The efficacy of gemcitabine and docetaxel chemotherapy for the treatment of relapsed and refractory osteosarcoma: A systematic review and pre-clinical study

Abstract

Introduction: Osteosarcoma is the most common primary malignancy of the bone. There is a lack of effective treatments for patients who experience relapsed osteosarcoma. One treatment for relapsed patients is gemcitabine and docetaxel combination chemotherapy (GEMDOX). This systematic review aimed to establish the efficacy of this chemotherapy regimen, as well as identify the common severe toxicities that are associated with it. Resistant osteosarcoma cell lines developed from MG-63 and HOS-143B were used to represent relapsed osteosarcoma patients in a pre-clinical study.

Results: We identified 11 retrospective and Phase II studies that were suitable for inclusion in our review. 10.65% of patients had a response to gemcitabine and docetaxel combination therapy and the disease control rate was 35% (n = 197). 36%, 35.3% and 18.04% of patients experienced grade 3 or 4 neutropenia, thrombocytopenia and anaemia respectively (n = 133). Male patients (X² = 9.14, p < 0.05) and those below the age of 18 (X ² = 10.94, p < 0.05) responded better to GEMDOX treatment than females and patients older than 18 years. The resistant osteosarcoma cell lines remained sensitive to either single-agent gemcitabine, docetaxel, and the combination of both. Cisplatin-resistant models (MG-63/CISR8 & HOS-143B/CISR8) were the most responsive to GEMDOX treatment compared to doxorubicin, methotrexate, and triple-combination resistant models.

Conclusion: GEMDOX treatment has potential efficacy in relapsed osteosarcoma patients especially those with cisplatin resistance. To directly compare the efficacy of GEMDOX therapy against other therapies randomised phase III clinical trials with adequate patient follow up must be performed to improve treatment options for osteosarcoma.

Keywords: docetaxel; gemcitabine; relapsed osteosarcoma.

FIGURE 1

PRISMA flow diagram detailing the search and selection process employed during the systematic literature search and review.

FIGURE 2

Disease control and toxicity outcomes of GEMDOX treatment. (A) Percentage of the patients included in the review whose disease was controlled with GEMDOX treatment. Disease control is defined as patients who experience CR, PR or SD. (B) Incidence of Grade 3–4 toxicities during GEMDOX treatment. Data are presented as percentage + 95% CI (n = 197).

FIGURE 3

Disease Control to combination of GEMDOX regimen by (A) age, and (B) dose of gemcitabine. Percentage of participants on y‐axis and the response of the participants on x‐axis. R represents participants who responded to the treatment (complete response, partial response and stable disease) and PD represents not responded (progressive disease). Data are presented as percentage + 95% CI, ***p < 0.001, X ² Age n = 161; Dose n = 88.

FIGURE 4

(A) Percentage of patients who <18 or ≥18 who experienced grade 3 or 4 toxicities. (B) Percentage of patients who received 675 or 1000 mg/m² of gemcitabine who experienced grade 3 or 4 toxicities. Data are presented as percentage + 95% CI, p > 0.05, X ² Age n = 105 and Dose n = 101.

FIGURE 5

Cytotoxicity assays were performed to determine the fold change of the gemcitabine, docetaxel and the combination of both. Fold resistance of gemcitabine, docetaxel and GEMDOX combination treatment on (A) MG‐63 resistant sublines and (B) HOS‐143B resistant sublines comparing to their parental cell lines. Error bars represent SEM (n = 3). *p < 0.05, **p < 0.01, ***p < 0.001, Two sample t‐test.