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.

Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma.

OBJECTIVE: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma. METHODS: The European Organization for Research and Treatment of Cancer (EORTC) 26981-22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors. RESULTS: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49-0.93). CONCLUSIONS: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.

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.

Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972.

BACKGROUND: Oligodendroglial tumors are chemosensitive, with two-thirds of patients responding to PCV combination chemotherapy with procarbazine, lomustine (CCNU) and vincristine. Temozolomide (TMZ), a new alkylating and methylating agent has shown high response rates in recurrent anaplastic astrocytoma. We investigated this drug in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after prior PCV chemotherapy and radiation therapy. PATIENTS AND METHODS: In a prospective non-randomized multicenter phase II trial patients were treated with TMZ 150 mg/m(2) on days 1-5 in cycles of 28 days for 12 cycles. Eligible patients had a recurrence after prior PCV chemotherapy, with measurable and enhancing disease as shown by magnetic resonance imaging. Pathology and all responses were centrally reviewed. RESULTS: Thirty-two eligible patients were included. In four patients the pathology review did not confirm the presence of an OD or OA. Twelve of 24 patients [50%, 95% confidence interval (CI) 29% to 71%] evaluable for response to first-line PCV chemotherapy had responded to PCV. Temozolomide was in general well tolerated; the most frequent side-effects were hematological. One patient discontinued treatment due to toxicity. In seven of 28 patients (25%, 95% CI 11% to 45%) with histologically confirmed OD an objective response to TMZ was observed. Median time to progression for responding patients was 8.0 months. After 6 and 12 months from the start of treatment, 29% and 11% of patients, respectively, were still free from progression. CONCLUSIONS: TMZ may be regarded as the preferred second-line treatment in OD after failure of PCV chemotherapy. Further studies on TMZ in OD are indicated.

Involvement of the peripheral nervous system in primary Sjögren's syndrome.

BACKGROUND: Involvement of the peripheral nervous system in patients with primary Sjögren's syndrome (SS) has been reported, but its prevalence in neurologically asymptomatic patients is not well known. OBJECTIVE: To assess clinical and neurophysiological features of the peripheral nervous system in patients with primary SS. PATIENTS AND METHODS: 39 (38 female) consecutive patients with primary SS, aged 20-81 years (mean 50), with a disease duration of 1-30 years (mean 8) were studied. The peripheral nervous system was evaluated by a questionnaire, physical examination, quantified sensory neurological examination, and neurophysiological measurements (nerve conduction studies). To assess autonomic cardiovascular function an orthostatic challenge test, a Valsalva manoeuvre, a forced respiration test, and pupillography were done. RESULTS: Abnormalities as indicated in the questionnaire were found in 8/39 (21%) patients, while an abnormal neurological examination was found in 7/39 (18%) patients. Abnormalities in quantified sensory neurological examination were found in 22/38 (58%) patients. In 9/39 (23%) patients, neurophysiological signs compatible with a sensory polyneuropathy were found. No differences were found in the autonomic test results, disease duration, serological parameters, or erythrocyte sedimentation rate between the patients with primary SS with and those without evidence of peripheral nervous involvement. CONCLUSION: Subclinical abnormalities of the peripheral nervous system may occur in patients with primary SS selected from a department of rheumatology, but clinically relevant involvement of the peripheral nervous system in this patient group is rare.

Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity.

High doses of adenotk were injected into the cerebrospinal fluid of rats and nonhuman primates (Macaca mulatta). Vector administration was followed by ganciclovir administration for 14 days. Despite the absence of clinical symptoms, analysis of the cerebrospinal fluid (CSF) and histopathological examination of the central nervous system (CNS) of the monkeys (3 weeks after vector injection) were consistent with a viral meningitis. Immunohistochemical analysis of the inflammatory infiltrates in the monkeys revealed the presence of T and B lymphocytes, indicating a combined cellular and humoral immune response to the vector. This latter was supported by the finding of intrathecal anti-adenovirus antibody synthesis. Rats receiving high intrathecal adenotk doses showed a transient and dose-dependent clinical toxicity consisting of lethargy, hyperemic eyes and weight loss. Histopathological examination of the meninges showed a shift from polymorphonuclear infiltrates during the first post-injection days to clusters of mononuclear cells after 7 days. Acute toxicity is probably related to the early, innate immune response to the vector. In a separate experiment, high levels of IL-8 and IL-6, were measured during the first 2-3 post-injection days in the CSF of two monkeys which received intrathecal adenoLacZ. Therefore, these cytokines seem to play an important role in initiating the nonspecific immune response. In one monkey which received adenotk, recombinant adenovirus was cultured from serum samples obtained at the 7th post-injection day. At this time-point, no vector could be isolated from CSF samples. Based on these preclinical data, we recommend careful dose finding for clinical studies that aim to treat patients with leptomeningeal metastases.

[Treatment of posttraumatic dystrophy]. / Behandeling van posttraumatische dystrofie.

Reflex sympathetic dystrophy, posttraumatic dystrophy or complex regional pain syndrome is a particular type of chronic pain. Although the origin is unknown, some believe that wide-dynamic range neurons located in the dorsal horn of the spinal cord play an essential role. Others consider the role of psychogenic factors underestimated. Until now, controlled clinical trials mainly directed at modulation of the sympathetic system have not revealed clearly effective therapies. Tests with guanethidine, phenylephrine, phentolamine or lidocaine have essentially been negative. Use of low dose glucocorticoids, dimethylsulphoxide, biphosphonates and epidurally applied clonidine require confirmation in studies of larger size. There are indications that invasive electrical spinal cord stimulation may have some effect; randomized studies in patients with posttraumatic dystrophy are needed. So far, only application of physical therapy at an early stage has clearly shown effective pain relief and would also lead to cost reduction.

Cancer pain: a neurological perspective.

Nerve pain in cancer is common, mainly manifested by a radiculopathy associated with vertebral metastasis, by a plexopathy caused by lymph-node involvement or, more rarely, by trigeminal involvement in cancer of the head and neck. Less frequent types of nerve pain can occur as late effects of antitumour therapy, including surgery, radiation and chemotherapy. The distinction between a nociceptive and a non-nociceptive nerve pain helps in determining the most appropriate symptomatic management.

Increased incidence of neurological complications in patients receiving an allogenic bone marrow transplantation from alternative donors.

OBJECTIVE: To compare the frequency and type of neurological complications after bone marrow transplantation (BMT) with an HLA identical unrelated donor or a mismatched related donor (alternative donors) to the neurological complications after matched sibling BMT for standard and high risk leukaemia or myelodysplastic syndromes. METHODS: Retrospective analysis of consecutively treated patients with (a) BMT from alternative donors (n=39), (b) treated with matched sibling BMT for standard risk leukaemia, myelodysplastic syndromes, or aplastic anaemia (n=53), and (c) treated with matched sibling BMT for high risk leukaemia, myelodysplastic syndromes, or aplastic anaemia (n=49). RESULTS: A total of 72 neurological complications were found. Most of these occurred within the first 6 months after transplant. Thirty six patients developed a severe neurological complication: 17 Alternative donor patients (44%) by contrast with six standard risk patients (11%) and 13 high risk patients (27%; p<0.005). The most frequent complication was a metabolic encephalopathy occurring in 18% of patients. Most of the encephalopathies were caused by either the transplant procedure, cyclosporin, systemic infections, microangiopathic thrombopathy, or by complications induced by graft versus host disease. Infections of the CNS developed in 9% of patients, cerebrovascular lesions in 3%. CONCLUSIONS: Severe neurological complications are more frequent after BMT from alternative donors. This is mainly due to increased treatment related morbidity and to more profound immunosuppression after BMT from alternative donors.

Phase II study of weekly dose-intensified cisplatin chemotherapy with oral etoposide in recurrent glioma.

BACKGROUND: In most patients with recurrent glioma chemotherapy is the only remaining treatment option. In general results of chemotherapy in these patients are poor, and trials on new regimens are indicated. Because relatively good results have been achieved with combinations of platin compounds and etoposide, we investigated a dose-intensified cisplatin regimen with oral etoposide. METHODS: Eligible patients, with recurrent glioma after surgery and radiation therapy were treated with two four week-cycles with cisplatin 70 mg/m2 on days 1, 8 and 15, combined with oral etoposide 50 mg daily on days 1-15. In responding or stabilized patients, treatment was continued with six four week-cycles of oral etoposide 50 mg/m2 on days 1-21. Toxicity was assessed using the NCI Common Toxicity Criteria, a 50% decrease in contrast enhancing area on MRI scan was considered a partial response. Time to progression was measured from the start of chemotherapy. RESULTS: Sixteen patients were included, 11 were progressive during or immediately after the induction cycles. Two patients achieved a partial response with a time to progression of 42 and 58 weeks. Three patients were stable for 11, 14 and 15 weeks respectively. Toxicity was modest. DISCUSSION: This dose-intensified cisplatin regimen did not result in a significant number of objective responses and even the number of 'stable disease' was small. Given the low response rate of this intensive treatment, we consider this intensive regimen inappropriate for these patients.

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

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.

Spinal epidural abscess complicating chronic epidural analgesia in 11 cancer patients: clinical findings and magnetic resonance imaging.

We reviewed the records of all patients who had received an epidural catheter for management of chronic cancer pain in a 3-year period (1993-1996). Patients with nervous system infections were identified, and pertinent clinical, radiological (magnetic resonance imaging), and bacteriological data were analyzed. We identified 11 patients who developed spinal epidural abscess (SEA). All of these had back pain; radicular signs occurred in seven patients and spinal cord compression in two patients. Magnetic resonance imaging revealed SEA in all 11 patients. SEA was iso- to hypointense on T1-weighted images and hyperintense on T2-weighted images relative to spinal cord. After gadolinium administration seven lesions showed characteristic rim enhancement while three showed minimal enhancement. No signs of diskitis or osteomyelitis were present, and the abscess was always localized to the posterior epidural space. Cultures were positive in all cases and revealed Staphylococcus epidermidis in eight and S. aureus in three. All patients were treated with intravenous antibiotics, and four had an additional decompressive laminectomy. Two patients died within 1 week of diagnosis from overwhelming septicemia despite apparently adequate antibiotic treatment. Within 4 weeks after diagnosis of SEA two patients died from widely metastatic disease, although infection may have contributed. One patient developed septicemia while receiving appropriate antibiotics and underwent emergency laminectomy. The neurological deficits recovered in all patients who survived the acute infectious episode. We conclude that patients with chronic epidural catheters for cancer pain require prompt neurological evaluation and magnetic resonance imaging when SEA is suspected. Early evaluation and treatment may lead to full recovery.

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.

The accumulation of topotecan in 9L glioma and in brain parenchyma with and without dexamethasone administration.

The accumulation of the topoisomerase I inhibitor topotecan in brain tumor as well as in brain around tumor (BAT) and normal brain following an intravenous bolus of topotecan of 0.5 mg/kg was investigated in rats bearing a 9L glioma. Also the influence of dexamethasone (Dex) on the uptake of topotecan was examined. Tumor, BAT and brain tissue as well as whole blood were collected at 1 h after an i.v. bolus of topotecan. Concentrations of total topotecan in tumor, BAT and brain were quantified with high-performance liquid chromatography (HPLC) and compared with concentrations in plasma of total topotecan. In brain tumor tissue the mean total topotecan concentration was 96 +/- 33 ng/g which was 20-fold higher than the accumulation of topotecan in normal brain tissue. In BAT intermediate concentrations of 13 +/- 4.9 ng/g were reached. Mean total topotecan concentration in plasma was 100 +/- 25 ng/ml. We did not find an influence of Dex on the uptake of topotecan in either tissue. We conclude that high tissue concentrations of topotecan can be reached in experimental brain tumors in rats. This observation may be useful in the design of clinical studies with topotecan.