Preradiation intracarotid cisplatin treatment of newly diagnosed anaplastic gliomas. The CNS Cancer Consortium.

PURPOSE: This phase II study was performed to assess the response of patients with newly diagnosed, untreated malignant gliomas (anaplastic astrocytoma [AA] and glioblastoma multiforme [GBM]) to intracarotid (IC) cisplatin. PATIENTS AND METHODS: Eligibility criteria included surgical intervention limited to biopsy only, measurable contrast-enhancing tumor, and unilateral tumor location within the vascular territory of one internal carotid artery. Patients were scheduled to receive four infusions of IC cisplatin (75 mg/m2 every 4 weeks) before beginning standard radiotherapy. Twenty-six patients were treated, and 22 were assessable for response. RESULTS: Ten patients (45%) showed a greater than 25% decrease in the enhancing tumor area before radiotherapy with stabilization or improvement of neurologic deficits, and three patients (14%) had a greater than 70% decrease in tumor area. The likelihood of response to IC cisplatin was not clearly linked to patient age, tumor histology, or pretreatment tumor size. Myelosuppression, nephrotoxicity, and ototoxicity were mild. Optic neuropathy occurred in one patient, seizures in two, and fatal postinfusion cerebral edema in one. CONCLUSION: This study design, which permits assessment of the drug sensitivity of the untreated glioma, has shown definite antitumor activity of IC cisplatin in newly diagnosed malignant glioma patients.

Randomized comparison of diaziquone and carmustine in the treatment of adults with anaplastic glioma.

PURPOSE: We conducted a phase III trial comparing intravenous (IV) diaziquone (AZQ) and carmustine (BCNU) as single agents in patients with cerebral anaplastic gliomas who had received surgery and radiotherapy. Its purpose was to compare the efficacy of AZQ with that of BCNU, the standard agent for brain tumor chemotherapy. PATIENTS AND METHODS: Randomization between the two regimens occurred 8 weeks after completion of radiotherapy. A total of 251 patients were randomized to receive either AZQ or BCNU, and there were no significant differences between the two treatment arms in any of the known prognostic variables, including age, histologic grade, and Karnofsky performance status (KPS). RESULTS: There was no significant difference in either time to tumor progression or survival between the two treatment arms. Age and histology were strong predictors of outcome, whereas KPS had relatively less effect. Three groups of patients with distinctly different outcomes could be identified: (1) older age (45+) and glioblastoma/gliosarcoma (GBM/GS) patients had a median survival of 37 weeks after randomization; (2) patients with either older age or GBM/GS had a median survival of 61 weeks; and (3) younger age (< 45) and non-GBM/GS (usually anaplastic astrocytoma) patients had a median survival of 147 weeks. Toxicity was primarily hematologic, although acute gastrointestinal toxicity and chronic pulmonary toxicity were more common with BCNU. Patients randomized to AZQ who had significant hematologic toxicity that required dose reduction after the first treatment cycle had significantly longer time to tumor progression and survival than those who did not require dose reduction (P = .011 and .016, respectively). CONCLUSION: There was no significant difference in efficacy between AZQ and BCNU in patients with anaplastic gliomas as tested in this study, although AZQ was somewhat better tolerated.

Steroid-induced weakness in patients with primary brain tumors.

Clinically significant steroid myopathy (SM) occurred in 23 (10.6%) of 216 adult patients with primary brain tumors who received 2 or more continuous weeks of daily dexamethasone therapy. SM occurred over a wide range of peak and cumulative doses of dexamethasone as well as a wide range of periods of continuous treatment. This was not an entirely random event, however, as two-thirds of the patients developed their weakness during the 9th through the 12th week of continuous dexamethasone treatment. The risk of developing SM was significantly lower in patients taking phenytoin than in patients who were not taking anticonvulsants. The only other patient or treatment factor associated with SM was a possible direct correlation with the appearance of a cushingoid body habitus. In this retrospective review, the occurrence of SM had a significant negative impact on the quality of life of all affected individuals. As expected, patients who tolerated a reduction in their steroid dose improved, while other patients suffered the combined effects of tumor progression and worsening myopathy. Substituting a nonfluorinated glucocorticoid for dexamethasone is probably advisable if neuro-oncology patients affected by SM cannot be weaned from the steroids.

The prognostic impact of prior low grade histology in patients with anaplastic gliomas: a case-control study.

At the time of recurrence, the majority of low-grade cerebral gliomas transform to a higher grade of histologic malignancy. The purpose of this study was to determine the survival outcome for patients whose anaplastic gliomas began as low-grade tumors compared with patients with de novo high-grade gliomas. Seventy-seven (11.5%) of 667 patients with anaplastic gliomas consecutively treated at the University of Alabama at Birmingham had histologically proven prior low-grade tumors. As a group, the patients with prior low-grade tumors would be expected to have a relatively favorable outcome, as they were younger and had a lower proportion of glioblastoma multiforme than the patients with de novo anaplastic gliomas. The provide a valid comparison, we performed a matched case-control study. We matched 68 patients from the prior low-grade group one-to-one with patients from de novo group for tumor histology, age, Karnofsky performance scores, and type of surgery, without knowledge of outcome. The two groups received comparable radiotherapy and chemotherapy. For the 68 patients with prior low-grade tumor, median actuarial survival from the time of diagnosis of malignant degeneration was 19.7 months and the 5-year survival rate was 22%, compared with 22.0 months and 28% for the 68 matched de novo patients. Kaplan-Meier survival curves for the two group did not significantly differ (p = 0.24 by logrank test). There were no significant survival differences between the patient subsets of prior low-grade versus de novo with glioblastoma, anaplastic astrocytoma, or anaplastic oligodendroglioma/mixed anaplastic glioma. The data indicate that the currently available treatment options, the survival outlook for patients with anaplastic gliomas, whose tumors arose from transformation of low-grade gliomas, is equivalent to the prognosis for patients with de novo anaplastic gliomas.

Antineuronal (anti-Ri) antibodies in a patient with steroid-responsive opsoclonus-myoclonus.

A 45-year-old woman developed opsoclonus, myoclonus, and severe truncal and gait ataxia. Serum and CSF contained IgG antibodies that appear to be identical to "anti-Ri" antibodies associated with paraneoplastic opsoclonus and ataxia. The patient had a fluctuating course with exacerbations that responded well to corticosteroids and later to cyclophosphamide. Her anti-Ri antibody titer has declined significantly but still remains high. After more than 3 years of follow-up, no neoplasm has been detected.

Neuronal antinuclear antibodies in a patient with Lambert-Eaton myasthenic syndrome and small-cell lung carcinoma.

A patient with small-cell lung carcinoma and the Lambert-Eaton myasthenic syndrome had circulating neuronal antinuclear antibodies. Serum stained the nuclei of all neurons in sections of human brain and identified a closely spaced group of 33-39 kDa proteins in immunoblots of human neuronal nuclei. These autoantibodies are indistinguishable from those recently identified in patients with paraneoplastic subacute sensory neuronopathy.

Paraneoplastic motor neuron disease and renal cell carcinoma: improvement after nephrectomy.

A 74-year-old man had a paraneoplastic motor neuron disease mimicking amyotrophic lateral sclerosis. He had an elevated erythrocyte sedimentation rate, other laboratory abnormalities, and a previously undiagnosed renal cell carcinoma. Four months after nephrectomy, his strength had improved and he had no fasciculations. Seven other patients with cancer and motor neuron disease improved or stabilized after tumor treatment. Even though it is rare, paraneoplastic motor neuron disease is important to diagnose because it may be treatable.

Novel chemotherapeutic approaches to brain tumors.

In reviewing the numerous investigational drug trials for patients with anaplastic gliomas over the past 20 years, it would be fair to say that there have been more than a few disappointments and that the real impact of many of these therapies on patients' duration and quality of survival has been minor at best. It is also fair to state that there has been progress in developing new types of chemotherapy and other agents, in devising new treatment strategies, and in gaining a deeper understanding of the problems that must be overcome to treat patients with anaplastic gliomas successfully. The past several years have seen the realization that oligodendroglioma, primary CNS lymphoma, and medulloblastoma are sensitive to chemotherapy treatments. It is hoped that future studies will delineate better the optimal use of chemotherapy for these tumors.

Neurologic paraneoplastic syndromes.

Several neurologic paraneoplastic disorders are believed to be caused by an autoimmune reaction against antigen(s) co-expressed by tumour cells and neurons. Of the paraneoplastic syndromes, the evidence for an autoimmune etiology is strongest for the Lambert-Eaton myasthenic syndrome, in which autoantibodies downregulate voltage-gated calcium channels at the presynaptic nerve terminal. For other syndromes, including cerebellar degeneration, multifocal encephalomyelitis, sensory neuronopathy, limbic encephalitis, opsoclonus-myoclonus, stiff person syndrome, and retinal degeneration, the autoimmune theory is supported by the presence of specific antineuronal antibodies. These antibodies serve as a useful diagnostic tool, but their actual role in causing neuronal injury and clinical disease remains unclear. Further understanding of immunopathogenesis awaits successful experimental models. Among different syndromes, a varied proportion of patients shows neurologic improvement with immunosuppressive treatments; it is likely that many patients have already suffered irreversible neuronal injury at the time of diagnosis.

Systemic beta-interferon therapy for recurrent gliomas: a brief report.

Recombinant beta-interferon in escalating dosages was administered intravenously three times weekly to seven patients with recurrent gliomas. No evidence of response was seen in any patient, either on neurological examination or by computerized tomography (CT). However, stabilization of tumor volume, assessed from contrast-enhanced CT scans, occurred for 8 to 26 weeks in three patients. Immediate progression of disease despite treatment occurred in four patients.

Intracarotid cisplatin chemotherapy for recurrent gliomas.

Forty patients with recurrent gliomas were treated with monthly intra-arterial infusions of cisplatin. Of the 35 evaluable patients, 12 (34%) responded with computerized tomography (CT) evidence of a decrease in tumor size; in 14 (40%) the tumor stabilized on CT scans, and in nine (26%) the disease progressed. The median survival period was 35.0 weeks for the responders and 27.5 weeks for all 35 patients. The primary toxicities were renal (reversible alterations in creatinine clearance), otological (severe hearing loss in one patient), and likely neurotoxicity in one patient who had received bilateral infusions following contralateral tumor progression. The authors are now using this form of regional chemotherapy sequentially before and following radiotherapy in newly diagnosed cases.

Central nervous system injury by therapeutic irradiation.

Therapeutic irradiation is the cornerstone of therapy for many neoplastic diseases but, at the same time, is capable of causing devastating injury to the brain and spinal cord. Thoughtful planning and meticulous execution of radiotherapy reduces the risk of neurotoxicity, but there remains a small and unavoidable risk of serious injury if an effective radiation dose is to be given. It is hoped that better understanding of the mechanisms of radiation injury will lead to safer yet equally effective therapies.

The remote effects of cancer on the nervous system.

Paraneoplastic syndromes are heterogeneous in their clinical presentations and their associations with particular tumor types and are an important part of the differential diagnosis of neurologic dysfunction in patients with or without a known neoplasm. Patients presenting with one of the more distinctive syndromes, such as subacute cerebellar degeneration, opsoclonus-myoclonus, and the Lambert-Eaton syndrome, should undergo a careful evaluation for the presence of an occult malignancy. The importance of looking for a monoclonal gammopathy in patients with certain polyneuropathies and motor neuron syndromes is also becoming clear. At this time, an autoimmune pathogenesis has been clearly demonstrated only for the Lambert-Eaton syndrome. Specific autoantibodies in other syndromes appear to be valuable diagnostic markers for the presence of an underlying malignancy, but the actual role of these antibodies in producing tissue damage and clinical disease is still unknown.

Paraneoplastic neuromuscular disorders-part I.

Paraneoplastic disorders ace uncommon but clinically important complications of a large number of neoplasms. Most paraneoplastic syndromes are thought to have an autoimmune etiology, although the weight of evidence supporting autoimmunity vanes among syndromes. Prompt diagnosis of a paraneoplastic disorder can increase the likelihood of a favorable neurologic and oncologic outcome. This article reviews the; clinical features, autoimmune aspects, diagnostic approach, and treatment options for patients with paraneoplastic disorders affecting the spinal cord, motor neurons, neuromuscular junction, and muscle. Part 2 of this review, to be published in the next issue, will discuss the paraneoplastic neuropathies.

Paraneoplastic neuromuscular disorders-part 2.

Paraneoplastic neuropathies are a clinically diverse group of disorders associated with a variety of neoplasms. This article reviews the clinical features, autoimmune aspects, diagnostic approach, and treatment options for patients with paraneoplastic neuropathies.

Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis.

OBJECTIVE: To report the presence of microscopic neoplasms of the testis in men with anti-Ma2-associated encephalitis (Ma2-encephalitis) and to discuss the clinical implications. METHODS: Orchiectomy specimens were examined using immunohistochemistry with Ma2 and Oct4 antibodies. RESULTS: Among 25 patients with Ma2-encephalitis younger than 50 years, 19 had germ-cell tumors, and 6 had no evidence of cancer. These 6 patients underwent orchiectomy because they fulfilled five criteria: 1) demonstration of anti-Ma2 antibodies in association with MRI or clinical features compatible with Ma2-encephalitis, 2) life-threatening or progressive neurologic deficits, 3) age < 50 years, 4) absence of other tumors, and 5) new testicular enlargement or risk factors for germ-cell tumors, mainly cryptorchidism or ultrasound evidence of testicular microcalcifications. All orchiectomy specimens showed intratubular-germ cell neoplasms unclassified type (IGCNU) and other abnormalities including microcalcifications, atrophy, fibrosis, inflammatory infiltrates, or hypospermatogenesis. Ma2 was expressed by neoplastic cells in three of three patients examined. Even though most patients had severe neurologic deficits at the time of orchiectomy (median progression of symptoms, 10 months), 4 had partial improvement and prolonged stabilization (8 to 84 months, median 22.5 months) and two did not improve after the procedure. CONCLUSIONS: In young men with Ma2-encephalitis, 1) the disorder should be attributed to a germ-cell neoplasm of the testis unless another Ma2-expressing tumor is found, 2) negative tumor markers, ultrasound, body CT, or PET do not exclude an intratubular germ-cell neoplasm of the testis, and 3) if no tumor is found, the presence of the five indicated criteria should prompt consideration of orchiectomy.

Antiamphiphysin antibodies with small-cell lung carcinoma and paraneoplastic encephalomyelitis.

Paraneoplastic encephalomyelitis developed as the presenting feature of small-cell lung carcinoma in 3 patients. Two patients with paraneoplastic encephalomyelitis manifested predominantly as subacute sensory neuronopathy did not improve after prednisone treatment and chemotherapy. The third patient had severe axial and limb rigidity and myoclonus, which partially improved after chemotherapy and treatment with intravenous immunoglobulin and prednisone. Serum from each patient immunocytochemically stained the neuropil and to a lesser degree the neuronal cytoplasm in human cerebral and cerebellar cortex. On immunoblots of human neuronal extracts, each patient's serum contained high-titer IgG antibodies reacting with a protein band of apparent molecular mass 125 kd. This autoantibody pattern is indistinguishable from antibodies recently identified in several women with breast carcinoma and stiff-man syndrome. Screening of a human brain complementary DNA expression library with patient serum yielded clones whose sequence is identical to that of the synaptic vesicle-related protein amphiphysin. Reverse transcriptase-polymerase chain reaction demonstrated expression of amphiphysin in 8 of 10 small-cell lung carcinomas and in 5 of 14 breast carcinomas. These observations highlight the clinical and serological heterogeneity of paraneoplastic central nervous system disorders: Patients with a given clinical syndrome may have different antineuronal antibodies, and patients with a given autoantibody specificity have differing clinical presentations.

Autoimmune central nervous system paraneoplastic disorders: mechanisms, diagnosis, and therapeutic options.

The presence of specific antineuronal antibodies in some patients with paraneoplastic central nervous system (CNS) disorders supports the theory that these syndromes have an autoimmune etiology. The anti-Purkinje cell antibodies (APCAs) in some patients with paraneoplastic cerebellar degeneration and ovarian or breast carcinomas stain the cytoplasm of Purkinje cells. APCAs react with several distinct neuronal protein autoantigens, including proteins featuring a "leucine zipper" sequence motif, which suggests that they function in regulating DNA transcription. Type 1 anti-neuronal nuclear antibodies (ANNA-1) associated with paraneoplastic encephalomyelitis and small-cell lung carcinoma stain the nucleus and cytoplasm of all neurons, and react with a group of 35- to 40-kd proteins in neuronal immunoblots. The protein targets of ANNA-1 belong to a family of RNA-binding proteins that probably regulate posttranscriptional processing of RNA. Type 2 anti-neuronal nuclear antibodies (ANNA-2) associated with paraneoplastic opsoclonus-ataxia and breast carcinoma also produce a panneuronal immunocytochemical staining pattern, but react with a group of higher-molecular-mass proteins (53-61 kd and 79-84 kd); these autoantigens probably also function as RNA-binding proteins. Several patients with paraneoplastic stiff-man syndrome have antibodies against a 128-kd synaptic protein. These antineuronal antibodies are highly specific (but not infallible) diagnostic markers for the presence of a neoplasm in patients who present with neurological dysfunction. The actual role of these autoantibodies in the pathogenesis of neuronal damage and clinical disease remains to be determined. Current management options for patients with CNS neurological paraneoplastic syndromes are very limited. Only a small minority of patients with paraneoplastic cerebellar degeneration or encephalomyelitis show significant neurological improvement after successful tumor treatment and/or immunosuppressive treatments, while patients with paraneoplastic opsoclonus or stiff-man syndrome have a somewhat better outlook.