A population pharmacokinetic/pharmacodynamic model of methotrexate and mucositis scores in osteosarcoma.

Methotrexate, when used in high doses (12 g/m²) in the treatment of osteosarcoma, shows wide between-subject variability (BSV) in its pharmacokinetics. High-dose methotrexate is associated with severe toxicity; therefore, therapeutic drug monitoring (TDM) is carried out to guide rescue therapy and monitor for nephrotoxicity. Mucositis is a commonly encountered dose-limiting toxicity that often leads to delays in subsequent courses of chemotherapy. This, in turn, results in a reduction in the dosing intensity, which is essential in the treatment of osteosarcoma. The aims of this study were to develop a population pharmacokinetic (PK) model from TDM using physiologically relevant covariates and to investigate the correlation between mucositis scores and methotrexate pharmacokinetics. In total, 46 osteosarcoma patients (30 men and 16 women; age, 4-51 years) were recruited, and blood samples were collected for routine TDM once every 24 hours. Mucositis scores, graded according to the National Cancer Institute Common Toxicity Criteria, were recorded for 28 of the patients (18 men and 10 women; age, 8-51 years) predose and postdose. A population PK model was developed in NONMEM VI. A 2-compartment PK model was chosen, and clearance (CL) was divided into filtration and secretion/metabolism components. All parameters were scaled with body weight, and, in addition, total CL was scaled with age- and sex-adjusted serum creatinine. Between-subject variability was modeled for all parameters, and between-occasion variability was included in CL. For a typical 70 kg man of 18 years or older, the parameter estimates for the final model were CL(filt) = 2.69 L/h/70 kg, CL(sec) = 10.9 L/h/70 kg, V1 = 74.3 L/70 kg, Q = 0.110 L/h/70 kg, and V2 = 4.10 L/70 kg. Sequential pharmacodynamic modeling consisted of mucositis scores as 5-point ordered categorical data. A significant linear relationship between individual area under the curve (AUC) and mucositis score probability was found, and the probability of having mucositis score ≥ 1 increased with increasing AUC and was almost 50% at the average cumulative AUC after 2 consecutive methotrexate doses.

The role of interferons in the treatment of osteosarcoma.

Interferons, a group of cytokines with antiangiogenic, direct antitumour and immunostimulating properties, have shown significant activity against osteosarcoma in vitro and in xenograft models. They have also been used in osteosarcoma clinical trials as a single adjuvant to surgery, with an apparent increase in relapse-free survival. In the ongoing EURAMOS 1 clinical trial, interferon alpha-2b is evaluated as an adjuvant treatment in osteosarcoma. This article reviews the rationale for the use of interferon in cancer with special reference to the treatment of osteosarcoma, including all published data of clinical efficacy in this disease.

Clinical trials in osteosarcoma treatment: patients' perspective through art.

Patients with osteosarcoma were encouraged to create artwork about their experiences of taking part in the EURAMOS 1 clinical trial. Art sessions allowed patients to express their feelings and talk openly about their condition and treatment. Each patient created artwork which reveals their experience through chemotherapy and surgery as well as their hopes for the future. Patients supported a positive focussed art activity which can help improve their quality of life during cancer treatment.

Management of osteosarcoma.

Improving cure rates for osteosarcoma continues to be a major challenge. The clinical management of individual patients is exacting and requires a skilled, experienced team including a surgeon, pathologist, oncologist, and radiologist, with support from specialist nurses and rehabilitation teams. Outcomes from treatment have improved little in 20 years and remain disappointing. Chemotherapy for osteosarcoma is among the most grueling of any given for solid tumors, and treatment of the primary tumor is associated with permanent disability of some degree in a significant proportion of patients. New systemic treatments remain beyond the horizon. In recognition of these difficulties, an international cooperation has begun with the opening of a randomized trial, European and American Osteosarcoma (EURAMOS) 1, in Europe and the United States. This study heralds a new era of clinical investigation into osteosarcoma, with the promise of valuable biologic insights and rapid evaluation of investigational strategies. Osteosarcoma should always be treated under the guidance of a specialist team, and we recommend that whenever possible, patients be offered entry into EURAMOS 1 or other well-designed clinical trials.