Musculoskeletal Toxicity Research Articles

Randomized Phase III Trial of Marimastat Versus Placebo in Patients With Metastatic Breast Cancer Who Have Responding or Stable Disease After First-Line Chemotherapy: Eastern Cooperative Oncology Group Trial E2196

To determine whether a matrix metalloproteinase inhibitor improves progression-free survival (PFS) in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy. One hundred seventy-nine eligible patients were randomly assigned to receive oral marimastat (10 mg bid; n = 114) or a placebo (n = 65) within 3 to 6 weeks of completing six to eight cycles of first-line doxorubicin- and/or taxane-containing chemotherapy for metastatic disease. Patients were evaluated every 3 months until disease progression. When comparing placebo with marimastat, there was no significant difference in PFS (median, 3.1 months v 4.7 months, respectively; hazard ratio, 1.26; 95% CI, 0.91 to 1.74; P = .16) or overall survival (median, 26.6 months v 24.7 months, respectively; hazard ratio, 1.03; 95% CI, 0.73 to 1.46; P = .86). Patients treated with marimastat were more likely to develop grade 2 or 3 musculoskeletal toxicity (MST), a known complication of the drug indicative of achieving a biologic effect, compared with patients administered placebo (63% v 22%, respectively; P < .0001). Patients with grade 2 or 3 MST had significantly inferior survival compared with patients who had grade 0 or 1 MST (median, 22.5 months v 28.2 months; P = .04). In addition, patients who had a marimastat plasma concentration of at least 10 ng/mL at month 1 and/or 3 were significantly more likely to have grade 2 to 3 MST (P < .0001). Marimastat does not prolong PFS when used after first-line chemotherapy for metastatic breast cancer. Patients with higher marimastat levels exhibited MST, and MST was associated with inferior survival.

Locoregional control in infants with neuroblastoma: role of radiation therapy and late toxicity

Purpose: To review patterns of failure in infants with neuroblastoma and determine late toxicity and efficacy of radiotherapy (RT) on locoregional control.Methods and Materials: From 1955 to 1998, 53 children (35 males and 18 females) <1 year old with neuroblastoma were seen at our institution. Twenty-one (40%) were ≤1 month of age (neonates). Seven congenital anomalies were seen in 4 children (atrial septal defect, pulmonary valve stenosis, and absent corpus callosum were seen in 1 patient each; the other child had atrial and ventricular septal defect, aortic arch hypoplasia, and mitral valve stenosis). Primary tumor was located in the adrenal gland in 26 (49%), abdomen/nonadrenal in 14 (26%), thorax in 9 (17%), neck in 2 (4%), and pelvis in 2 (4%). All infants were retrospectively staged according to the International Neuroblastoma Staging System (INSS); 8 had Stage 1, 7 Stage 2A, 6 Stage 2B, 15 Stage 3, 6 Stage 4, and 11 Stage 4S. All patients, except 11 with Stage 4S and 4 with Stage 4, had resection of the primary tumor. Sixteen infants had pathologic involvement of regional lymph nodes (LN+). Twenty patients received RT. Kilovoltage beams were used in 10, megavoltage photons in 9, and electrons in 1 child. Fifteen received RT to the primary site and regional nodes (postoperative 8, preoperative 7). Postoperative doses ranged from 15 to 25 Gy whereas preoperative doses ranged from 12 to 31 Gy using a median fraction size of 1.5 Gy. Chemotherapy was employed in 22 of 53 patients (42%) with the most common agents being cyclophosphamide in 22 and doxorubicin in 11. Median follow-up was 13.1 years (range, 2–41 years).Results: Tumor control: The 5-year overall and freedom from progression rates were 79 ± 9% and 81 ± 11%; the locoregional control rate was 88 ± 9%. INSS Stage was a prognostic factor for overall survival (p = 0.03) and freedom from progression (p = 0.035). Gender, age (≤1 month vs. >1 month), and primary site were not found to impact on survival or progression. None of the Stage 1, 2A, or 2B patients recurred. One of 15 Stage 3 and 5 of 6 Stage 4 children recurred (6 distant metastases, 4 local failure). Four of 6 (67%) LN+ patients treated with locoregional RT and 8 of 10 (80%) LN+ patients treated without RT were locally controlled. There was no isolated locoregional relapse. Two Stage 4S patients died of respiratory compromise secondary to hepatomegaly. RT toxicity: For the 20 infants who received RT, 13 are alive with long-term follow-up ranging from 9.3 to 41 years, median 23 years. The 10 and 15-year musculoskeletal toxicity rates were 38.5% and 47.3% for those receiving RT and 3.3% for no RT (p = 0.02, log-rank test). Five of 6 infants <6 months of age and 1 of 7 ≥6 months developed musculoskeletal toxicity. Musculoskeletal effects were seen in 6 RT patients and included bony hypoplasia in 6, scoliosis in 5, soft tissue hypoplasia in 3, slipped capital femoral epiphysis in 2, kyphosis in 1, and osteochondroma in 1. Three required orthopedic intervention, all receiving ≥20 Gy. One child developed bowel obstruction at 21 months and another developed a leiomyosarcoma in the treatment field 34 years after RT.Conclusions: Our study shows that most LN+ infants achieve locoregional control without RT. Infants <6 months receiving RT were the most susceptible to musculoskeletal abnormalities. Further studies are needed to determine if cardiovascular anomalies are more frequently seen in children with neuroblastoma.

A phase I dose escalation study of the matrix metalloproteinase inhibitor BAY 12-9566 administered orally in patients with advanced solid tumours

BackgroundThis phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced solid tumours, and to identify the maximum tolerated dose and dose for use in subsequent studies. Patients and methodsBAY 12-9566 was administered to 29 patients at doses ranging from 100 mg o.d. to 1600 mg (given either 400 mg q.i.d. or 800 mg b.i.d.). Blood samples for pharmacokinetic analyses were drawn on days 1–5, day 15 and days 29 and 30. Patients were continued on daily oral treatment of BAY 12-9566 until a dose limiting toxicity or tumour progression occurred. ResultsA maximum tolerated dose was not defined because plasma levels of BAY 12-9566 could not be sufficiently increased, even with escalating doses of drug. Pharmacokinetic analysis suggested that absorption was saturable at higher doses. The predominant toxicities related to drug were asymptomatic reversible effects on platelets and transaminases and mild anemia. There were no significant musculoskeletal toxicities. No objective responses were seen at the doses tested, but stable disease was observed in some patients based on tumour measurements. ConclusionsThe recommended dose of BAY 12-9566 for further studies is 800 mg b.i.d. as this dose provides maximal plasma levels that can be achieved with a convenient dosing schedule for a chronically administered oral agent

The use of HMG-CoA reductase inhibitors to prevent accelerated graft atherosclerosis in heart transplant patients.

Initial trials hint that HMG-CoA reductase inhibitors may have a role in preventing or retarding the progression of AGAS. Whether the potential of HMG-CoA reductase inhibitors to prevent AGAS is due to their lipid-lowering effect, immunomodulating properties, or a combination of both is also not completely known at present. Further study is needed to fully identify their mode of preventing AGAS and, more important, to determine their usefulness and role in preventing AGAS, especially since concurrent HMG-CoA reductase inhibitor use with cyclosporine is not innocuous. Potential for a pharmacokinetic drug interaction, which results in an elevation of HMG-CoA reductase inhibitor concentrations, exists when these two agents are used together, thus increasing the potential for the HMG-CoA reductase inhibitor to cause musculoskeletal complications. When such combination therapy is used, the likelihood of this interaction can be reduced by prescribing the HMG-CoA reductase inhibitor conservatively--using the smallest effective dose and increasing the daily dosage slowly. Although the risk of musculoskeletal toxicity exists at any HMG-CoA reductase inhibitor dosage, most patients should be able to tolerate daily dosages of up to 20 mg of lovastatin, 10 mg of simvastatin, and 40 mg of pravastatin. Patients also need to be made aware of and monitored for musculoskeletal symptoms suggestive of myositis and/or myalgias. In addition, the avoidance of elevated cyclosporine concentrations and when practical, monitoring of HMG-CoA reductase inhibitor concentrations are recommended.

Ciprofloxacin safety in a pediatric population.

We conducted a retrospective study primarily to estimate the risk of musculoskeletal toxicities associated with ciprofloxacin administration in a pediatric population. In addition risks of hepatic and renal disorders associated with ciprofloxacin therapy were calculated. Adverse events in this study were restricted to those that required physician referral or hospitalization and occurred within 45 days of receiving a prescription for ciprofloxacin. From 2 resource databases, > 1700 patients < or = 17 years who received at least 1 ciprofloxacin prescription were identified between January, 1988, and December, 1993. In this population there were no cases of newly diagnosed acute arthritis or serious liver or kidney disease that were likely ciprofloxacin-induced. One patient was diagnosed with hemolytic-uremic syndrome, which may have been exacerbated by ciprofloxacin therapy. Surveillance of ciprofloxacin usage in a pediatric population failed to demonstrate serious or unusually high rates of any adverse events, including joint toxicity.

13-cis-retinoic acid in the treatment of elderly patients with acute myeloid leukemia. A phase II pilot study of the eastern cooperative oncology group

The management of acute myeloid leukemia in the elderly (65 years and older) is unsatisfactory because of poor patient tolerance of standard myeloablative chemotherapy. The authors conducted a Phase II study to evaluate the effectiveness and toxicity of 13-cis-retinoic acid (CRA) in the therapy of elderly patients with acute myeloid leukemia (AML). Patients presenting with leukocyte counts less than 20,000/microliters were treated with CRA alone. Those with leukocyte counts of 20,000/microliters or greater were pretreated with hydroxyurea, followed by CRA. Twelve of 18 patients received at least 4 weeks of CRA and were thus considered evaluable for toxicity and response. No objective responses were observed. Cis-retinoic acid administration was well tolerated; only modest dermatologic, musculoskeletal, and gastrointestinal toxicity was observed. Alternative therapeutic strategies should be investigated in this subpopulation of AML patients.

Skeletal toxicity with isotretinoin therapy: a clinico-radiological evaluation.

Skeletal toxicity is known to occur with high doses of isotretinoin (greater than 2 mg/kg/day). We have attempted to evaluate the clinical significance and document the extent of musculoskeletal toxicity associated with a relatively low dose of isotretinoin (0.5 mg/kg/day) used in the treatment of severe acne. Radiographs of 120 patients were examined. Twelve per cent showed minor changes (four patients had spinal hyperostoses and 10 had calcaneal hyperostoses). None of the musculoskeletal changes we observed was clinically significant. Comparison with matched control X-rays showed 8% of the controls to have similar non-significant changes. Follow-up of 11 of the patients with abnormal X-rays showed minor deterioration in one patient, no change in four and improvement in six. Thus, doses of 0.5 mg/kg/day isotretinoin in such patients did not produce any significant long-term musculoskeletal changes. With increasing use of this beneficial drug in acne, radiologists and dermatologists should be aware of its skeletal toxicity.

A clinical study of the effects of etretinate on bone in children and adolescents

Recent reports have described the development of skeletal abnormalities in patients treated with etretinate (Tigason®). We have therefore examined 19 children and adolescents who have been continuously treated with etretinate for several years (median duration of treatment 5 years). Their overall mean daily dose ranged from 0·4 to 1 mg/kg (median 0·8 mg/kg). All subjects received musculoskeletal assessment and a 99mtechnetium methylene diphosphonate (99mTc MDP) whole body bone scan, which results in a lower total radiation dose than a skeletal survey, and is more sensitive. Bone scans identify sites of abnormal turnover of bone earlier than plain radiographs, and are valuable in the early assessment of abnormalities of the growth plate, provided high resolution collimation is used. These studies revealed no evidence of significant bony abnormality in any patient. We therefore believe that long‐term etretinate therapy can probably be given with a low risk of musculoskeletal toxicity if certain precautions are taken, particularly use of low doses, early investigation of musculoskeletal symptoms and regular 99mTc MDP bone scans.

Surveillance for skeletal toxicity of children treated with etretinate.

Following recent reports of the development of skeletal abnormalities in patients treated with etretinate (Tigason), we have examined 19 children and adolescents on long-term treatment with etretinate, using 99mtechnetium methylene diphosphonate (99mTcMDP) whole body bone scans and musculoskeletal assessment. No significant bony abnormalities were detected. We believe that the available evidence does not warrant alarm, and that long-term etretinate therapy can probably be given with a low risk of musculoskeletal toxicity if certain precautions are taken, in particular the use of low maintenance dose levels, early investigation of symptoms of musculoskeletal pain or stiffness, and regular 99mTcMDP bone scans.