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Biomedical subjects

David R Macdonald

Publications and source records attributed to David R Macdonald.

7 recordsLinked to original sources
PubMed2006

High-dose chemotherapy with stem cell rescue as initial therapy for anaplastic oligodendroglioma: long-term follow-up.

We previously reported a phase 2 trial of 69 patients with newly diagnosed anaplastic or aggressive oligodendroglioma who were treated with intensive procarbazine, CCNU (lomustine), and vincristine (PCV) followed by high-dose thiotepa with autologous stem cell rescue. This report summarizes the long-term follow-up of the cohort of 39 patients who received high-dose thiotepa with autologous stem cell support. Thirty-nine patients with a median age of 43 (range, 18-67) and a median KPS of 100 (range, 70-100) were treated. Surviving patients now have a median follow-up of 80.5 months (range, 44-142). The median progression-free survival is 78 months, and median overall survival has not been reached. Eighteen patients (46%) have relapsed. Neither histology nor prior low-grade oligodendroglioma correlated with risk of relapse. Persistent nonenhancing tumor at transplant was identified in our initial report as a significant risk factor for relapse; however, long-term follow-up has not confirmed this finding. Long-term neurotoxicity has developed only in those patients whose disease relapsed and required additional therapy; no patient in continuous remission has developed a delayed neurologic injury. This treatment strategy affords long-term disease control to a subset of patients with newly diagnosed anaplastic oligodendroglioma without evidence of delayed neurotoxicity or myelodysplasia.

Adolescent↗
PubMed2005

Benefit of temozolomide compared to procarbazine in treatment of glioblastoma multiforme at first relapse: effect on neurological functioning, performance status, and health related quality of life.

Since high-grade malignant gliomas can seldom be treated curatively, the main aim of first line therapy is to improve progression free survival (PFS), to reduce morbidity, and to preserve, if not restore neurological functions and the capacity to perform daily activities. Focusing on a single clinical efficacy parameter in clinical trials may provide a potentially biased result, as for patients the overall result of treatment entails a more complex picture of weighing and balancing gains and losses on different outcome measures. In this paper we address different clinical outcomes measures separately and we illustrate the value of multiple outcome measures using the results of a recent clinical trial comparing temozolomide with procarbazine in the treatment of Glioblastoma Multiforme. Compared with procarbazine, temozolomide not only prolonged PFS, but also maintained neurological functioning and performance status for a longer period of time, and also improved health-related quality of life (HRQL). All these statistically significant outcomes demonstrate a remarkable consistency. In addition, temozolomide showed a trend of extending overall survival over procarbazine.

Antineoplastic Agents↗
PubMed2003

High-dose chemotherapy with stem cell rescue as initial therapy for anaplastic oligodendroglioma.

PURPOSE: Anaplastic oligodendroglioma is a chemosensitive glial neoplasm. To improve disease control and postpone cranial radiotherapy, we designed a phase II study of intensive procarbazine, lomunstine and vincristine followed by high-dose thiotepa with autologous stem cell rescue for patients with newly diagnosed anaplastic or aggressive oligodendroglioma. PATIENTS AND METHODS: Sixty-nine patients with a median age of 42 (range: 18-67) and a median Karnofsky Performance Score of 90 (range: 70-100) were enrolled. Sixteen patients had a prior diagnosis of low-grade oligodendroglioma and 16 had mixed oligoastrocytoma pathology. Only patients with demonstrably chemosensitive enhancing tumors or those free of enhancing tumor after surgery and induction therapy were eligible to receive high-dose thiotepa. RESULTS: Thirty-nine patients (57%) completed the transplant regimen; their estimated median progression-free survival is 69 months and median overall survival has not been reached. Twelve transplanted patients (31%) relapsed. Neither histology nor prior low-grade oligodendroglioma correlated with relapse; however, persistent non-enhancing tumor at transplant conferred an increased risk of relapse (p = 0.028). The transplant regimen was well-tolerated; median hospital stay was 20 days (range: 7-43) with a median time to ANC and platelet engraftment of 10 days. Thirty patients (43%) did not receive high-dose thiotepa because of stable or progressive disease (n = 21), excessive toxicity (n = 4), refusal of further therapy (n = 2), failure to obtain insurance coverage (n = 2), or other (n = 1). No treatment-related or long-term neurotoxicity was seen in the transplanted patients. CONCLUSIONS: High-dose chemotherapy with stem cell rescue as initial treatment for anaplastic oligodendroglioma is feasible and associated with prolonged tumor control in some patients.

Adolescent↗
PubMed2003

New frontiers in the treatment of malignant glioma.

Despite many technologic advances in neuroimaging, neurosurgery, and radiation therapy, there has been little improvement in survival for patients with malignant glioma. Given the failure of traditional treatment approaches to significantly improve survival in patients with malignant gliomas, research in this field has focused on gaining a better understanding of the molecular pathogenesis of gliomas with the goal of identifying novel drug targets and therapeutic strategies. The influence of molecular genetics on response and survival has been best shown in oligodendrogliomas. The hallmarks of low-grade and anaplastic oligodendrogliomas are their exquisite sensitivity to chemotherapy and favorable prognosis, which are correlated with loss of heterozygosity of chromosomes 1p and 19q. Together, loss of heterozygosity of 1p and 19q appears to confer responsiveness to chemotherapy and to correlate with improved survival. In contrast, deletion of the CDKN2A gene is correlated with poor response to chemotherapy and poor survival, and loss of heterozygosity of chromosome 10q is associated with shorter progression-free and overall survival compared with intact 10q. A variety of other molecular genetic abnormalities have been recognized in gliomas, and these genetic changes are not only important prognostic factors, but also offer new therapeutic targets. With the increased use of improved surgical and radiotherapy techniques and targeted biologic therapy over the next 20 years, many patients with malignant gliomas may be cured or their disease may be controlled for the long term. Molecular profiling of patients using gene chip technology will likely become commonplace, and many patients will receive a tailored treatment regimen based on the unique genetic profile of their tumor.

Antineoplastic Agents↗
PubMed2002

Ki-67: a prognostic factor for low-grade glioma?

PURPOSE: Immunohistochemical techniques were used to detect the expression of Ki-67, a nuclear proliferation marker, in 180 low-grade glioma tumor specimens to determine whether Ki-67 is a prognostic predictor of survival or tumor recurrence. MATERIALS AND METHODS: A clinical database of 180 low-grade glioma patients (35 children aged </=18 years and 145 adults) was compiled. Eighty patients had received postoperative radiotherapy (RT) and 100 patients had had RT deferred until the time of tumor progression/recurrence. Ki-67 indexes were evaluated retrospectively on tumor specimens from these patients using a semiautomated computer analysis technique. Ten observations were averaged per patient. The maximal Ki-67 value was recorded. RESULTS: The correlation between the Ki-67 index and survival was much higher for the averaged Ki-67 value than for the maximal value. Of the tumor specimens, 29% had a negative Ki-67 index (i.e., zero Ki-67 positive cells) and 7.7% had an average Ki-67 index of >/=5%. An average Ki-67 value of >/=5% was prognostically significant for reduced cause-specific survival (CSS, p = 0.05) and a Ki-67 level >/=10% was strongly significant of a poor survival outcome (p = 0.009). Ki-67 was not prognostically significant for progression-free survival. Other prognostically significant factors for CSS included age (p = 0.05), Karnofsky performance status (p = 0.0001), radiation dose (p = 0.02), extent of surgical resection (biopsy vs. others, p = 0.004), and timing of radiation (p = 0.0005). Ki-67 did not remain an independent statistically significant factor for CSS on multivariate analysis. Age and Ki-67 positivity (both maximal and average values) directly correlated (i.e., advancing age was associated with a higher Ki-67 index). When the patient group was further subdivided by age and timing of RT (postoperative vs. deferred), the prognostic significance of Ki-67 for CSS was lost. Within the deferred RT subgroup, a maximal Ki-67 >2% was associated with a worsened CSS. Within the pediatric population, Ki-67-negative patients had a 5-year CSS and progression-free survival of 100%. The 5-year CSS and progression-free survival declined significantly to 84% and 67% for patients with tumors demonstrating any degree of Ki-67 positivity (p = 0.005 and p = 0.006, respectively). CONCLUSION: Ki-67 is a useful predictor of CSS in low-grade gliomas; however, it is not independent of other prognostic factors, particularly age. Although Ki-67 was not helpful in predicting which adult patients were likely to benefit from postoperative RT, the results of the present study indicate a possible utility in the selection of pediatric patients for RT and in the selection of poorer prognosis patients for clinical trials.

Adolescent↗
PubMed2002

Stabilization of disease progression by hydroxyurea in patients with recurrent or unresectable meningioma.

OBJECT: The management of certain meningiomas of the skull base and those involving the dural venous sinuses remains a challenge. In recent reports it has been suggested that hydroxyurea chemotherapy can cause regression of unresectable and recurrent meningiomas. The authors report their experience in using hydroxyurea for the treatment of patients with recurrent or unresectable meningiomas. METHODS: Hydroxyurea was administered at a dosage of approximately 20 mg/kg/day to 11 women and nine men (median age 59 years, range 31-75 years) with recurrent or unresectable intracranial meningiomas (12 basal, two parasagittal, and six multiple). In 16 patients the meningiomas were benign, in three they had atypical features, and in one the meningioma was malignant. All patients had measurable residual disease. Four patients with benign meningiomas had previously received radiotherapy (two were treated with conventional fractionated radiotherapy and two with stereotactic radiosurgery), three with atypical meningiomas received conventional fractionated radiotherapy, and the one with a malignant meningioma received conventional radiotherapy with additional stereotactic radiosurgery. Tumor enlargement was documented in all patients on neuroimages obtained before initiation of hydroxyurea therapy. All patients were evaluable for response to therapy. In 12 patients with benign meningiomas, the disease had stabilized on neuroimages obtained posttreatment (median duration of treatment 122 weeks, range 8-151 weeks), and two of these showed clinical improvement. One patient with a benign meningioma experienced a minor partial response that was noted after 39 weeks of treatment and was confirmed on neuroimaging and clinical evaluations. In three others with benign meningiomas, progression was confirmed on neuroimages obtained after 41, 55, and 66 weeks, respectively: the 1-year freedom from progression rate was 0.93 (standard error 0.07) in patients with benign meningiomas. In three patients with atypical meningiomas, the tumors had progressed on neuroimages obtained after 12, 19, and 45 weeks, respectively. In the patient with a malignant meningioma, progression was confirmed on neuroimages obtained at 24 weeks. Hydroxyurea has been reasonably well tolerated, although one patient discontinued therapy because of moderate myelosuppression. CONCLUSIONS: Although tumor regression appears uncommon, these results indicate that hydroxyurea may arrest progression of unresectable or recurrent benign meningiomas.

Adult↗