The association of pre-treatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme.

Neutrophil-lymphocyte ratio (NLR) is a marker of systemic inflammatory response and its elevation has recently been shown to be a poor prognostic factor in many malignancies including colon, prostate and bladder cancer. The primary aim of this study was to assess the prognostic impact of NLR in a clinically annotated cohort of patients with glioblastoma multiforme (GBM). We hypothesised that elevated NLR would be associated with worse prognosis. Between 2004 and 2009, 137 patients had surgery for GBM and were assessed for consideration of adjuvant therapy at our institution. Of these, 84 patients with an evaluable pre-corticosteroid full blood count result were identified and included in the final analysis. Median overall survival was 9.3 months (range 0.7-82.1). On univariate analysis, age >65 years, gender, ECOG performance status ≥2, frontal tumour, extent of surgical resection, completion of adjuvant chemoradiation protocol and NLR > 4 were significantly correlated with overall survival. Patients with NLR > 4, had a worse median overall survival at 7.5 months versus 11.2 months in patients with NLR ≤ 4 (hazard ratio 1.6, 95 % CI 1.00-2.52, p = 0.048). On multivariate analysis NLR > 4 remained an independent prognostic indicator for poor outcome. These data are an important reminder of the potential relevance of host immunity in GBM. In our cohort, NLR > 4 conferred a worse prognosis independent of other well established prognostic factors. If validated in other cohorts NLR may prove to be a useful addition in predicting prognosis in GBM patients. The demonstration that host immunity plays a role in GBM biology suggests that investigation of emerging therapies which modulate host immune response are warranted in this disease.

Phase I trial of sorafenib in patients with recurrent or progressive malignant glioma.

Sorafenib is an inhibitor of multiple kinases that has demonstrated antiproliferative and antiangiogenic activity in a number of in vitro and in vivo model systems. A phase I study was conducted to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Sorafenib was given orally, twice a day (BID), continuously in 28-day cycles. The dose was escalated in 2 groups of patients stratified by use of enzyme-inducing antiseizure drugs (± EIASDs). Dose-limiting toxicity (DLT) was defined as any grades 3-4 nonhematological toxicity, grade 4 hematological toxicity, and febrile neutropenia. The number of evaluable patients enrolled in the +EIASD and -EIASD arms were 23 and 24, respectively. DLTs were predominantly dermatological and gastrointestinal effects, as observed in previous clinical trials of sorafenib. The MTD was 600 mg BID for patients receiving EIASDs and 800 mg BID for those who were not. The plasma pharmacokinetics of sorafenib were not significantly affected by the concurrent administration of EIASDs. The MTD of sorafenib given orally BID on a continuous basis was established as 600 mg BID in patients with malignant glioma who were concurrently receiving EIASDs and 800 mg BID in those who were not. Further evaluation is warranted of sorafenib at the recommended MTD against recurrent or progressive malignant glioma in combination with other molecularly targeted drugs or in the newly diagnosed setting concurrent with chemoradiation.

Survival of patients with newly diagnosed glioblastoma multiforme treated with RSR13 and radiotherapy: results of a phase II new approaches to brain tumor therapy CNS consortium safety and efficacy study.

PURPOSE: The objectives of this phase II study were to determine survival, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 2,4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid (RSR13, efaproxiral) 100 mg/kg per day administered with standard cranial radiotherapy (RT) for the treatment of glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin, is a radiation-enhancing agent that noncovalently binds to hemoglobin, reduces oxygen-binding affinity, and increases oxygen unloading to hypoxic tissue. PATIENTS AND METHODS: Fifty patients with newly diagnosed GBM (Karnofsky performance status >or= 60) were enrolled onto this multicenter phase II study. Patients received daily RSR13 100 mg/kg intravenously infused for 30 minutes immediately before cranial RT (60 Gy in 30 fractions). Supplemental oxygen was given during RSR13 infusion and continued until after the RT treatment was completed. RT was given within 30 minutes of the end of RSR13 infusion. PK and PD determinations were performed. RESULTS: The median survival for the RSR13-treated patients was 12.3 months with 1-year and 18-month survival rates of 54% and 24%, respectively. Twenty-four percent of patients had greater than grade 2 toxicity, which was generally transient and self-limited. A significant PD effect on hemoglobin-oxygen binding affinity was demonstrated for most patients. CONCLUSION: RSR13 (100 mg/kg) administered immediately before cranial RT is well tolerated and is pharmacodynamically active. Median survival in excess of 1 year is favorable.

Toxicity, efficacy, and pharmacology of suramin in adults with recurrent high-grade gliomas.

PURPOSE: To determine the toxicity, efficacy, and pharmacology of suramin in patients with recurrent or progressive recurrent high-grade gliomas. PATIENTS AND METHODS: Fifty adults were to receive suramin. However, if no responses were seen in the first ten patients, the study was to be terminated. A total of 12 patients were enrolled onto this trial. Ten patients had glioblastoma multiforme, and 11 had received prior nitrosoureas. RESULTS: Drug-related toxicities were modest and reversible. Three patients developed grade 3 to 4 neutropenia, constipation, diarrhea, or nausea. No CNS bleeding was observed. Median time to progression was 55 days (range, 17 to 242 days) and median survival was 191 days (range, 42 to 811 days). No partial or complete responses were seen at 12 weeks. However, the clinical outcome of three patients suggests that evidence of suramin activity may be delayed. One patient who "progressed" after 12 weeks of suramin had a subsequent marked reduction in tumor size and has maintained an excellent partial response for over 2 years without other therapy. Two others had disease stabilization and lived for 16 and 27 months. Pharmacokinetics from 11 patients revealed that all reached target suramin concentrations. CONCLUSION: This study demonstrates that suramin is well tolerated by patients with recurrent high-grade gliomas and may have efficacy in this disease. Its pharmacology seems unaffected by anticonvulsants. As a result of this data, suramin and radiation are now being administered concurrently to patients with newly diagnosed glioblastoma multiforme, with survival as the primary outcome.

Feasibility of quantitative pain assessment in outpatient oncology practice.

PURPOSE: Although physicians view failure to assess pain systematically as the most important barrier to outpatient cancer pain management, little is known about pain assessment in this setting. We sought to determine whether pain is routinely assessed and whether routine quantitative pain assessment is feasible in a busy outpatient oncology practice. PATIENTS AND METHODS: We conducted a pre- and postintervention chart review of 520 randomly selected medical and radiation oncology patient visits at a community hospital-based private outpatient practice. The intervention consisted of training health assistants (HAs) to measure and document patient pain scores by using a visual analog scale. The main outcome measures included HA documentation of patient pain scores, quantitative and qualitative mention of pain in the physician note, and analgesic treatment before and after the intervention. RESULTS: After the intervention, HA documentation of pain scores increased from 1% to 75.6% (P < .0001). Physician documentation increased from 0% to 4.8% for quantitative documentation (P < .01), and from 60.0% to 68.3% for qualitative documentation (not significant). Of all the patients, 23.1% reported significant pain. Subgroups with greater pain included patients actively receiving radiation treatments and patients with lung cancer. Of patients with significant pain, 28.2% had no mention of pain in the physician note and 47.9% had no documented analgesic treatment. CONCLUSION: Quantitative pain assessment was virtually absent before our intervention but easily implemented and sustained in a busy outpatient oncology practice. Pain score collection identified a high prevalence of pain, patient subgroups at risk for pain, and a significant proportion of patients with pain that was neither evaluated nor treated by their oncologists.

Lack of efficacy of 9-aminocamptothecin in adults with newly diagnosed glioblastoma multiforme and recurrent high-grade astrocytoma. NABTT CNS Consortium.

9-Aminocamptothecin (9-AC) was administered as a 72-h i.v. infusion every 2 weeks to a total of 99 adults with high-grade astrocytomas. Fifty-one patients with newly diagnosed glioblastoma multiforme received 9-AC treatment prior to radiation therapy and 48 patients with high-grade astrocytomas were treated at the time of tumor recurrence. Upon entrance into these research protocols, all patients had measurable disease that was evaluated on a monthly basis with volumetric CT or MRI scans. A partial response was defined by > or =50% reduction in the contrast enhancing volume on stable or decreasing doses of glucocorticoids. The study specified that all apparent responders would have central review of their radiologic studies and histopathology. The initial patients treated with 9-AC were also receiving anticonvulsants and were noted to have minimal myelosuppression with this chemotherapy. Thus, 9-AC doses were escalated from the previously reported maximum tolerated dose (MTD) of 850 microg/m2/24 h. We then established new MTDs for patients receiving enzyme-inducing anticonvulsants. We defined these MTDs to be 1,776 microg/m2/24 h for newly diagnosed, previously untreated patients and 1,611 microg/m2/24 h for patients with recurrent disease. Twenty-two patients with newly diagnosed glioblastoma multiforme received 9-AC at doses > or =1,776 microg/m2/24 h. Of these, 18 had evaluable disease on central review, and 0 of 18 (0%) demonstrated a partial or complete response. Twenty-one patients with recurrent high-grade astrocytomas were treated at 1,611 microg/m2/24 h; 20 had evaluable disease and 0 of 20 (0%) had a partial or complete response. Thus, the overall response rate in the 38 evaluable patients treated at the MTD was 0 of 38 (0%). Furthermore, of the 51 evaluable patients who were treated at doses less than the MTD, only one partial response was observed, yielding an overall response rate of 2%. Evidence of drug failure was rapid with tumor progression in one-half of patients after 2 drug cycles. 9-AC lacks evidence of substantial activity in patients with newly diagnosed or recurrent high-grade astrocytomas.

Phase I trial to determine the safety, pharmacodynamics, and pharmacokinetics of RSR13, a novel radioenhancer, in newly diagnosed glioblastoma multiforme.

PURPOSE: To determine the safety, pharmacokinetics, and pharmacodynamic effect of 2-[4-(3, 5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylproprionic++ + acid (RSR13) 100 mg/kg/d with radiation therapy (RT) for glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin (HgB), is a novel radioenhancing agent that noncovalently binds to HgB, thereby reducing oxygen binding affinity and increasing tissue oxygen release to hypoxic tissues. PATIENTS AND METHODS: In this multi-institutional, dose frequency-seeking trial, 19 adult patients with newly diagnosed GBM received RSR13 100 mg/kg every other day or daily along with cranial RT (60 Gy/30 fractions). RSR13 was given over 1 hour by central venous access with 4 L/min of O(2 )by nasal cannula, followed by RT within 30 minutes. Pharmacokinetic (PK) and pharmacodynamic (PD) determinations were performed. The PD end point was shift in P50, the oxygen half-saturation pressure of HgB. RESULTS: Grade 3 dose-limiting toxicity occurred in none of the patients with every-other-day dosing and in two of the 10 patients with daily dosing. Grade 2 or greater toxicity occurred in three out of nine and six out of 10, respectively. PK and PD data demonstrate that a substantial PD effect was reliably achieved, that PD effect was related to RBC RSR13 concentration, and that there was no significant drug accumulation even with daily dosing. The mean shift in P50 was 9.24 +/- 2.6 mmHg (a 34% increase from baseline), which indicates a substantial increase in tendency toward oxygen unloading. CONCLUSION: Daily RSR13 (100 mg/kg) during cranial RT is well tolerated and achieves the desired PD end point. A phase II trial of daily RSR13 for newly diagnosed malignant glioma is currently accruing patients within the New Approaches to Brain Tumor Therapy Central Nervous System Consortium to determine survival outcome.

Leptomeningeal carcinomatosis.

Leptomeningeal carcinomatosis occurs in approximately 5% of patients with cancer. This disorder is being diagnosed with increasing frequency as patients live longer and as neuro-imaging studies improve. The most common cancers to involve the leptomeninges are breast cancer, lung cancer, and melanomas. Tumour cells reach the leptominges by hematogenous spread or by direct extension from pre-existing lesions and are then disseminated throughout the neuroaxis by the flow of the cerebrospinal fluid. Patients present with signs and symptoms from injury to nerves that traverse the subarachnoid space, direct tumour invasion into the brain or spinal cord, alterations in blood supply to the nervous system, obstruction of normal cerebrospinal fluid (CSF) flow pathways, or general interference with brain function. The diagnosis is most commonly made by lumbar puncture although the CSF cytology is persistently negative in about 10% of patients with leptomeningeal carcinomatosis. Radiologic studies may reveal subarachnoid masses, diffuse contrast enhancement of the meninges, or hydrocephalus without a mass lesion. Without treatment, the median survival of patients with this disorder is 4-6 weeks and death occurs from progressive neurologic dysfunction. Early diagnosis and therapy is critical to preserving neurologic function. Radiation therapy to symptomatic sites and disease visible on neuroimaging studies and intrathecal chemotherapy increases the median survival to 3-6 months. The major favorable prognostic factors include excellent performance status, absence of serious fixed neurologic deficits, normal CSF flow scans, and absent or responsive systemic tumour. Aggressive therapy for this disorder is often accompanied by a necrotizing leukoencephalopathy which becomes symptomatic months after treatment with radiation and intrathecal methotrexate. As currently available therapies are toxic and provide limited benefits, novel approaches are being studied. Further information on the mechanisms of neurotoxicity from antineoplastic agents is critical to providing better outcomes for this increasing common complication of cancer.

Central nervous system cancers in first-degree relatives and spouses.

The increasing incidence of high-grade astrocytomas in the elderly, the associations between these malignancies and environmental factors, and case reports suggesting a familial component to these tumors prompted this study of primary brain tumors in first-degree relatives and spouses. This article describes the findings in 154 patients from 72 consecutive families accrued to the National Familial Brain Tumor Registry from 1991 to 1996. Medical records, pathological slides, and demographic data were reviewed for each identified case. Parents and children were affected in 33 families, siblings in 27, and husbands and wives in 12. The median age of the patients was 50.5 years, 55% were men, and 70% had high-grade astrocytomas. The pattern of tumor occurrence in this population is different from most familial cancers. These tumors did not involve multiple generations or occur at an unusually early age. In addition, the cases tended to cluster in time, with 47% of the familial and 50% of the husband-wife cases occurring within a 5-year span. In families with an affected parent and child, the diagnosis was made in the child before the parent in 45% of the cases. Prognostic factors for these patients appear to be similar to that reported for typical high-grade astrocytomas. This study demonstrates that primary brain tumors can occur in families without a known predisposing hereditary disease. The ages of these patients, the clustering of cases in time, the few affected generations, and the occurrence of brain tumors in spouses suggest that environmental exposures may be important in the etiology of this neoplasm. Although this hypothesis requires further study, it is plausible given the known associations in animals and humans between high-grade astrocytomas and radiation, toxic chemicals, and viruses.

The effects of sequential versus concurrent chemotherapy and radiotherapy on survival and toxicity in patients with newly diagnosed high-grade astrocytoma.

PURPOSE: To determine the effects of sequential versus concurrent administration of cranial radiotherapy and cisplatin/carmustine (BCNU) chemotherapy on survival and toxicity in newly diagnosed high-grade astrocytomas. METHODS AND MATERIALS: From 1988 to 1996, 101 patients were treated on 2 therapeutic protocols for malignant glioma that used the identical chemotherapy regimen but differed in the timing of cranial radiotherapy. The eligibility criteria for the 2 protocols were identical. In the first protocol (1988-1991, 52 patients), cisplatin 120 mg/BCNU 120 mg i.v. over 72 h, was given for 3 monthly cycles prior to cranial radiotherapy. After a response rate of 42%, with a median survival of 13 months was achieved with this sequential regimen, a successor protocol (1992-1996, 49 patients) was developed in which cranial radiotherapy began concurrently with the start of the identical chemotherapy regimen. Chemotherapy was delayed but not discontinued if prolonged grade III/IV hematologic toxicity was experienced, but protocol therapy was discontinued if disease progression or thromboembolic events occurred. Survival outcome and hematologic toxicity were compared for the patients treated on these protocols. RESULTS: Seventy-seven percent of sequentially-treated patients and 68% of concurrently-treated patients completed all planned therapy. Kaplan-Meier survival was similar to concurrent or sequential administration of chemotherapy and radiotherapy (median 12.8 months vs. 13.8 months, respectively). Hematologic toxicity was significantly less in sequentially- versus concurrently-treated patients, with median nadir per cycle (2.9 vs. 1.8 x 10(3)/mm3) (p < 0.001), and incidence of grade 3/4 leukopenia 40% versus 77% (p = 0.002). There was also an increase in platelet transfusion requirements in concurrently-treated patients, but no significant worsening of anemia. We postulate that the worsened leukopenia results from the effects of concurrent radiotherapy on circulating stem cells. CONCLUSION: Concurrent radiotherapy with this regimen of cisplatin and BCNU chemotherapy did not improve survival, but did increase hematologic toxicity. Therefore, we do not recommend further testing of the concurrent regimen, whereas the sequential regimen is currently under evaluation in a Phase III trial of the Eastern Cooperative Oncology Group and the Southwest Oncology Group. In addition, these studies demonstrate that relatively small radiotherapy fields can deliver a dose to circulating stem cells sufficient to worsen the hematologic toxicity of concurrent myelosuppressive chemotherapy, a phenomena which should be considered in the design of combined modality protocols for other body sites.

Cancer pain management in developing countries: a mosaic of complex issues resulting in inadequate analgesia.

Cancer pain is often undertreated even in developed countries with abundant resources and easy access to oral, parenteral, and transdermal opioids. The problems in developing nations are more complex, and as a result, these medications are not available to the vast majority of patients in Latin and South America, Eastern Europe, Asia, and Africa. Some of the reasons for this are reviewed, with India cited as a case example. In spite of serious efforts by the World Health Organization and other bodies to make oral opioids available and to educate government officials and physicians, little progress has been made in relieving pain in cancer patients in the developing world. Novel approaches that address fundamental concerns regarding opioid availability in these countries are desperately needed. One such approach, which is currently under development, is presented in this manuscript. This has the potential to make opioids available to patients in rural areas, improve compliance in the poorly educated patient, reduce the number of follow-up visits necessary for medication refills, and reduce the risk that opioids will be diverted to illicit channels. The potential for relieving cancer pain and the magnitude of this problem worldwide make it imperative that innovative approaches be tailored to the complex social issues and limited resources common to developing nations.

Increased 9-aminocamptothecin dose requirements in patients on anticonvulsants. NABTT CNS Consortium. The New Approaches to Brain Tumor Therapy.

BACKGROUND: High grade astrocytomas remain uniformly fatal despite aggressive surgery and radiotherapy. As existing chemotherapeutic agents are of limited benefit, clinical trials are underway to screen new drugs, such as 9-aminocamptothecin (9-AC), for activity in high grade astrocytomas. PURPOSE: This study was designed to estimate the efficacy of 9-AC in patients with newly diagnosed glioblastoma multiforme and recurrent high grade astrocytomas. The planned dose of 9-AC for this trial was 850 microg/m2 per 24 h as a 72-h continuous intravenous infusion every 2 weeks. This was the maximum tolerated dose (MTD) on this schedule in multiple phase I studies in patients with systemic malignancies. However, we found this dose subtherapeutic in our patient population. As a result, the purpose of the study was altered to determine the MTD. METHODS: A group of 32 patients were studied using 850 microg/m2 per 24 h with a provision to escalate to 1000 microg/m2 per 24 h if the first three cycles of 9-AC were without significant hematologic toxicity. Once it was determined that myelosuppression did not occur in patients on anticonvulsants, dose escalations were initiated using the continual reassessment method. Dose escalations were conducted independently in newly diagnosed and recurrent patients and in those taking and not taking hepatic enzyme-inducing anticonvulsants. Pharmacologic studies were conducted during the first cycle of 9-AC. Toxicity was determined using the NCI common toxicity criteria and efficacy was assessed using serial volumetric brain scans. RESULTS: 9-AC was administered to 59 patients, 31 with newly diagnosed glioblastoma multiforme and 28 with recurrent high grade astrocytomas. No grade III-IV myelosuppression was noted in the 29 patients (128 cycles) on phenytoin, carbamazepine, phenobarbital, and/ or valproic acid who received 850 microg/m2 per 24 h. In contrast, two of three patients (five cycles) who were not taking anticonvulsants developed grade IV myelosuppression. Steady-state total 9-AC plasma levels were lower in patients on anticonvulsants (median 25.3 nM) than in patients who were not taking anticonvulsants (median 76.5 nM). Dose escalations performed in 27 additional patients determined the MTD in patients taking anticonvulsants to be 1776 microg/m2 per 24 h for patients with newly diagnosed tumors and 1611 microg/m2 per 24 h for patients with recurrent disease. CONCLUSIONS: We describe a new and unexpected drug interaction between 9-AC and anticonvulsants. This is similar to recent findings with paclitaxel, and suggests that higher than "usual" doses of some chemotherapeutic agents are required in patients on anticonvulsants. Prospectively defined dose escalations and pharmacologic studies are essential for the careful evaluation of new chemotherapeutic agents in patients with brain tumors.

Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New Approaches to Brain Tumor Therapy Central Nervous System Consortium.

PURPOSE: The purpose of this study was to determine the response rate of paclitaxel administered at maximal tolerated doses (MTD) in patients with newly diagnosed glioblastoma multiform. PATIENTS AND METHODS: All patients in this multicenter study were 45 years or older and had measurable residual tumor on postoperative MRI scans. Up to 3 cycles of paclitaxel were administered as a continuous 96-hour intravenous infusion prior to radiation, provided that the tumor did not enlarge on serial MRIs. The initial 10 patients were treated with the previously recommended phase II dose of 140 mg/m2. Less than anticipated toxicity led to the development of a phase I/II study in 24 patients in which paclitaxel doses were escalated separately in patients receiving (+EIAED) or not receiving (-EIAED), concomitant enzyme-inducing antiepileptic drugs. Paclitaxel plasma steady-state concentrations (Css) were measured during the first cycle of chemotherapy. Response was the primary efficacy endpoint for this study, although survival was also assessed. RESULTS: The MTD was 140 mg/m2 in the -EIAED, and 200 mg/m2 in the +EIAED patient groups. The mean Css for the -EIAED patients treated at 140 mg/m2 was 38 nM, whereas the mean Css for +EIAED patients were 17 nm at 140 mg/m2, 27 nM at 175 mg/m2, 46 nM at 200 mg/m2, and 51 nM at 230 mg/m2. One patient, who had a verified partial response, had his diagnosis changed to an anaplastic oligodendroglioma on subsequent central neuropathologic review. None of the 15 assessable glioblastoma patients treated at or above the MTD doses showed a radiographic response to paclitaxel. The median survival of eligible patients on this protocol was 355 days (95% CI, 255 to 485 days), which is similar to the survival of comparable patients treated with conventional therapy. CONCLUSIONS: These results suggest that (1) paclitaxel given as a 96-hour infusion at the MTD has minimal activity in patients with untreated glioblastoma, (2) the concomitant administration of EIAEDs alters the pharmacology of paclitaxel, resulting in a lower Css, reduced systemic toxicity, and higher dose requirements, (3) this study design, in which a new agent is given prior to radiation therapy (with serial monitoring of MRI), did not adversely affect survival in this patient population.

Phase II study of continuous infusion carmustine and cisplatin followed by cranial irradiation in adults with newly diagnosed high-grade astrocytoma.

PURPOSE: To evaluate the activity and toxicity of carmustine (BCNU) and cisplatin administered as a 72-hour continuous intravenous infusion before radiation in adults with newly diagnosed high-grade astrocytomas. PATIENTS AND METHODS: Fifty-two patients with a Karnofsky performance status greater than 60 and no prior antineoplastic therapy entered this protocol. The median age of the patients was 55 years. Eighty-eight percent had glioblastoma multiforme and 12% had anaplastic astrocytomas. BCNU (40 mg/m2/d) and cisplatin (40 mg/m2/d) were administered concurrently as a 72-hour infusion every 3 to 4 weeks. Radiation was begun 4 weeks after the third cycle of chemotherapy or earlier for progressive disease. Responses required a > or = 50% reduction in contrast-enhancing volume. RESULTS: Forty patients (77%) completed three chemotherapy infusions, five (10%) received two infusions, and seven (13%) received only one. Fifty-one patients completed radiation. Seventeen (42%) patients with measurable disease had a partial response (PR) to chemotherapy, 23 (53%) had stable disease (SD), and two (4%) had progressive disease (PD) on chemotherapy. The median survival time for all patients was 13 months. Survival rates at 1, 2, 3, and 5 years were 62%, 19%, 12%, and 5%, respectively. Grade III to IV leukopenia occurred in 32% of patients; 63% received platelet transfusions and 58% required RBCs. Neutropenic fevers were rare and no intracranial hemorrhages or treatment-related deaths were noted. Nausea, vomiting, peripheral neuropathy, hearing loss, and thromboembolic events were relatively common. CONCLUSION: This chemotherapy regimen appears to have significant activity and may prolong survival in adults with newly diagnosed high-grade astrocytoma.

Interstitial fluid flow along white matter tracts: a potentially important mechanism for the dissemination of primary brain tumors.

High grade astrocytomas remain incurable even though these tumors often appear localized on modern imaging studies, rarely metastasize to systemic sites, and can be aggressively treated with surgery and radiation therapy. Recent data suggest that the dissemination of astrocytoma cells along white matter tracts to distant regions of the brain may be responsible for the poor survival of these patients and the limited impact of local therapies. Movement of astrocytoma cells along these white matter tracts can be active or passive in nature. To study the potential for tumor dissemination by bulk flow of interstitial fluid resulting from peritumoral edema. 20 microL of tritiated inulin, Evans Blue, and rat albumin were injected stereotactically into the right frontal lobe and the left temporal lobe at the gray-white matter junction in Sprague-Dawley rats. Six hours later, the rats were sacrificed and the brains were removed, frozen and prepared for quantitative autoradiography and histologic analysis. Interstitial flow rates were calculated from the autoradiographs, and flow pathways were determined from the movement of Evans Blue, inulin and histologic data. In each animal injected in the frontal lobe, Evans Blue and inulin were primarily confined to large ipsilateral white matter tracts and extended from the frontal injection site to the occipital lobe. The average interstitial fluid flow rate in the association fibers of the external capsule was 0.86 mm/hr. In contrast, the animals receiving temporal lobe injections had Evans Blue and inulin confined to the temporal lobe. The average interstitial fluid flow rate in the white matter tracts of the temporal lobe was 0.61 mm/hr. The rapid and preferential flow of interstitial fluid along white matter tracts and the differences in the clearance of extracellular fluid observed between the frontal and temporal lobes may have important clinical implications. These data suggest that aggressive treatment of peritumoral edema, expansion of radiotherapy ports, and consideration of the location of the tumor in treatment planning may improve therapeutic outcomes for some patients. An improved understanding of the mechanisms of tumor dissemination is crucial to designing more effective therapeutic approaches for patients with this devastating malignancy.

Neoplastic meningitis following surgical resection of isolated cerebellar metastasis: a potentially preventable complication.

Neoplastic meningitis (NM) occurs in approximately 8% of all cancer patients. To confirm a clinical impression that NM is relatively common in patients who undergo surgical resection of an isolated cerebellar metastasis (ICM), a retrospective study was performed. All patients who underwent a surgical resection of an isolated CNS metastasis at The Johns Hopkins Hospital between January 1991 and June 1993 were identified. Their charts, laboratory and pathologic data, radiologic studies, survival and cause of death were reviewed. A total of 66 patients were identified fifty-five patients underwent a surgical resection of a supratentorial metastasis while 11 patients (6 females and 5 males) underwent a surgical resection of an isolated cerebellar metastasis. The ages of patients with cerebellar metastases ranged from 23 to 74 years at the time of diagnosis with a median age of 49 years. All 11 patients had stable systemic disease and an excellent performance status. Five patients had tumors from lung, 2 from breast, and 4 from other sites. Each was expected to have a long survival. However, 4 of the 11 patients (36%) developed unequivocal NM at 1, 3, 6, and 7 months following surgical resection and all died within 1 month from the diagnosis of NM. Two patients had a positive CSF cytology and the other two had multiple enhancing leptomeningeal metastases on MRI. Two additional patients died of progressive neurological disease without evidence of local recurrence, yet were never formally evaluated for NM and two were lost to follow-up. Thus, the incidence of NM in this patient population is at least 36%. In the 55 patients who had resections of supratentorial metastases, only 1 patient (2%) developed NM. This study suggests that NM following surgical resection of an ICM may be common and may result in the premature demise of patients with excellent performance status, minimal systemic disease, and a reasonable life expectancy. Further studies are needed to determine if prophylactic intrathecal chemotherapy administered perioperatively could diminish the incidence of clinically apparent NM in this patient population.