Analyzing temozolomide medication errors: potentially fatal.

The EORTC-NCIC regimen for glioblastoma requires different dosing of temozolomide (TMZ) during radiation and maintenance therapy. This complexity is exacerbated by the availability of multiple TMZ capsule strengths. TMZ is an alkylating agent and the major toxicity of this class is dose-related myelosuppression. Inadvertent overdose can be fatal. The websites of the Institute for Safe Medication Practices (ISMP), and the Food and Drug Administration (FDA) MedWatch database were reviewed. We searched the MedWatch database for adverse events associated with TMZ and obtained all reports including hematologic toxicity submitted from 1st November 1997 to 30th May 2012. The ISMP describes errors with TMZ resulting from the positioning of information on the label of the commercial product. The strength and quantity of capsules on the label were in close proximity to each other, and this has been changed by the manufacturer. MedWatch identified 45 medication errors. Patient errors were the most common, accounting for 21 or 47% of errors, followed by dispensing errors, which accounted for 13 or 29%. Seven reports or 16% were errors in the prescribing of TMZ. Reported outcomes ranged from reversible hematological adverse events (13%), to hospitalization for other adverse events (13%) or death (18%). Four error reports lacked detail and could not be categorized. Although the FDA issued a warning in 2003 regarding fatal medication errors and the product label warns of overdosing, errors in TMZ dosing occur for various reasons and involve both healthcare professionals and patients. Overdosing errors can be fatal.

Bevacizumab-induced oral mucositis in background of cutaneous plaque-type psoriasis.

OBJECTIVE: To report the serial development of oral mucositis following infusion of bevacizumab in a young woman with a malignant brain tumor and history of cutaneous psoriasis. CASE SUMMARY: A 29-year-old woman with a history of active cutaneous psoriasis and a malignant glioneuronal tumor was treated with bevacizumab for 2.5 years. With each infusion of bevacizumab, she developed oral mucositis within 36 hours. She received temozolomide as part of concurrent therapy with radiation and as maintenance therapy; it was discontinued after continuous therapy for 1.5 years. Bevacizumab 10 mg/kg was added after 7 cycles of maintenance temozolomide, as the tumor had minimal response and evidence of increased perfusion with angiogenesis on imaging studies. All medication, including temozolomide, was evaluated and eventually discontinued, with the exception of bevacizumab, which remained the drug suspected of causing the mucositis. DISCUSSION: Oral mucositis is a frequent adverse effect of cytotoxic chemotherapy, but has not been reported with bevacizumab. The Naranjo probability scale indicated a probable adverse drug reaction. This likely indicates that bevacizumab is one of many drugs known to induce exacerbation of psoriatic disease. We speculate that oral mucositis developed as bevacizumab-induced generation of proinflammatory cytokines within the vascular endothelium, leading to mucosal damage and ulceration. In addition, interruption of reparative angiogenic pathways with bevacizumab likely contributed to the severity of mucositis. CONCLUSIONS: Clinicians should be aware that bevacizumab can potentially exacerbate psoriatic disease.

De novo malignant optic chiasm glioma with initial clinical response to steroids.

Malignant optic nerve glioma (MONG) is a rare but uniformly fatal disease that remains poorly understood. We describe a notable case of this rare disease occurring in the optic chiasm. Normal brain imaging and normal ophthalmic examination two years prior to diagnosis provide evidence for de novo genesis of MONG in our patient. Early response to steroids highlights the degree to which MONG can initially mimic inflammatory optic neuropathies and chiasmal syndromes. Our case also demonstrates a poor outcome with MONG even with current advanced therapy for glioblastoma including radiotherapy plus concomitant and adjuvant temozolomide (the EORTC/NCIC regimen) and bevacizumab.

Update on meningiomas.

Although meningiomas are the most common tumor in the central nervous system, their incidence, epidemiology, and clinical outcomes have historically been poorly defined. This has been attributed to their benign course, difficulty obtaining histologic diagnosis, and lack of uniform database registration. Their clinical behavior can range from a silent incidentaloma to a lethal tumor. Projections of an aging population should raise medical awareness of an expectant rise in the incidence of meningiomas. This disease increases with advancing age, has a female predilection, and exposure to ionizing radiation is associated with a higher risk for disease development. There have been minimal advances in treatment, except in radiation therapy. Although no U.S. Food and Drug Administration-approved systemic therapy exists, there are treatment options that include hydroxyurea and sandostatin. Currently, no molecularly targeted therapy has provided clinical benefit, although recurring molecular alterations are present and novel therapies are being investigated.

Descriptive epidemiology of selected olfactory tumors.

Olfactory tumors, especially olfactory neuroblastomas (ON) and carcinomas with neuroendocrine differentiation (CND), are extremely rare, and little descriptive epidemiologic information is available. The objective of this study was to more fully describe selected olfactory tumors using a large population-based cancer incidence database. The Surveillance, Epidemiology and End Results (SEER) 9 registries limited-use data were reviewed from 1973 to 2006 for selected nasal cavity (C30.0) and accessory sinus (C31.0-31.9) tumors. Frequencies, incidence rates, and relative survival rates were estimated using SEER*Stat, v6.5.2. The majority of cases were squamous cell carcinoma (SCC), while the incidence of ON was greater than CND. For ON, the incidence was highest in the 60-79 year age group, while for SCC, the incidence was highest in the 80+ year age group. For CND, the incidence leveled off in the oldest age groups. Survival rates were highest for ON (>70% alive at 5 years after diagnosis) and poorest for CND (44% alive at 5 years). Adjuvant radiation therapy did not improve survival over surgery alone in ON. In SCC, survival was worse in patients who received adjuvant radiation compared to patients who had surgery alone. Our analysis confirms some previously published information, and adds new information about the incidence and demographics of ON and CND. In addition, our analysis documents the lack of benefit of adjuvant radiation in ON. It is not feasible to conduct prospective trials in patients with these rare diseases, and the importance of registry data in learning about olfactory tumors is emphasized.

Aggression in a patient with primary brain tumor: ethical implications for best management.

We present a case of a 55-year-old male diagnosed with glioblastoma (GB) involving the left frontal, parietal, and temporal lobes that developed aggression and committed a violent act against his wife. Aggression and violence have rarely been presented in the neuro-oncology literature, but have been well documented in stroke and dementia literature. We discuss the case along with the ethical principles as well as best management practices that may have been employed. As our therapies improve overall survival in brain tumors, aggression is an important behavior that the field must acknowledge.

Evaluation of the Modified Diet in Renal Disease equation for calculation of carboplatin dose.

BACKGROUND: Serum creatinine (SCr)-based formulas are used to estimate glomerular filtration rate (GFR) when calculating a dosage for carboplatin using the Calvert equation, but these formulas often underestimate measured GFR. The Modified Diet in Renal Disease (MDRD) equation appears to be a more accurate estimate of GFR in patients with chronic kidney disease, but this equation has not been studied extensively in patients with cancer. OBJECTIVE: To determine the absolute difference between the dose of carboplatin administered (traditional SCr-based formulas used to estimate GFR) and the dose calculated using the MDRD equation to estimate GFR and compare the frequencies of thrombocytopenia, neutropenia, and dosage modifications between subjects in whom the difference in dose was 20% or more (divergent) or less than 20% (nondivergent). METHODS: A retrospective analysis was conducted using data from patients who received carboplatin. Inclusion criteria were receipt of at least 2 doses of carboplatin, either as monotherapy or combination therapy, and documentation of desired area under the concentration-time curve (AUC). Patients were excluded if the baseline values needed to estimate GFR using the MDRD equation were not available. The absolute difference between the dose of carboplatin administered and that calculated using the MDRD equation was determined and, from this comparison, the subjects were divided into 2 groups (divergent vs nondivergent). RESULTS: The medical records of 186 adults who received more than 2 doses of carboplatin were included in the analysis. The doses were divergent in 89 (48%) patients. The mean target AUC values were 5.3 mg/mL/min and 5.1 mg/mL/min in the divergent and nondivergent groups, respectively, and most patients received cytotoxic regimens with a relatively low risk of febrile neutropenia. The frequencies of neutropenia, thrombocytopenia, and dosage modifications were similar between the 2 groups. Use of the MDRD equation to calculate the carboplatin dosage did not appear to result in a change in the frequency of myelosuppression or the need for dose modifications compared with traditional SCr-based formulas. CONCLUSIONS: The traditional SCr-based formulas for the calculation of carboplatin dosage should be used to estimate carboplatin dose until more data become available regarding the use of the MDRD equation in this population.

Malignant pineal germ-cell tumors: an analysis of cases from three tumor registries.

The exact incidence of pineal germ-cell tumors is largely unknown. The tumors are rare, and the number of patients with these tumors, as reported in clinical series, has been limited. The goal of this study was to describe pineal germ-cell tumors in a large number of patients, using data from available brain tumor databases. Three different databases were used: Surveillance, Epidemiology, and End Results (SEER) database (1973-2001); Central Brain Tumor Registry of the United States (CBTRUS; 1997-2001); and National Cancer Data Base (NCDB; 1985-2003). Tumors were identified using the International Classification of Diseases for Oncology, third edition (ICD-O-3), site code C75.3, and categorized according to histology codes 9060-9085. Data were analyzed using SAS/STAT release 8.2, SEER*Stat version 5.2, and SPSS version 13.0 software. A total of 1,467 cases of malignant pineal germ-cell tumors were identified: 1,159 from NCDB, 196 from SEER, and 112 from CBTRUS. All three databases showed a male predominance for pineal germ-cell tumors (>90%), and >72% of patients were Caucasian. The peak number of cases occurred in the 10- to 14-year age group in the CBTRUS data and in the 15- to 19-year age group in the SEER and NCDB data, and declined significantly thereafter. The majority of tumors (73%-86%) were germinomas, and patients with germinomas had the highest survival rate (>79% at 5 years). Most patients were treated with surgical resection and radiation therapy or with radiation therapy alone. The number of patients included in this study exceeds that of any study published to date. The proportions of malignant pineal germ-cell tumors and intracranial germ-cell tumors are in range with previous studies. Survival rates for malignant pineal germ-cell tumors are lower than results from recent treatment trials for intracranial germ-cell tumors, and patients that received radiation therapy in the treatment plan either with surgery or alone survived the longest.

Complete response of CNS-involved olfactory neuroendocrine tumor using multimodal therapy.

INTRODUCTION: Locally advanced tumors in the olfactory area commonly have central nervous system (CNS) involvement and are often incurable. CASE REPORT: We report the treatment of a 25-year-old male patient who presented with a large, neuroendocrine tumor arising from the ethmoid complex. This locally invasive lesion extended beyond the orbits and into the anterior cranial fossa with associated intracranial involvement. An endoscopic nasal biopsy demonstrated a poorly differentiated neuroendocrine tumor. The patient was treated with 4 cycles of combination induction chemotherapy with irinotecan and cisplatin followed by radiation therapy with concurrent weekly cisplatin. He had a complete response to this therapy confirmed with biopsies that demonstrated no residual disease at 8 weeks after chemoradiotherapy. He remained disease free one and a half years following surgery. CONCLUSION: To our knowledge, this combination treatment approach has not been reported in the literature.

Incidence of brain metastasis at initial presentation of lung cancer.

BACKGROUND: No reliable estimates are available on the incidence of brain metastasis (BM) in cancer patients. This information is valuable for planning patient care and developing measures that may prevent or decrease the likelihood of metastatic brain disease. METHODS: We report the first population-based analysis on BM incidence at cancer diagnosis using the Kentucky Cancer Registry (KCR) and Alberta Cancer Registry (ACR). All cancer cases with BM were identified from KCR and ACR, with subsequent focus on metastases from lung primaries; the annual number of BMs at initial presentation was derived. Comparisons were made between Kentucky and Alberta for the stage and site of organ involvement of lung cancer. RESULTS: Low incidence of BM was observed in the United States until mandatory reporting began in 2010. Both the KCR and ACR recorded the highest incidence of BM from lung cancer, with total BM cases at initial presentation occurring at 88% and 77%, respectively. For lung cancer, stage IV was the most common stage at presentation for both registries and ranged from 45.9% to 57.2%. When BM from lung was identified, the most common synchronous organ site of metastasis was osseous, occurring at 28.4%. CONCLUSION: Our analysis from the Kentucky and Alberta cancer registries similarly demonstrated the aggressive nature of lung cancer and its propensity for BM at initial presentation. Besides widespread organ involvement, no synchronous organ site predicted BM in lung cancer. BM is a common and important clinical outcome, and use of registry data is becoming more available.

Long-term treatment with temozolomide in malignant glioma.

Six months of maintenance temozolomide (TMZ) following concurrent TMZ chemotherapy and radiation therapy has become the standard of care in the treatment of glioblastoma. In addition, TMZ has also been used to treat other forms of glioma although less evidence of efficacy exists. TMZ administration longer than 6months is common in clinical practice, but it is unusual for the drug to be administered longer than 1 to 2years. We report five patients who received long-term treatment with TMZ chemotherapy at normal dosing levels. One of these patients was diagnosed with glioblastoma, two with anaplastic astrocytoma, one with gliosarcoma, and one with oligo-astrocytoma. The length of treatment in our group of patients ranged from 45 to 85 cycles of TMZ. Common Terminology Criteria for Adverse Events (CTCAE) developed by The National Cancer Institute was used to classify toxicity. Two patients experienced no toxicity per CTCAE guidelines. One patient experienced grade I thrombocytopenia, one developed grade I leukopenia, and one experienced both grade I thrombocytopenia and grade I nausea, all which resolved with either withholding TMZ for 1month or supportive treatment. Our report provides evidence that long-term TMZ chemotherapy is a therapeutic option when appropriately monitored.

Primary CNS germ cell tumors: current epidemiology and update on treatment.

Primary central nervous system (CNS) germ cell tumors (GCTs) are a heterogeneous group of lesions that account for 0.5 % of all primary brain and CNS tumors, occurring at an incidence rate of 0.10 per 100,000 person-years in the United States with approximately 90 % of the cases before the age of 20 years. Primary CNS GCTs demonstrate a remarkable difference in incidence based on gender and location within the brain with males having a 15:1 incidence in the pineal region while the gender incidence is nearly 1:1 in the rest of the brain. Also, historically the incidence was noted to be significantly higher in Japan and East Asia, but recent studies in Japan demonstrate similar incidence as in the United States. They are broadly classified as germinomas and non-germinomatous germ cell tumors (NGGCTs) based on clinicopathologic features. Germinomas are sensitive to treatment with radiotherapy and chemotherapy with high cure rates and carry an excellent prognosis, while NGGCTs display various forms of differentiation, have a poorer prognosis and are refractory to therapy. Standard management of CNS GTCs remains unsettled and ongoing research aims to achieve best possible survival rates and post-treatment quality of life by reduction in treatment intensity.

Delayed response and survival from NovoTTF-100A in recurrent GBM.

We present a 48-year-old male with recurrent glioblastoma (GBM) who was enrolled in the NovoTTF-100A landmark phase III study and has been on device for >6 years. During this time, his magnetic resonance images demonstrated initial growth followed by a slow decrease in enhancement with continued residual disease. Long-term survivors in patients with recurrent GBM are rare, especially in the absence of definitive local treatment such as surgery or radiosurgery. We present the clinical, imaging and pathological findings for this patient in relation to use of the NovoTTF-100A device.

Going past the data for temozolomide.

The benefit of six cycles of adjuvant temozolomide was documented in a randomized phase III (EORTC-NCIC CE.3) trial, and this therapy, following combined temozolomide and radiation, is the standard of care for patients with newly diagnosed glioblastoma. We comment on the differences in the length of adjuvant therapy in both clinical practice and national studies (e.g. RTOG 0825), usually doubling the length in the EORTC/NCIC study, and relate to historic adjuvant trials for solid tumors.

Hematologic adverse events associated with temozolomide.

PURPOSE: Temozolomide (TMZ) is a widely used oral alkylating agent that has been associated with the development of severe hematologic adverse events (HAEs). Limited clinical information about HAEs is available. METHODS: We searched the FDA MedWatch database for TMZ and obtained all MedWatch reports on TMZ submitted to the FDA from November 1, 1997 to September 3, 2008. We defined major HAEs, namely agranulocytosis, aplasia, aplastic anemia (AA), leukemia (various), myelodysplastic syndrome (MDS), and lymphoma, and several minor HAEs. RESULTS: A total of 5,127 reports on 3,490 patients were submitted to MedWatch. Among these, we identified 112 cases of major HAEs. Of the 44 reported deaths, the major HAE was considered the cause in 32 cases. The median duration of TMZ treatment was 6 weeks [0.5-108 weeks]. Seventy-six cases of AA or aplasia and 17 cases of leukemia represented the most common major HAE. Important minor HAEs were bone marrow failure and pancytopenia/pancytopenia-like with 325 combined cases; these reports are clinically similar to aplastic anemia. CONCLUSION: The hematologic toxicity profile of TMZ differs from that of other alkylating agents. TMZ HAEs are emerging as significant concerns. Among alkylating agents, AA appears unique to TMZ, and the high rate warrants disclosure of patients. The duration of TMZ exposure prior to the development of AA may be quite short. The risk of AML/MDS is low, but the length of follow-up is insufficient to assess the true risk.

Prolonged activity of bevacizumab in adenocarcinoma of the lung with multiple brain metastases.

Patients with lung cancer having multiple brain metastases have poor outcomes. We present long-term disease treatment in a 60-year-old woman having greater than thirty brain metastases of NSCLC adenocarcinoma with a mutant allele of EGFR treated with differing chemotherapies including erlotinib, but disease response in the brain only with bevacizumab. Although initially restricted in use, increasing clinical reports have demonstrated safety of bevacizumab use in brain-involved cancer patients. Our case highlights that disease response to bevacizumab is similar in the brain to systemic disease and likely overcomes anatomical barriers that can limit other therapeutic agents.

Unusual CNS presentation of thyroid cancer.

As advanced therapies allow cancer patients to live longer, disease failure in the central nervous system increases from limited therapeutic penetration. Primary thyroid malignancies rarely metastasize to the brain and have a small number of investigations in literature on the subject. The majority of brain metastases involve the brain parenchyma, reflecting the mass and blood distribution within the brain and central nervous system. Here, we report two cases of the most common differentiated thyroid cancers; follicular thyroid cancer having brain involvement from extra-axial growth and papillary thyroid cancer having brain involvement from a single intraventricular metastasis, presumed as metastasis from the vascular choroid plexus. Both of our cases had widespread systemic involvement. For our follicular thyroid cancer, brain involvement was a result of extra-axial growth from cavarial bone, and our papillary thyroid cancer had brain involvement from a single intraventricular metastasis that was initially resected and nearly a year later developed extensive brain involvement. Unlike the usual gray-white junction metastases seen in the majority of metastatic brain tumors, including thyroid, our cases are uncommon. They reflect differences in tumor biology that allows for spread and growth in the brain. Although there is growing genetic knowledge on tumors that favor brain metastases, little is known about tumors that rarely involve the brain.