Ch.J. Vecht

Phase II Study of First-Line Chemotherapy With Temozolomide in Recurrent Oligodendroglial Tumors: The European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971

PURPOSE Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy. PATIENTS AND METHODS In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed. RESULTS Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression. CONCLUSION TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted.

Prevention of Cisplatin Neurotoxicity with an ACTH(4–9) Analogue in Patients with Ovarian Cancer

Abstract In a randomized, double-blind, placebo-controlled study, we assessed the efficacy of an ACTH(4–9) analogue, Org 2766, in the prevention of cisplatin neuropathy in 55 women with ovarian cancer. The analogue was given subcutaneously in a dose of 0.25 mg (low dose) or 1 mg (high dose) per square meter of body-surface area before and after treatment with cisplatin and cyclophosphamide (75 and 750 mg per square meter every three weeks). The threshold of vibration perception was used as the principal measure of neurotoxicity. After four cycles of chemotherapy, the mean (±SEM) threshold value for vibration perception in the placebo group increased from 0.67±0.12 to 1.61±0.43 μm of skin displacement (P<0.0001). In the high-dose treatment group, there was no increase in the threshold value after four cycles (from 0.54±0.12 to 0.50±0.06 μm). After six cycles of chemotherapy, the threshold value was 5.87±1.97 μm in the placebo group (more than an eightfold increase from base line), as compared with 0.88±0.1...

Dose‐effect relationship of dexamethasone on Karnofsky performance in metastatic brain tumors A randomized study of doses of 4, 8, and 16 mg per day

The purpose of this study was to determine whether lower doses of dexamethasone for treatment of brain tumor edema are as effective as the conventional dose of 16 mg/d. We consecutively executed two double-blind randomized trials in patients with CT-proven brain metastasis and Karnofsky scores of 80 or less. In the first series, we compared 8 mg dexamethasone per day versus 16 mg/d; in the second series, 4 mg/d versus 16 mg/d. Standardized evaluation of quality of life and side effects took place at days 0, 7, 28, and 56. We randomized a total of 96 patients and evaluated eighty-nine. The Karnofsky score improved in the 8-mg group, which had improvement of 8.0 ± 10.1 (mean ± SD) points at day 7 versus 7.3 ± 14.2 points in the 16-mg group. In the second series, the 4-mg group had improvement of 6.7 ± 11.3 points at day 7 and 7.1 ± 18.2 points at day 28 versus 9.1 ± 12.4 and 5.6 ± 18.5 points in the 16-mg group. Toxic effects occurred more frequently in the 16-mg group (p < 0.03). We conclude that administration of 4 mg dexamethasone per day for treatment of brain tumor edema results in the same degree of improvement as does administration of 16 mg/d after 1 week of treatment in patients who have no signs of impending herniation. Toxic effects are dose-dependent and, during a 4-week period, occurred more frequently in patients using 16 mg/d. Following radiotherapy to the brain or other antitumor therapy, tapering of dexamethasone from 4 mg/d should preferably be temporized over about 4 weeks.

Supratentorial low grade astrocytoma: prognostic factors, dedifferentiation, and the issue of early versus late surgery

BACKGROUND A retrospective study of patients with low grade astrocytoma was carried out because the best management of such patients remains controversial. Prognostic factors were identified by multivariate analysis. Special attention was paid to the effect of extent and timing of surgery. METHODS Ninety patients with low grade astrocytoma were studied. Seventy two patients had resective surgery, 15 had a diagnostic biopsy only, and three patients had resective surgery after initial biopsy. RESULTS Significant prognostic factors for survival were age, preoperative neurological condition, epilepsy as the single sign, extent of surgery, and histology. The extent of surgery was highly significant on univariate analysis (p=0.002); however, after correction for age and preoperative symptoms this was considerably reduced (p=0.04). A subgroup of 30 patients with epilepsy as their single presenting symptom was identified. Thirteen of these patients were treated immediately after diagnosis, whereas the other 17 patients were initially followed up and treated only after clinical or radiological progression. Survival in both groups was identical (63% survival rate after five years) and much better than survival for the whole group (27% survival rate after five years). Malignant dedifferentiation was observed in 25 (70%) of 36 patients who were reoperated, after a median period of 37 months. This period was 41 months for the subgroup of patients with epilepsy only and 28 months for the remaining patients. CONCLUSIONS Due to the retrospective nature of the study only restricted conclusions can be drawn. Low grade glioma with epilepsy as the single symptom has a much better prognosis than if accompanied by other symptoms. This prognosis is not influenced by the timing of surgery. It seems, therefore, safe to defer surgery until clinical or radiological progression in low grade glioma with epilepsy only.

Initial bolus of conventional versus high‐dose dexamethasone in metastatic spinal cord compression

We randomly assigned dexamethasone in an initial bolus of 10 mg IV or 100 mg IV followed by 16 mg daily orally to 37 patients with metastatic spinal cord compression. The average pain score before the start of treatment was 5.2 (SD = 2.8) and decreased significantly (p < 0.001) to 3.8 at 3 hrs, 2.8 at 24 hrs, and 1.4 after 1 week. There were no differences between the conventional and high-dose group on pain, ambulation, or bladder function.

The diagnostic accuracy of magnetic resonance imaging and cerebrospinal fluid cytology in leptomeningeal metastasis

Abstract Diagnostic decision making in the case of patients suspected of having leptomeningeal metastasis (LM) can be very difficult. The results of cerebrospinal fluid (CSF) cytology can be repeatedly negative, and the predictive value of gadolinium-enhanced magnetic resonance imaging (MRI) is not well known. We report the results of CSF cytology and Gd MRI in 61 patients with known cancer, suspected of having LM. We combined our data with those from a similar study and calculated the sensitivity and specificity of CSF and Gd MRI, in the absence of a “gold standard diagnosis.” CSF cytology was positive for LM in 35 patients and MRI in 38. With CSF cytology sensitivity 75% and specificity 100%, with Gd MRI sensitivity was 76% but specificity only 77%. We conclude that Gd MRI provides strong support in the diagnosis of LM in patients with cancer who have negative results on CSF cytology.

Peripheral neurotoxicity induced by docetaxel

Article abstract-Docetaxel, a new semisynthetic taxoid used as an antineoplastic agent, induced a predominantly sensory neuropathy in 20 of 41 patients. We assessed neurotoxicity in all patients participating in four phase II trials conducted in our institution. The neuropathy was evaluated by a clinical sum-score for symptoms and signs and by measurement of the Vibration Perception Threshold (VPT). The severity of neuropathy was graded according to the National Cancer Institutes Common Toxicity Criteria. Neuropathic symptoms were mild in most patients. However, at cumulative doses above 600 mg/m2, 3 of 15 patients developed a moderate and 1 of 15 patients a severe neuropathy. There was a significant correlation between the cumulative dose of docetaxel and the post-treatment sum-score (p = 0.002). We found no correlation between post-treatment VPT and clinical sum-score or between post-treatment VPT and the cumulative dose of docetaxel. We conclude that docetaxel produces a mild and predominantly sensory neuropathy in a high proportion of treated patients. This neurotoxicity appeared to be dose dependent and may be severe and disabling at higher dose levels. Determination of the VPT is not a reliable method to monitor docetaxel-induced neuropathy. NEUROLOGY 1996;46: 104-108

Clinical characteristics of severe peripheral neuropathy induced by docetaxel (Taxotere)

BACKGROUND Docetaxel, a semi-synthetic taxane may cause a usually mild sensory neuropathy. We describe the clinical characteristics of five patients who developed a more severe neuropathy following treatment with docetaxel. PATIENTS AND METHODS All patients were treated in phase II studies with 100 mg/m2 docetaxel in three weekly cycles, without steroid administration. RESULTS The clinical picture in these patients was dominated by a sensory neuropathy, but in one case severe weakness was present. Another patient developed Lhermittes sign. Signs and symptoms are usually reversible after discontinuation of docetaxel administration, but in three patients symptoms worsened for some time after the end of treatment before improvement occurred. CONCLUSION Severe docetaxel neuropathy may especially occur following treatment with cumulative dosage over 600 mg/m2; in patients treated with this dosage a moderate or severe neuropathy may not be rare.

Antineuronal antibodies in patients with neurologic complicat'lons of primary Sjögren's syndrome

Neurologic complications of both the central and peripheral nervous systems occur frequently in patients with primary Sjögrens syndrome (primary SS), but the underlying cause of these complications is unknown. We studied the presence of antineuronal antibodies in relation to neurologic complications in a consecutive series of 45 patients with primary SS. Twenty-five patients had neurologic complications: 12 patients with polyneuropathy, three with psychiatric disorders, four with carpal tunnel syndrome, seven with migraine, seven with myalgia, and four with other complications (transverse myelitis, stroke, Bells palsy, and pyramidal signs). Ten patients had more than one neurologic complication. Eleven patients had major and 14 had minor complications according to criteria used for rating neurologic complications in patients with systemic lupus erythematosus. Antineuronal antibodies were present in six of 11 (55%) patients with major neurologic complications and in four of 34 (11%) of patients without major neurologic complications (p = 0.001). This difference could be attributed mainly to the group of patients with polyneuropathy. Three of the 10 sera of patients with positive antineuronal antibodies had antibodies reacting with a 38-kd neu-ronal protein on immunoblotting, identical to the anti-Hu antibody reactivity in paraneoplastic neurologic disease associated with small-cell lung cancer.

Paclitaxel (Taxol) induces cumulative mild neurotoxicity

Paclitaxel (Taxol), a new antineoplastic drug, has been reported to be neurotoxic at doses above 200 mg/m2 per course. It is uncertain whether neurotoxicity is related to cumulative amounts of paclitaxel. Neuropathy was prospectively assessed in 18 patients with breast cancer, receiving between two and eight courses of 135 or 175 mg/m2 of paclitaxel. Vibratory perception thresholds (VPT) and tendon reflex scores were proportionally related to the corresponding cumulative amounts of paclitaxel (P = 0.002; P = 0.0003). The amounts of paclitaxel administered between the first and last assessments (175-1225 mg/m2) were related to concomitant changes in VPT (P = 0.034). Paclitaxel had no clear neurotoxic threshold; if present, it lies below 540 mg/m2. Rather, VPT appeared to increase 0.1 micron per 400 mg/m2 over the entire range of 175-1225 mg/m2 of paclitaxel. Clinical neuropathy prevailed in 0/8 patients at screening and in 5/10 patients at the final assessment (P = 0.029). Neuropathy never exceeded grade 1. Thus, although neurotoxicity of paclitaxel is frequent and cumulative, it remains mild or subclinical up to at least 1400 mg/m2 administered over eight cycles.