Herman Hugenholtz

A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis

Cerebral metastasis is a common oncologic problem that occurs in 15–30% of cancer patients; approximately half such metastases are single. Previous retrospective studies and two randomized trials reported that the addition of surgical extirpation prior to radiation therapy increased survival, neurologic function, and quality of life compared with radiation alone in patients with a single brain metastasis.

Subtle Neuropsychological Deficits in Patients with Good Recovery after Closed Head Injury

This study demonstrates residual mental deficits in patients who have apparently recovered after closed head injury. Twenty closed head injury patients were compared to 20 normal control subjects matched for age, sex, handedness, education, language, and IQ. All received a series of neuropsychological tests. Discriminant function analysis significantly differentiated the two groups. Correct classification of individuals as having suffered a head injury or not was 85%. The head injury patients did have primary impairment on tests of divided attention. Litigation was not a factor. We propose that this impairment of information processing reflects residual brain damage secondary to the closed head injury.

How long does it take to recover from a mild concussion

&NA; Twenty‐two adults with mild concussions were assessed 5 times during the first 3 months after injury. The initial tests were performed within 72 hours of injury. Each evaluation included a neurological examination and neuropsychological reaction time (RT) tests of simple and choice RT variations. The concussed subjects were compared with control subjects matched for age, sex, and education. The time of day of the testing was equated for the two groups. None of the concussed subjects had a significant neurological deficit and none was hospitalized. There was no significant difference in the number of errors by the two groups on the RT tests. On the simple RT test, requiring a predetermined response to a specific signal, there was no significant difference between the groups, although the concussed group was approximately 28 ms slower on the average than the control group. On the choice RT tests, however, which demand an increased amount of attention and information processing, the concussed subjects were significantly slower than the normal control group, especially during the 1st month after injury. Even after 3 months, the concussed subjects had not yet attained the skill of the control group. Analysis of the response curves over time suggested two processes: an improvement in the concussed group and a slowing in the control group. Within the concussed group, there was no correlation of RT with the severity of the concussion. Even mild concussions can cause significant attentional and information processing impairment in the absence of any apparent neurological problems. Specific neuropsychological tests are necessary to reveal the deficit. A significant impairment seems to last for several weeks. There is a gradual improvement over 3 months, suggesting a recovery process.

Penetration of VP-16 (etoposide) into human intracerebral and extracerebral tumors

SummaryVP-16 100 mg/m2 was given intravenously to 10 patients undergoing surgical resection of intracerebral tumors, and the drug was assayed in resected tumor using high pressure liquid chromatography. VP-16 concentrations varied from undetectable (<.1 µg/g) to 5.9 µg/g (mean, 1.4 µg/g). VP-16 concentrations in tumors were lower than concurrent plasma concentrations. In addition, intracerebral tumors had a lower concentration of VP-16 than did extracerebral tumors (mean VP-16 concentration, 3.9 µg/g) from 7 patients receiving VP-16 50–100 mg/m2 intravenously. Plasma pharmacokinetics of VP-16 were different in our patients with intracerebral tumors than in previously studied patients with extracerebral tumors and it is unclear what role this may have played invariability of tumor VP-16 concentrations. VP-16 concentrations were similar in glioblastomas and brain metastases. Specimens from patients with small cell undifferentiated carcinoma of the lung had the highest VP-16 concentrations. A patient who had both viable and necrotic tumor resected during an occipital lobectomy had a higher drug concentration in the necrotic than in the viable area of tumor. In addition, VP-16 concentration decreased as a function of distance into brain from the tumor. Based on our data, VP-16 might be expected to have less activity against intracerebral than against extracerebral human tumors.

Spontaneous dissecting aneurysm of the extracranial vertebral artery.

Spontaneous dissection of a cervical vertebral artery secondary to fibromuscular hyperplasia is uncommon, is often painful, and may be followed after a latent interval by further symptoms of embolism, occlusion, or hemorrhage. Accordingly, the lesion is potentially hazardous and warrants treatment when recognized.

Intracarotid Chemotherapy with a Combination of 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU), cis-Diaminedichloroplatinum (Cisplatin), and 4'-O-Demethyl-1-O-(4,6-O-2-thenylidene-β-D-glucopyranosyl)epipodophyllotoxin (VM-26) in the Treatment of Primary and Metastatic Brain Tumors

Thirty-seven patients with intracranial primary or metastatic tumors were treated with an intraarterial combination of BCNU, cisplatin, and VM-26 to determine the efficacy, toxicity, and maximal tolerated doses for the combination. A transfemoral fluoroscopic approach was used to catheterize temporarily the internal carotid or vertebral artery. Thirteen of 19 (68%) evaluable primary brain tumors and 9 of 16 (56%) evaluable brain metastases responded. The response rate was lower in patients previously treated with both cranial irradiation and i.v. chemotherapy than in patients less heavily pretreated (54% vs. 82%), although even patients previously treated i.v. with all three of the study drugs responded. All five patients with both extracranial and intracranial evaluable tumor deposits experienced a greater response of their intracranial than of their extracranial tumor. Ipsilateral retinal and neurological toxicity were dose-limiting, with major toxicity (permanent decreased vision or hemiparesis) occurring in five of nine (56%) patients receiving doses of BCNU greater than or equal to 100 mg/m2 plus cisplatin, 60 mg/m2 plus cisplatin, 60 mg/m2, plus VM-26, 175 mg/m2. Only 9% of the patients treated with a lower VM-26 dose developed permanent severe toxicity, and the doses that we now recommend are: BCNU, 100 mg/m2; cisplatin, 60 mg/m2; and VM-26, 150 mg/m2. The response rate was also dose-related (100% at the highest doses tested vs. 57% at the lower doses).(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I study of intracarotid administration of carboplatin

Fifteen patients were treated in a Phase I study of intracarotid carboplatin (200-400 mg/m2) in 5% dextrose and water infused over 15 to 30 minutes through a transfemoral catheter with a 0.2-micron inline filter. This study was done because intravenous carboplatin has less neurotoxicity than cisplatin and is active against brain tumors. Eleven men and four women ranging in age from 37 to 72 years (median, 59 years) were treated. The Eastern Cooperative Oncology Group performance status was 1 in 3, 2 in 4, and 3-4 in 8 patients. Eight patients had one to three previous chemotherapy regimens; previous radiotherapy had failed in 13 patients. The response of patients in the Phase I study follows: glioblastoma, 6 failed; not evaluated because of early death from pulmonary embolus, 1; recurrent Grade II and III glioma, 1 stable (minor response with neurologic improvement) and 2 failed; malignant oligodendroglioma, 1 failed; brain metastases from nonsmall cell lung cancer, 1 partial remission, 1 stable (minor response), and 1 failed; brain metastases from unknown primary, 1 stable (minor response with neurological improvement). Median survival was 9 weeks. Nausea was mild to moderate. One patient had granulocytopenia, and 2 had thrombocytopenia (mild). At 200 mg/m2 (2 patients), 1 had a focal seizure. At 300 mg/m2 (9 patients), 2 with abnormally small arteries had severe pain early in the treatment and posttreatment ipsilateral conjunctival edema, decreased vision, and cerebral edema (with partially reversible increased hemiparesis); 1 other had mild decrease in ipsilateral vision and 1 had transient aphasia on removal of the catheter (possibly the result of a vascular spasm).(ABSTRACT TRUNCATED AT 250 WORDS)

Human central nervous system and plasma pharmacology of mitoxantrone

Mitoxantrone 5–6 mg/m2 was administered IV to 10 consenting patients prior to surgical resection of an intracerebral tumor. Plasma pharmacokinetic parameters were calculated and concentration of mitoxantrone in intracerebral tumors was determined. Concentrations of mitoxantrone were also determined in autopsy tissues of one of the patients who expired 192 days after receiving the drug. The plasma pharmacokinetics were best described by a 3 compartment model, with a t1/2γ of 4.74±5.53 h. Mitoxantrone concentrations in the intracerebral tumors were potentially cytotoxic and ranged from 4 to 322 ng/g. In all but one case, mitoxantrone concentration was higher in tumor than in concurrent plasma samples. There was no obvious relation between tumor mitoxantrone concentration and peak plasma mitoxantrone concentration or time from mitoxantrone administration to tumor removal. Low grade gliomas and viable tumors tended to have lower mitoxantrone concentrations than did other tumor types and necrotic tumors. In the patient undergoing autopsy, highest mitoxantrone concentrations were found in liver, thyroid and heart.

Cisplatin plus cytosine arabinoside in adults with malignant gliomas

SummaryA combination of cisplatin and cytosine arabinoside was used to treat 21 patients with glioblastomas and 5 patients with recurrent grade 11 gliomas. Cisplatin 60–100 mg/m2 was given I.V. in 250 ml 0.45% saline and preceded by 500 ml dextrose 5% in 0.45% saline. Mannitol 50 g was given I.V. concurrently with the cisplatin. Cytosine arabinoside 500–1000 mg/m2 was given by rapid I.V. infusion immediately after the cisplatin. Of 25 evaluable patients, 10 (40%) experienced objective tumor shrinkage on CT scan, and 6 (24%) stabilized. There were 2 complete remissions. Patients who had had no prior treatment had a higher response rate (58%) than those previously treated (23%). Myelosuppression occurred in some patients 2–3 weeks after treatment. Gastrointestinal toxicity (vomiting and diarrhea) was dose-limiting. Two patients had possible neurological toxicity. Recommended doses for further studies are cisplatin 90 mg/m2 and cytosine arabinoside 900 mg/m2.

Combined intraarterial and systemic chemotherapy for intracerebral tumors.

Twenty-six patients with intracerebral tumors (predominantly gliomas) were treated with intraarterial BCNU, VM-26, and cisplatin combined with the systemic administration of VM-26, methotrexate, vincristine, bleomycin, and procarbazine. Oral glycerol was given before i.v. VM-26. Twelve patients responded (46% of all patients and 63% of the fully evaluable patients). The response rate for gliomas was 50% if all patients were considered and 71% if only fully evaluable patients were considered. The response rate did not seem to be affected by glioma grade, prior chemotherapy, or pretreatment performance status. Median time to tumor progression for responders was 19 weeks. Median survival from initiation of treatment was 21 weeks for evaluable patients and 17 weeks for all patients. Median survival from initial diagnosis was 55 weeks. Myelosuppression was dose-limiting for the systemic chemotherapy. Reversible neurological toxicity was common, but tolerable. One patient developed ipsilateral blindness, and two patients developed prolonged neurological toxicity. Pulmonary toxicity was also seen. Vertebral artery infusions proved feasible, although difficult and more toxic than carotid infusions. Overall, this regimen was not more active than the intraarterial combination of BCNU, VM-26, and cisplatin without the systemic chemotherapy. Further studies of more intensive intracarotid therapy combined with different systemic drugs are being initiated.