Local progression and pseudo progression after single fraction or fractionated stereotactic radiotherapy for large brain metastases. A single centre study.

PURPOSE: The 1-year local control rates after single-fraction stereotactic radiotherapy (SRT) for brain metastases > 3 cm diameter are less than 70%, but with fractionated SRT (FSRT) higher local control rates have been reported. The purpose of this study was to compare our treatment results with SRT and FSRT for large brain metastases. MATERIALS AND METHODS: In two consecutive periods, 41 patients with 46 brain metastases received SRT with 1 fraction of 15 Gy, while 51 patients with 65 brain metastases received FSRT with 3 fractions of 8 Gy. We included patients with brain metastases with a planning target volume of > 13 cm(3) or metastases in the brainstem. RESULTS: The minimum follow-up of patients still alive was 22 months. Comparing 1 fraction of 15 Gy with 3 fractions of 8 Gy, the 1-year rates of freedom from any local progression (54% and 61%, p = 0.93) and pseudo progression (85% and 75%, p = 0.25) were not significantly different. Overall survival rates were also not different. CONCLUSION: The 1-year local progression and pseudo progression rates after 1 fraction of 15 Gy or 3 fractions of 8 Gy for large brain metastases and metastases in the brainstem are similar. For better local control rates, FSRT schemes with a higher biological equivalent dose may be necessary.

Adjustment of treatment increases quality of life in patients with epilepsy: a randomized controlled pragmatic trial.

BACKGROUND AND PURPOSE: Complaints about side-effects of antiepileptic drugs (AEDs) may be overlooked in clinical practice. We assessed the value and risks of an active intervention policy for reported complaints in a randomized controlled pragmatic trial. METHODS: This randomized controlled pragmatic trial included 111 adults treated for epilepsy in seven general hospitals. They were considered well-managed by their treating physician, but reported moderate to severe complaints on a questionnaire (SIDAED, assessing SIDe effects in AED treatment). The intervention was adjustment of AED treatment (53 patients), either reduction of dose or switch of AED, versus continuation of treatment unchanged (58 control patients) during 7 months. Primary outcomes were quality of life (Qolie-10) and complaints score. Secondary outcome measures were the occurrence of seizures or adverse events. RESULTS: After 7 months, the relative risk (RR) for improvement in quality of life was 1.80 (1.04-3.12) for the intervention group compared to control and the RR of decrease in complaints was 1.34 (0.88-2.05). In 58% of patients randomized to adjustment, the medication had indeed been changed. DISCUSSION: In conclusion, despite a possible risk of seizure recurrence, adjustment of drug treatment in well-managed patients with epilepsy, who report considerable complaints, improves the quality of life.

EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force.

The objectives have been to establish evidence-based guidelines and identify controversies regarding the management of patients with brain metastases. The collection of scientific data was obtained by consulting the Cochrane Library, bibliographic databases, overview papers and previous guidelines from scientific societies and organizations. A tissue diagnosis is necessary when the primary tumor is unknown or the aspect on computed tomography/magnetic resonance imaging is atypical. Dexamethasone is the corticosteroid of choice for cerebral edema. Anticonvulsants should not be prescribed prophylactically. Surgery should be considered in patients with up to three brain metastases, being effective in prolonging survival when the systemic disease is absent/controlled and the performance status is high. Stereotactic radiosurgery should be considered in patients with metastases of 3-3.5 cm of maximum diameter. Whole-brain radiotherapy (WBRT) after surgery or radiosurgery is debated: in case of absent/controlled systemic cancer and Karnofsky Performance score of 70 or more, one can either withhold initial WBRT or deliver early WBRT with conventional fractionation to avoid late neurotoxicity. WBRT alone is the treatment of choice for patients with single or multiple brain metastases not amenable to surgery or radiosurgery. Chemotherapy may be the initial treatment for patients with brain metastases from chemosensitive tumors.

A cross-sectional study of subjective complaints in patients with epilepsy who seem to be well-controlled with anti-epileptic drugs.

OBJECTIVES: Side-effects of anti-epileptic drugs (AEDs) may be overlooked in patients with epilepsy in everyday clinical practice. The aim of this study was to assess the prevalence and severity of subjective complaints in patients who were considered to be well-controlled and to assess whether these complaints are related to medication, personality traits, or other determinants. METHODS: We included patients with epilepsy who were considered to be well-controlled in a cross-sectional study in seven hospitals in the Netherlands. Their medication had not been changed for six months and an apparent reason to change the medication was lacking at the time of enrolment. Subjective complaints were assessed with a 46-item questionnaire. Using multivariable linear regression modeling, we assessed whether patient characteristics, epilepsy characteristics, medication, quality of life (Qolie-10), and personality traits (SCL-90) explained the presence and severity of complaints. RESULTS: Of 173 included patients, 67% reported moderate to severe subjective complaints on the questionnaire. Cognitive complaints were reported most frequently. Multivariate modeling showed that 61% of the variance in reported complaints could be explained by included determinants. The prevalence and severity of complaints was associated with AED polytherapy and higher scores on psycho neuroticism. CONCLUSIONS: Patients who were considered to be well-controlled proved to report an unexpectedly high number of subjective complaints. Both medication and aspects of personality contributed to the level of complaints. Our study illustrates that subjective side-effects are easily overlooked in everyday clinical practice, possibly because in practice a generally phrased question is used to detect side-effects.

Distribution of recombinant adenovirus in the cerebrospinal fluid of nonhuman primates.

Gene therapy by administration of vectors into the cerebrospinal fluid (CSF) may be used in treatment of leptomeningeal metastases (cancer gene therapy) as well as in treatment of neurodegenerative disorders, traumatic injury, and chronic pain. Recombinant adenoviruses are attractive vectors for intra-CSF administration because they can efficiently transfer genes into the nonreplicating cells of the central nervous system (CNS). In addition, they can be produced in high titers and, because no producers cells are introduced, the risk of CSF obstruction by clustering cells is circumvented. However, successful application requires favorable distribution dynamics, high transduction efficiency, and long-lasting transgene expression. In this study we examined the distribution of a recombinant adenovirus containing the lacZ gene after administration into the CSF of nonhuman primates. After intraventricular and suboccipital administration, homogeneous distribution of the vector along the meninges covering the brain and spinal cord was obtained, as demonstrated by extensive and intense blue staining of cells, predominantly in the arachnoid and pia mater. In one animal we also found beta-galactosidase activity in the cervical paraspinal fat and in one of the deep cervical lymph nodes, indicating drainage of the vector or vector products with CSF into cervical lymph. This route of vector clearance from the CNS may result in antigenic presentation and an effective immune response and may explain the sixfold higher serum antibody titers after intrathecal injection of adenovirus as compared with intranasal application in Fischer rats. We conclude that distribution dynamics of recombinant adenovirus after intra-CSF administration are excellent. However, because of the immune response elicited by the virus, even after administration to the CNS, development of immunomodulating strategies remains a challenge.

Herpes simplex virus thymidine kinase gene therapy for rat malignant brain tumors.

Transfer of a herpes simplex virus-derived thymidine kinase (HSV-tk) gene into brain tumor cells and subsequent ganciclovir (GCV) treatment has been shown by others to be an effective treatment in rats with intracerebrally inoculated 9L gliosarcomas. Mechanism of action and reproducibility are, however, still a matter of debate. We have used the same model to test the therapeutic effects of both retrovirus- and adenovirus-mediated transfer of the HSV-tk gene followed by GCV treatment. Survival time of rats with intracerebral 9L tumors was significantly prolonged after a single administration of adenovirus carrying a HSV-tk gene as compared to controls. Retrovirus-mediated gene transfer also resulted in significantly prolonged survival time when recombinant retrovirus-producing cells were transplanted. Direct injection of the recombinant retrovirus, HSV-tk-expressing cells, virus-producing cells without GCV administration and recombinant retrovirus-lacZ or interleukin-2 (IL-2)-producing cells did not result in tumor cell kill. In the present study, no significant difference in survival of 9L brain tumor carrying rats was found after treatment with adenovirus as compared to retrovirus-mediated HSV-tk-mediated gene transfer and subsequent GCV treatment.

Homovanillic acid and 5-hydroxyindoleacetic acid cerebrospinal fluid levels. A study with and without probenecid administration of their relationship to the state of consciousness after head injury.

Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured in the lumbar cerebrospinal fluid of 98 patients after closed head injury. The HVA levels decreased in patients, whether or not they were given the drug probenecid, which inhibits the active transport of these acids from the brain. The decline of HVA was more notable in patients with the longest duration of unconsciousness. The HVA levels showed no correlation with the state of consciousness at the moment of the lumbar puncture. The 5-HIAA levels were below normal in the conscious patients, but paradoxically, at about normal levels in unconscious patients. The overall results suggest a decreased cerebral dopamine and serotonin metabolism after head injury.

Antineuronal antibodies in patients with neurologic complications of primary Sjögren's syndrome.

Neurologic complications of both the central and peripheral nervous systems occur frequently in patients with primary Sjögren's 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, Bell's 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 neuronal protein on immunoblotting, identical to the anti-Hu antibody reactivity in paraneoplastic neurologic disease associated with small-cell lung cancer.

Neurolymphomatosis of the median nerve.

A patient with a non-Hodgkin's lymphoma had a painful axonal neuropathy of the median nerve due to lymphomatous infiltration. The median nerve lesion was the only site of tumor recurrence for 5 months and could be diagnosed with MRI. The median neuropathy responded to chemotherapy.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral neurotoxicity induced by docetaxel.

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 Institute's 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 produced 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.

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 less than 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.

99mTc-SPECT in the diagnosis of skull base metastasis.

OBJECTIVE: To evaluate the role of bone SPECT in diagnosing metastasis to the skull base in cancer patients. BACKGROUND: Skull base metastasis often causes characteristic clinical syndromes. Antitumor treatment ameliorates or stabilizes symptoms in most patients. Diagnosis may be difficult when neuroimaging studies are negative (as occurs in about one-quarter of patients). Case reports have suggested a role for bone SPECT in these patients. METHODS: We reviewed the charts of all patients (1993-1996) at our institution who had skull base SPECT and at least one neuroimaging study (CT or MRI) for clinically suspected metastasis to the base of the skull. Bone SPECT, CT, and MRI were blindly re-evaluated. RESULTS: We studied 56 patients, of whom 36 had skull base metastasis. Twenty patients had other causes of the clinical syndrome, including leptomeningeal and posterior fossa metastasis, or benign causes. In 29 of 36 patients (81%) with skull base metastasis, CT or MRI clearly demonstrated the lesion. Bone SPECT identified a hot spot in the appropriate region of the skull base in 28 of 36 patients (78%). All seven patients with negative CT or MRI had positive SPECT and four of these had a response to anti-tumor treatment. CONCLUSIONS: SPECT of the skull base can demonstrate lesions not identifiable by CT or MRI. In cancer patients suspected of having skull base metastasis, we recommend SPECT of the skull base when CT or MRI studies are negative.

Medical therapy of malignant nerve pain. A randomised double-blind explanatory trial with naproxen versus slow-release morphine.

It is uncertain whether there exists a nociceptive component in malignant nerve pain responsive to NSAIDs and opioids. 20 patients with malignant nerve pain were randomly assigned to treatment with naproxen 1500 mg versus slow-release morphine 60 mg daily during 1 week, followed by cross-over medication during the second week in a double-blind, double-dummy protocol. In the 16 evaluable patients, a significant (P < 0.05) reduction of 26% (S.E. +/- 7.9) in pain intensity was reached at day 7, compared to baseline pain. At day 7, significant pain relief of 32% (P < 0.05) was observed in the naproxen group, but not in the morphine group (21%, P = 0.14). Patients using morphine needed approximately twice as much paracetamol rescue than patients using naproxen. Additional pain relief could be observed in 4/9 patients with cross-over medication. These data support the concept of a nociceptive component in malignant nerve pain responding to NSAIDs and opioids, and favour the combination of both an anti-inflammatory drug and an opioid for symptomatic pain relief.

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.

Phase I study of DABIS maleate given once every 3 weeks.

DABIS maleate is an alkylating quaternary nitrogen. In a phase I study DABIS maleate was administered as a single intravenous infusion once every 3 weeks. 32 patients with solid tumours were studied, at least 3 per dose level (50-1400 mg/m2). Dose-limiting toxicity was severe paresthaesias in the face, around the mouth and in the tongue. Cerebellar ataxia developed at 750 mg/m2 or higher. Haematological toxicity was minimal. Nausea and vomiting were mild to moderate. No other non-haematological side-effects were noted. The recommended dose for phase II studies at once every 3 weeks is 750 mg/m2 intravenously as a 15 min infusion.

Phase II study of a short course of weekly high-dose cisplatin combined with long-term oral etoposide in metastatic malignant melanoma.

The results of cytostatic therapy in metastatic melanoma are very disappointing. In phase II studies with high-dose cisplatin regimens, a remarkably high response rate was observed. In a phase I study with a short course of weekly cisplatin, combined with oral etoposide, we were able to reach, in most patients, a cisplatin dose intensity of 60 mg/m2/week. We performed a phase II study with this schedule in metastatic malignant melanoma. 15 consecutive patients were entered in the study. Treatment consisted of cisplatin 70 mg/m2 on days 1, 8, 15 and days 29, 36, 43 combined with oral etoposide 50 mg daily, days 1-15 and days 29-43. Patients with a response or stable disease continued treatment with oral etoposide 50 mg/m2 daily, days 1-21 every 4 weeks. All patients were evaluable for response and toxicity. The majority of the patients received six cycles of cisplatin with the planned cisplatin dose intensity of 60 mg/m2/week. A partial response was observed in 2 patients (13%; 95% confidence interval (CI) 2-44%) of, respectively, 22 and 12 weeks; stable disease was observed in 6 patients. Toxicity consisted mainly of alopecia and bone marrow suppression. 4 patients had tinnitus, one patient had neurotoxicity grade 1. The regimen studied has only limited activity in metastatic melanoma in spite of the high-dose intensity of cisplatin reached with this schedule.

Neurotoxicity is not enhanced by increased dose intensities of cisplatin administration.

It is uncertain whether intensive dosing schedules of cisplatin, intended to attain a higher anti-tumour efficacy, alter the severity of cisplatin-induced neuropathy. We assessed the development of neuropathy in three groups of patients treated with cisplatin in different dosing schedules. The severity of neuropathy was determined by measurement of the vibration perception threshold (VPT) before treatment and during follow-up for 2-12 months after the last cycle. 66 patients were treated with an intensive weekly regimen of doses varying from 70 to 85 mg/m2 in 1 day (trial A), 21 patients with a 3-weekly combination chemotherapy containing cisplatin 75 mg/m2 in 1 day (trial B) and 20 patients with a 3-weekly regimen containing cisplatin 20 mg/m2 for 5 consecutive days (trial C). The mean dose intensity achieved was 59 mg/m2/week in trial A, 21 mg/m2/week in trial B and 33 mg/m2/week in trial C. The maximum post-treatment VPT correlated significantly with pretreatment VPT (P < 0.001) and with the cumulative dose of cisplatin (P < 0.001). Following correction for these two variables, the maximum posttreatment VPT did not show a statistically significant association with dose intensity. These results suggest that neuropathy is not related to dose intensity of cisplatin. This implies that treatment with more intensive dosing schedules, employing equal cumulative doses of cisplatin, does not result in a concomitant increase in neurotoxicity within a cumulative dose range of 280-675 mg/m2.

Phase II study on cisplatin and ifosfamide in recurrent high grade gliomas.

27 patients with recurrent high grade glioma following surgery and radiation therapy were treated with 100 mg/m2 cisplatin and 6 g/m2 ifosfamide per cycle, administered on days 1-3 in 4 week cycles, for a maximum of six cycles. Toxicity was assessed after every cycle. Response was assessed following every second cycle, and a 50% decrease of the largest cross-sectional tumour area on contrast enhanced magnetic resonance imaging or computed tomography scan was considered a partial response (PR). A total of 95 cycles was administered; 26 patients were evaluable for response. In 5 patients (19%), a PR was obtained (median time to progression (TTP): 34 weeks). Stable disease was observed in 6 patients (23%, median TTP: 22 weeks). The most frequent toxicity was haematological: 37% of cycles were complicated by a grade 3 or 4 leucopenia. 1 patients died, probably as a consequence of increased cerebral oedema induced by the cisplatin hydration schedule. Determination of the cisplatin concentration in this patient showed a 10-fold increase in the tumour concentration as compared with that in normal brain tissue, demonstrating the absence of a blood-brain barrier in the tumour. In conclusion, generally this schedule was well tolerated, but it is of moderate activity for recurrent glioma.

Post-axillary dissection pain in breast cancer due to a lesion of the intercostobrachial nerve.

Seven patients with breast carcinoma and post-axillary dissection pain are described. They complained about pain in the axilla, inner side of the upper arm and/or shoulder. All had undergone a partial or radical breast amputation including an axillary lymph node dissection. On neurological examination all had evidence of a lesion of the intercostobrachial nerve. The pain was not associated with lymphedema and only one patient had undergone radiotherapy to the axillary and supraclavicular area. Post-axillary dissection pain is probably a more appropriate name than the usual post-mastectomy pain for this syndrome. During the dissection, the intercostobrachial nerve is often lesioned, which may give rise to neuropathic pain of that nerve.