS PS 0, 13.0 months [95% CI, 2.3-23.8]; PS 1, 8.2 months [95% CI, 5.4-11.1]; PS ≥2, 6.2 months [95% CI, 2.2-10.3]; and unknown PS, 5.4 months [95% CI, 2.2-8.5]). In multivariate analysis only PS showed a significant difference. No difference in PFS was found between 5 and 9 g/m2 ifosfamide treatment or PS.ConclusionThis study suggests that ifosfamide is an effective second-line treatment for patients with recurrent/metastatic osteosarcoma.Implications for practiceIfosfamide monotherapy is commonly used as second-line treatment in osteosarcoma, although large series to support this are lacking. This retrospective study reports overall and progression-free survival for regimens with 5 g/m2 and with 9 g/m2 . This study was unable to show a significant difference in survival between 5 and 9 g/m2 but showed an important impact of World Health Organization performance status on overall survival. This study sets a standard and reference for comparison with the multiple phase II studies under development.

Project description:LESSONS LEARNED:Using a randomized crossover design and continuous variables such as change in hearing threshold and biomarkers of acute renal injury as short-term endpoints, it was determined that pantoprazole, an organic cation transporter 2 inhibitor, did not ameliorate cisplatin-associated nephrotoxicity or ototoxicity.Cystatin C is a robust method to estimate glomerular filtration rate in patients with cancer. Using a patient-reported outcome survey, all patients identified tinnitus and subjective hearing loss occurring "at least rarely" after cycle 1, prior to objective high-frequency hearing loss measured by audiograms.New therapies that improve outcome with less acute and long-term toxicity are needed. BACKGROUND:Organic cation transporter 2 (OCT2), which is a cisplatin uptake transporter expressed on renal tubules and cochlear hair cells but not on osteosarcoma cells, mediates cisplatin uptake. Pantoprazole inhibits OCT2 and could ameliorate cisplatin ototoxicity and nephrotoxicity. Using a randomized crossover design, we evaluated audiograms, urinary acute kidney injury (AKI) biomarkers, and glomerular filtration rate (GFR) estimated from cystatin C (GFRcysC) in patients receiving cisplatin with and without pantoprazole. MATERIALS AND METHODS:Cisplatin (60 mg/m2 × 2 days per cycle) was administered concurrently with pantoprazole (intravenous [IV], 1.6 mg/kg over 4 hours) on cycles 1 and 2 or cycles 3 and 4 in 12 patients with osteosarcoma (OS) with a median (range) age of 12.8 (5.6-19) years. Audiograms, urinary AKI biomarkers, and serum cystatin C were monitored during each cycle. RESULTS:Pantoprazole had no impact on decrements in hearing threshold at 4-8 kHz, post-treatment elevation of urinary AKI biomarkers, or GFRcysC (Fig. 1, Table 1). Histological response (percent necrosis) after two cycles was similar with or without pantoprazole. All eight patients with localized OS at diagnosis are alive and in remission; three of four patients with metastases at diagnosis have died. CONCLUSION:Pantoprazole did not ameliorate cisplatin ototoxicity or nephrotoxicity. The decrease in GFRcysC and increase in N-acetyl-ß-glucosaminidase (NAG) and creatinine demonstrate that these biomarkers can quantify cisplatin glomerular and proximal tubular toxicity. OCT2 inhibition by pantoprazole did not appear to alter antitumor response or survival.

Project description:BackgroundThe standard of care (SOC) for muscle-invasive bladder cancer (MIBC) includes cisplatin-based combination chemotherapy in the neoadjuvant setting followed by radical cystectomy. Older patients often do not receive SOC due to perceived toxicity concerns despite guideline-directed recommendations.ObjectiveTo characterize the safety and efficacy of neoadjuvant accelerated methotrexate, vinblastine, adriamycin, and cisplatin (aMVAC) in MIBC patients as a function of age.Design, setting, and participantsA retrospective analysis was conducted in 186 MIBC patients treated at Fox Chase Cancer Center between January 1, 2002 and December 31, 2018. Adults with histologically proven muscle-invasive urothelial cancer were eligible. The exclusion criteria included nonurothelial histology, lack of muscularis propria invasion, and primary upper tract or metastatic disease.InterventionNeoadjuvant chemotherapy with aMVAC.Outcome measurements and statistical analysisPatients were stratified by age (<65, 65-74, and >75 yr old). Renal function was assessed at baseline and at time points after treatment. Clinicopathologic variables were compared between age groups to determine efficacy.Results and limitationsThere were no statistically significant differences in dose reductions, treatment interruptions, time to surgery, or adverse events when patients were stratified by age in univariate and multivariate analyses. Full safety data were not available due to the retrospective nature of the study. Baseline renal function was significantly worse among older patients, and the percent decline in creatinine clearance was greater with older age. We found comparable efficacy of aMVAC regardless of age.ConclusionsAccelerated MVAC was safe and demonstrated efficacy in MIBC irrespective of age in this single-center, retrospective study. Careful selection based on clinical variables, and not age, should identify patients able to receive neoadjuvant chemotherapy.Patient summaryWe examined the feasibility of the standard cisplatin-based chemotherapy regimen given prior to surgery in patients with muscle-invasive bladder cancer. Elderly patients experienced a greater decline in kidney function with treatment but not more complications than younger patients and tolerated therapy with minimal dose changes, resulting in benefit regardless of age.

Dataset Information

The efficacy and safety comparison of first-line chemotherapeutic agents (high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide) for osteosarcoma: a network meta-analysis.

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The efficacy and safety comparison of first-line chemotherapeutic agents (high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide) for osteosarcoma: a network meta-analysis.

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