Biomedical subjects

Najat C Daw

Publications and source records attributed to Najat C Daw.

At least 19 recordsLinked to original sources

PubMed2007

Analysis of biologic surrogate markers from a Children's Oncology Group Phase I trial of gefitinib in pediatric patients with solid tumors.

This trial evaluated the effect of gefitinib on the plasma circulating levels of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP)-2 and -9 of patients treated on a pediatric Phase I trial. Complete plasma correlative studies were obtained from 16 of the 25 enrolled patients. There was a trend for lower MMP-2 baseline levels in patients with partial response or stable disease. The Ewing sarcoma from the only patient with partial response lacked egfr mutations. Gefitinib did not induce any significant variation in the levels of the assessed parameters, and none of these determinations showed significant predictive or prognostic value.

Adolescent↗

PubMed2006

Cefixime allows greater dose escalation of oral irinotecan: a phase I study in pediatric patients with refractory solid tumors.

PURPOSE: Irinotecan is active against a variety of malignancies; however, severe diarrhea limits its usefulness. In our phase I study, the intravenous formulation of irinotecan was administered orally daily for 5 days for 2 consecutive weeks (repeated every 21 days) to children with refractory solid tumors. Our objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of oral irinotecan and to evaluate whether coadministration of cefixime (8 mg/kg/d beginning 5 days before irinotecan and continuing throughout the course) ameliorates irinotecan-induced diarrhea. PATIENTS AND METHODS: In separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m2/d without cefixime and then from 45 to 60 and 75 mg/m2/d with cefixime. RESULTS: Without cefixime, diarrhea was dose limiting at irinotecan 45 mg/m2/d. Myelotoxicity was not significant at any dose. The MTD was 40 mg/m2/d without cefixime but 60 mg/m2/d with cefixime. Systemic exposure to SN-38 at the MTD was significantly higher with cefixime than without cefixime (mean SN-38 area under the curve: 19.5 ng x h/mL; standard deviation [SD], 6.8 ng x h/mL v 10.4 ng x h/mL; SD, 4.3 ng x h/mL, respectively; P = .030). CONCLUSION: Cefixime administered with oral irinotecan is well tolerated in children and allows greater dose escalation of irinotecan. Because diarrhea is a major adverse effect of both intravenous and oral irinotecan, further evaluation of the use of cefixime to ameliorate this adverse effect is warranted.

Administration, Oral↗

PubMed2006

Metastatic osteosarcoma.

BACKGROUND: The outcome of patients with metastatic osteosarcoma treated in two consecutive trials from 1986 to 1997 was analyzed to evaluate the efficacy of carboplatin-based multiagent chemotherapy and to identify prognostic factors. The initial study (OS-86) used ifosfamide, cisplatin, doxorubicin, and high-dose methotrexate, and the subsequent study (OS-91) used the same agents at similar doses, but carboplatin was substituted for cisplatin. METHODS: Twelve patients (median age, 15.1 yrs) were treated in OS-86 for osteosarcoma metastatic to the lung only (11 patients) or bone only (1 patient), and 17 patients (median age, 15.1 yrs) were treated in OS-91 for osteosarcoma metastatic to the lung only (12 patients), bone only (2 patients), lung and bone (2 patients), or other site (1 patient). RESULTS: Patients with metastatic disease enrolled in OS-86 and those with metastatic disease enrolled in OS-91 did not differ in terms of demographic features, histologic subtype, site of primary tumor, or site of metastases. There was a difference in survival according to treatment protocol (P = 0.054). All survivors (four of whom were enrolled in OS-86 and one of whom was enrolled in OS-91) had lung metastases only. Five-year survival estimates for patients with lung metastases only were 45.5 +/- 13.7% (OS-86) and 8.3 +/- 5.6% (OS-91) (P = 0.084). Unilateral lung metastases (P = 0.006), no more than three lung nodules (P = 0.014), and surgical remission (P = 0.001) were associated with improved survival probability. CONCLUSIONS: The poor outcome of patients with metastatic osteosarcoma treated in OS-91 justifies the use of cisplatin with its associated toxicity in patients with high-risk disease.

Adolescent↗

PubMed2006

Pediatric surface osteosarcoma: clinical, pathologic, and radiologic features.

BACKGROUND: Osteosarcoma (OS) arising from the surface of bone is far less common than its intramedullary counterpart. Although surface OSs share some radiographic and clinical features, they can be divided into three distinct histologic subtypes. PROCEDURE: We reviewed the clinical, radiographic, and pathologic features of 14 cases of pediatric surface OS treated at St. Jude Children's Research Hospital between 1970 and 2003. RESULTS: Seven patients had parosteal, five had periosteal, and two had high-grade surface OS. The median age at diagnosis was 16.2 years (range, 13.6-18.5 years). Nine patients were male; 11 were Caucasian. None had metastatic disease at diagnosis. Primary tumor sites included distal femur (n = 6), mid to proximal femur (n = 4), and mid to proximal tibia (n = 4). All 14 patients were treated with surgery, and 7 (1 with parosteal, 4 with periosteal, 2 with high-grade tumors) received chemotherapy. One patient experienced pulmonary metastasis of periosteal OS 16 months and 43 months after diagnosis; long-term disease-free survival followed resection of the metastatic tumors. Twelve patients remained alive and disease-free a median of 10 years (range, 1.5-25.4 years) after diagnosis. One patient died of high-grade surface OS 1.8 years after diagnosis, and one patient with periosteal OS died of gastric cancer 18.2 years after diagnosis of OS. CONCLUSIONS: The histologic grade predicts the clinical behavior of pediatric surface OS. Complete resection is the treatment of choice regardless of tumor subtype. Whereas chemotherapy is not indicated for parosteal OS, its role in periosteal OS remains controversial.

Adolescent↗

PubMed2006

Case reports: polymethylmethacrylate lung embolus after limb-salvage surgery of the distal femur.

Limb-salvage surgery for malignant tumors frequently involves reconstruction with an endoprosthesis anchored to bone by using third-generation cementing techniques. A 10-year-old boy with osteosarcoma had a pulmonary embolus caused by polymethylmethacrylate after having limb-salvage surgery that used high-pressure cementing techniques. He experienced transient postoperative chest pain, and a new wedge-shaped radiodense pulmonary lesion appeared on a computed tomography scan of the chest. A thoracotomy for resection of suspected metastatic osteosarcoma revealed a pulmonary infarct caused by cement embolization. Awareness of this potential complication should prompt investigation of possible pulmonary embolism and may prevent unnecessary thoracotomy.

Biopsy↗

PubMed2006

Distinguishing benign from malignant pulmonary nodules with helical chest CT in children with malignant solid tumors.

PURPOSE: To retrospectively assess whether computed tomographic (CT) findings can indicate the benign or malignant nature of pulmonary nodules in pediatric patients with malignant solid primary tumors. MATERIALS AND METHODS: With institutional review board approval, waived parental and patient consent, and HIPAA compliance, the authors determined the incidence of malignancy among 81 pulmonary nodules that were sampled at biopsy within 3 weeks after chest CT (January 1999 to September 2003) in 41 young patients with malignant solid tumors. Three radiologists independently and retrospectively reviewed these scans and the available previously obtained scans, classifying nodules as benign, malignant, or indeterminate on the basis of their number, unilateral versus bilateral distribution, size, margins (indistinct vs distinct), calcification, growth, and associated adenopathy. These classifications were compared with nodule histologic type, and interreviewer agreement was assessed. RESULTS: The median patient age was 14.8 years (mean, 13.7 years; range, 5-21 years). Twenty-four of the 41 patients (58%) had at least one biopsy-proved malignant nodule. Four (10%) patients had both benign and malignant nodules; 17 (42%) had only benign nodules. Reviewer 1 classified 65% (39 of 60) of nodules correctly; reviewer 2, 57% (37 of 65); and reviewer 3, 67% (43 of 64). Interreviewer agreement was slight to moderate (kappa </= 0.43, P </= .03). In contrast to findings in adults, sharply defined nodules in younger individuals were more likely to be malignant (P = .03) and nodule size was not associated with malignancy (P >/= .32). CONCLUSION: The frequency of benign nodules and the inconsistency of predictions based on CT features suggest the need for better predictors of pulmonary nodules being malignant or benign, so as to reduce unnecessary thoracotomy in pediatric patients with solid malignancy. .

Adolescent↗

PubMed2006

Osteosarcoma among children aged 5 years or younger: the St. Jude Children's Research Hospital experience.

Osteosarcoma primarily affects adolescents. The authors reviewed the records of eight patients aged 5 years or younger (of 470 patients with osteosarcoma) treated at their institution. Tumors (seven of high grade and one of low grade) arose mostly in the appendicular skeleton; one patient had metastases. One patient with low-grade osteosarcoma survived after surgery alone. Two with active disease died of chemotherapy toxicity. The remaining five (three received chemotherapy) underwent surgery and are long-term survivors. Two who underwent hemipelvectomy or hip disarticulation would likely have undergone limb-sparing surgery today. These findings and a review of the similar cases in the literature suggest that osteosarcoma's clinical characteristics are similar among young children and older children.

Age Factors↗

PubMed2005

Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors.

PURPOSE: We have shown in xenograft studies that the antitumor activities of topotecan and irinotecan are highly schedule- and dose-dependent, with a high frequency of response at low, protracted dose schedules. Preclinical and clinical data suggest that topotecan and irinotecan have different antitumor activities and mechanisms of resistance, and non-overlapping toxicities, providing a rationale for their combination. Combining both agents may increase the amount of camptothecin delivered to the tumor, without additive toxicity. METHODS: We conducted a phase I study in children with refractory solid tumors to determine the maximum tolerated dose (MTD) of irinotecan when administered with a targeted systemic exposure (TSE) of topotecan and to define the dose-limiting toxicity (DLT) of this combination. Irinotecan was administered IV over 60 min followed by topotecan over 30 min daily for 5 days for two consecutive weeks. We initially fixed the topotecan-TSE to 80+/-10 ng*h/ml and investigated the ability to escalate irinotecan (starting dose 16 mg/m2/d). Topotecan and irinotecan pharmacokinetics were determined. RESULTS: Eleven patients (median age 10 years) were enrolled. Owing to DLT, irinotecan was de-escalated to 12 (level -1; n = 3) and 9 (level -2; n = 3) mg/m2/day, and topotecan-TSE was reduced to 60+/-10 ng*h/ml (level -3; n = 2). DLTs were neutropenia (n = 8), typhlitis (n = 5), and skin rash (n = 1). MTD could not be reached. Median (range) irinotecan and topotecan lactone systemic clearances were 50.3 (16.6-76.2) l/h/m2 and 27.6 (14.7-55.9) l/h/m2, respectively. The pharmacokinetics profile of each agent was similar to that seen in previous single agent studies. One patient with neuroblastoma and one with rhabdomyosarcoma had a partial and a complete response, respectively. CONCLUSION: Despite promising antitumor activity, the combination of topotecan and irinotecan given on a protracted schedule does not warrant further development in children due to unacceptable toxicity.

Adolescent↗

PubMed2005

Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to > or = 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 microg/mL (range, 1.2 to 3.6 microg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.

Administration, Oral↗

PubMed2005

Infections in children and young adults with bone malignancies undergoing limb-sparing surgery.

BACKGROUND: The epidemiology, risk factors, and efficacy of therapy for infections complicating limb-sparing surgery (LSS) are not understood completely. METHODS: The authors conducted a retrospective review of children and adolescents with bone malignancies who underwent LSS. RESULTS: One hundred three patients underwent 104 LSS procedures. Patients experienced a median of 4 infections (range, 0-13 infections), including focal bacterial infections in 67% of patients and bacteremia in 21% of patients. Infections at the LSS site occurred in 26% of patients, and 21% of patients developed orthopedic device infections (ODIs). Compared with patients without ODIs, patients who developed ODIs were more likely to be African American and to have wound infections, and they were less likely to have tumors of the femur than the tibia. In a multivariate analysis, only African-American race and local infection at the LSS site retained a significant association with ODIs. Among survivors, patients who developed ODIs were more likely to undergo amputation (odds ratio [OR], 24.0; 95% confidence interval [95%CI], 5.1-114.0; P < 0.001) and were less likely to have good functional outcomes (OR, 0.02; 95%CI, 0.002-0.15; P < 0.001) compared with patients who did not have an ODI. Overall, only 1 of 22 patients with an ODI was treated successfully without removal of the orthopedic device or amputation. CONCLUSIONS: Current treatment for bone malignancies is complicated by an unexpectedly high incidence of infection. ODI was the most common reason for amputation and poor functional outcomes. The identification of risk factors for ODI may allow modifications of therapy that reduce the incidence and severity of infection, but prevention of all ODIs will require novel strategies.

Adolescent↗

PubMed2005

Development and validation of limited sampling models for topotecan lactone pharmacokinetic studies in children.

PURPOSE: To develop and validate a pharmacokinetic limited sampling model (LSM) for intravenous and oral topotecan pharmacokinetic studies in children. METHODS: Topotecan lactone concentration-time data from five trials were used to develop and validate LSM for intravenous and oral topotecan. Based on full sampling from one intravenous study (30 patients; 195 studies), a LSM for intravenous topotecan was determined using a modification of the D-optimality algorithm. For oral topotecan we used full sampling data from one oral topotecan study (27 patients; 47 studies) to develop an LSM. Accuracy and bias of each LSM were determined relative to the full sampling method. Predictive performance of the LSM was validated using additional data and Monte-Carlo simulations based on these data. RESULTS: LSM for intravenous topotecan includes: 5 min, 1.5, and 2.5 h after the end of the 30 min infusion. The median accuracy (absolute predicted error) and bias (predicted error) are < or =8% and < or =6.1%, respectively. For oral topotecan, the optimal LSM includes: 15 min, 1.5, and 6 h. The median accuracy and bias are 6% and 4%, respectively. CONCLUSIONS: Our results indicate that the optimal sampling times for the intravenous LSM for topotecan in children consist of: predose, and 5 min, 1.5, and 2.5 h after the end of infusion. For oral topotecan the sample times are predose, 15 min, 1.5, and 6 h after dose administration. These LSM are invaluable to children receiving topotecan because it minimizes inconvenience and blood collection.

Administration, Oral↗

PubMed2005

Osteosarcoma of the pelvis in children and young adults: the St. Jude Children's Research Hospital experience.

BACKGROUND: Pelvic osteosarcomas are difficult to resect. The authors reviewed their institution's experience with patients who had such tumors to characterize the patients' clinical findings and to assess the impact of surgical resection on outcome. METHODS: A review was conducted of the records from patients with pelvic osteosarcoma who were treated at the authors' institution between January, 1970 and March, 2004. RESULTS: Among 442 patients with osteosarcoma, 19 patients (4%) had high-grade tumors arising in the pelvic bones, including the ilium in 15 patients, the pubis in 2 patients, and the sacrum in 2 patients. The median patient age at diagnosis was 16.8 years. Four tumors were secondary to radiation therapy. Five patients had metastases in the lung (n = 4 patients) or bone (n = 1 patient) at diagnosis. Ten tumors were chondroblastic. The median greatest tumor dimension for the 13 tumors with known size was 10 cm. Ten patients had unresectable pelvic tumors, and 9 patients underwent hemipelvectomy (2 internal and 7 external); complete resection with negative margins was achieved in 5 patients. Four patients survived, including one patient who survived with disease. Of the three patients who survived disease-free, one patient underwent complete resection, one patient underwent incomplete resection (nonviable tumor at the soft tissue margin) with a good response to chemotherapy, and one patient with a sacral tumor underwent radiotherapy only for local control. Of the 9 patients who underwent resection, 7 experienced disease recurrence (n = 5 patients) or progression (n = 2 patients) at distant sites and died. All patients with metastatic disease at diagnosis died. CONCLUSIONS: Pelvic osteosarcomas often were large and unresectable. A high propensity for metastasis contributed to the poor outcome of patients with pelvic osteosarcoma. New therapeutic approaches are needed.

Adolescent↗

PubMed2005

PET/CT in the evaluation of childhood sarcomas.

OBJECTIVE: Our objective was to review our preliminary experience with PET/CT in evaluating childhood sarcomas including rhabdomyosarcoma (n = 28), the Ewing's sarcoma family of tumors (n = 14), nonrhabdomyosarcoma soft-tissue sarcoma (n = 9), osteosarcoma (n = 8), chondrosarcoma (n = 1), and embryonal sarcoma (n = 1). CONCLUSION: We found PET/CT useful in depicting an unknown primary rhabdomyosarcoma and detecting unsuspected and unusual metastatic sites of childhood sarcomas. It was useful in monitoring response to chemotherapy, radiation therapy, and radiofrequency ablation and aided the postoperative evaluation of tumor resection sites.

Child↗

PubMed2005

Cephalosporin-resistant pneumococci and sickle cell disease.

Sickle cell anemia patients have 600 times the risk for invasive pneumococcal disease than their healthy peers. High-level cephalosporin resistance was described in the 1990s in healthy children from Tennessee, but its prevalence in sickle cell disease patients is unknown. Pneumococcal isolates from sickle cell disease patients from Tennessee were subjected to multilocus sequence typing to characterize antimicrobial drug-resistant strains. Twenty-one percent of strains were resistant to cefotaxime and penicillin. Of the 14 cephalosporin-resistant strains, 9 were sequence types previously described as highly cephalosporin resistant, while resistance was found for the first time in 3 clones: Maryland6B, ST660, and a novel clone, ST1753. High-level cephalosporin resistance exists in more settings than initially recognized, and its high prevalence in sickle cell disease patients may decrease the efficacy of third-generation cephalosporins in invasive pneumococcal disease.

Anemia, Sickle Cell↗

PubMed2004

Telomerase expression predicts unfavorable outcome in osteosarcoma.

PURPOSE: Osteosarcoma is distinct from most cancers in that the majority of osteosarcomas lack telomerase expression and use the alternative lengthening of telomeres (ALT) mechanism to maintain telomeres. Laboratory studies suggest that compared with ALT, telomerase expression is associated with increased tumor aggressiveness. We evaluated the clinical significance of telomerase expression in human osteosarcoma. PATIENTS AND METHODS: Fifty-six osteosarcomas from 51 patients treated at St Jude Children's Research Hospital between 1982 and 2003 were evaluated for telomerase enzyme activity, mRNA expression of the catalytic component of telomerase (TERT), and presence of the ALT pathway. RESULTS: Outcome analysis was based on TERT mRNA expression in the primary tumor samples from 44 patients. Fourteen primary tumors expressed TERT mRNA (32%; eight TERT only, six TERT and ALT) and 30 did not express TERT mRNA (68%; 29 ALT, one no ALT). Progression-free survival (PFS) was inferior in the TERT-positive group compared with the TERT-negative group (3-year estimates, 21.4% +/- 9.5% v 63.7% +/- 11.1%; P =.014). Likewise, overall survival was inferior in the TERT-positive group compared with the TERT-negative group (3-year estimates, 42.9% +/- 12.2% v 70.0% +/- 9.9%; P =.031). Among 31 patients with nonmetastatic disease at diagnosis, PFS was lower in the TERT-positive group compared with the TERT-negative group (3-year estimates, 33.3% +/- 13.6% v 72.0% +/- 11.5%; P =.092). CONCLUSION: Telomerase expression in primary tumor samples is associated with decreased PFS and OS in patients with osteosarcoma. Additional studies are warranted to better define the clinical utility of this molecular marker.

Adolescent↗

PubMed2004

Pediatric gastrointestinal stromal tumors and leiomyosarcoma.

BACKGROUND: With the introduction of molecularly targeted therapy for gastrointestinal stromal tumors (GISTs), it became important to distinguish GISTs from leiomyosarcomas (LMSs). The authors sought to characterize the clinicopathologic features of these tumors in pediatric patients. METHODS: The authors reviewed the medical records of 11 patients for whom GIST or LMS was diagnosed between March 1962 and July 2002 at St. Jude Children's Research Hospital and reclassified the tumors according to current histologic and immunophenotypic criteria. The authors also reviewed the literature pertaining to pediatric GISTs and LMSs. RESULTS: Seven patients had GISTs, and four had LMS. The median age of the patients at diagnosis was 11.5 years. At diagnosis, metastases were present in one patient with GISTs and in another with LMS. Unlike the focal distribution of CD117 (KIT) in LMS, diffuse and strong immunostaining was observed in GISTs. Only GISTs expressed CD34. Six patients underwent complete resection (four with GISTs and two with LMS), four patients underwent incomplete resection (three with GISTs and one with LMS), and one patient (with LMS) underwent a biopsy only. Radiotherapy or chemotherapy was used to treat one patient with GISTs and three patients with LMS. One patient with a high-risk GIST (largest dimension of 32 cm and high mitotic count) was treated with adjuvant imatinib mesylate outside the preferred setting of a clinical trial, due to concerns regarding the high risk of tumor recurrence. Four patients with GISTs and two with LMS survived median disease-free a median of 10.4 years and 4.3 years after diagnosis, respectively. Tumors in all but one survivor were completely resected. CONCLUSIONS: KIT staining helped to distinguish GISTs from LMSs. Surgery was the treatment of choice for both entities, and tumor resectability was a key prognostic factor.

Adolescent↗

PubMed2004

Outcome after local recurrence of osteosarcoma: the St. Jude Children's Research Hospital experience (1970-2000).

BACKGROUND: Despite improvements in therapy for osteosarcoma, approximately 4-10% of patients experience a local recurrence and have a poor prognosis. METHODS: The authors analyzed prognostic factors for survival in 26 patients with a local recurrence of osteosarcoma who were treated between 1970 and 2000. RESULTS: The initial surgical procedure was amputation in 20 patients (76.9%) and limb salvage in 6 patients (23.1%). The median time from the diagnosis of osteosarcoma to local recurrence was 1.2 years (range, 1.2 months-6.1 years). Eleven patients (42.3%) developed an isolated local recurrence and 15 patients (57.7%) developed local and distant recurrence. The 5-year estimate of postrecurrence survival (PRS) (+/- 1 standard error) for the 26 patients was 19.2% +/- 7.7%. Recurrence > or = 2 years from the time of diagnosis was found to predict a better outcome (5-year PRS of 50.0% +/- 20.4%) compared with earlier recurrence (10.0% +/- 5.5%) (P = 0.037). Patients with negative margins after initial surgery were found to have improved survival (5-year PRS of 33.3% +/- 13.6%) compared with patients with positive margins (7.1% +/- 4.9%) (P = 0.015). Patients who underwent complete surgical resection at the time of recurrence were found to have a better PRS (5-year PRS of 41.7% +/- 14.2%) compared with patients who did not undergo surgery (0% +/- 0%) (P < 0.001). CONCLUSIONS: The prognosis for patients after local recurrence of osteosarcoma is poor. Complete surgical resection at the time of recurrence is essential for survival. Positive margins at the time of initial surgical resection and early recurrence appear to be poor prognostic factors.

Adolescent↗

PubMed2004

High-dose methotrexate pharmacokinetics and outcome of children and young adults with osteosarcoma.

BACKGROUND: High-dose methotrexate (HDMTX) is used frequently in combination regimens that include nephrotoxic chemotherapy. The authors evaluated the impact of factors such as age and prior nephrotoxic agents on MTX pharmacokinetics in children and young adults with osteosarcoma and examined whether MTX pharmacokinetic parameters were associated with outcome. METHODS: The authors evaluated MTX pharmacokinetics in 140 patients who were treated with 1083 courses of HDMTX on 3 consecutive studies of multiagent chemotherapy at a single institution. The influence of MTX pharmacokinetics on the outcome of 107 patients with localized disease was examined. RESULTS: Mean peak MTX concentrations > or = 1000 microM were achieved in 135 patients (96%). MTX clearance was decreased after cisplatin therapy (P = 0.01), after cisplatin in combination with ifosfamide therapy (P < 0.0001), and after MTX therapy (P = 0.003). In patients with localized osteosarcoma, a higher mean MTX area under the curve, a higher mean peak concentration of MTX, a longer mean time above a threshold concentration (500 microM), and a lower mean MTX clearance were associated with lower probability of event-free survival (EFS). Patients who had a mean peak MTX plasma concentration > 1500 microM were found to have a worse outcome (estimated 5-year EFS, 58.5% +/- 6.7%) compared with patients who had a mean peak concentration < or = 1500 microM (estimated 5-year EFS, 75.5% +/- 6.6%; P = 0.02). CONCLUSIONS: When HDMTX (12 g/m(2)) was used with multiagent therapy for patients with osteosarcoma, very high MTX exposures were associated with poorer outcome. The prospective evaluation of MTX pharmacokinetics and their relation to outcome in a large study is warranted to further substantiate the current findings and to elucidate the causative mechanism.

Adolescent↗