The impact of ethnicity and cardiovascular risk on the pharmacologic management of osteoarthritis: a US perspective.

Many individuals with osteoarthritis (OA) also have other chronic, comorbid conditions, such as obesity, hypertension and diabetes, which can compound the risk for developing cardiovascular adverse events that have been associated with specific analgesics, most notably nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitor NSAIDs. Pharmacotherapy may be further complicated by genetic factors that may influence drug metabolism in certain individuals. These risks may vary according to race and ethnicity. Black and Hispanic populations are known to have a higher prevalence of cardiovascular risk factors and disease, and a substantial proportion of black and Hispanic individuals possess genotypes of the cytochrome P450 (CYP) 2C9 enzyme involved in the metabolism of many NSAIDs and the CYP2D6 enzyme involved in metabolism of the dual opioid agonist/norepinephrine-serotonin reuptake inhibitor tramadol. As a result, the efficacy and safety of available analgesics may vary between patients in different racial and ethnic groups. This review article focuses on racial and ethnic differences in cardiovascular risk and genetic factors altering drug efficacy and safety and evaluates the pharmacologic options that can be used for the management of OA in these populations. Particular emphasis is given to the place of topical NSAIDs and capsaicin in the management of OA patients for whom systemic exposure to available pharmacotherapy poses particular risk. Evidence-based guidelines in OA management, as they relate to appropriate patient-specific pharmacotherapy, are also examined.

Clinical trial data in support of changing guidelines in osteoarthritis treatment.

Goals for the management of osteoarthritis (OA) emphasize pain relief, reduction of inflammation, and improvement in functioning. Among pharmacological pain management interventions, nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently recommended as the most effective treatment option for OA. However, the use of traditional oral NSAIDs is associated with risk of serious adverse events involving the gastrointestinal, cardiovascular, and renal systems. Topical NSAIDs are an alternative with well-established tolerability and efficacy in the treatment of OA of the knee or hand. While the management of OA pain is evolving toward the more widespread use of topical NSAIDs, some OA management guidelines have yet to incorporate these agents in their recommendations. This review examines the efficacy and tolerability of topical NSAIDs, their current placement in OA management guidelines, and their potential role in enabling pain specialists to provide individualized care for their patients with OA.

Evolving guidelines in the use of topical nonsteroidal anti-inflammatory drugs in the treatment of osteoarthritis.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a standard treatment for osteoarthritis (OA), but the use of oral NSAIDs has been linked to an elevated risk for cardiovascular and gastrointestinal adverse events and renal toxicity. Topical NSAIDs are thought to afford efficacy that is comparable to oral formulations while reducing widespread systemic drug exposure, which may provide a benefit in terms of safety and tolerability. As a result, European treatment guidelines have, for many years, recommended the use of topical NSAIDs as a safe and effective treatment option for OA. Following the recent approval of several topical NSAID formulations by the US Food and Drug Administration, US treatment guidelines are increasingly recommending the use of topical NSAIDs as an alternative therapy and, in some cases, as a first-line option for OA. This commentary summarizes OA treatment guidelines that are currently available and discusses their potential evolution with regard to the increased inclusion of topical NSAIDs.

Rapid recurrence and malignant transformation of pilocytic astrocytoma in adult patients.

Pilocytic astrocytoma is a slow-growing, circumscribed glioma that most frequently occurs within the pediatric population. In general, surgical resection for pilocytic astrocytoma is thought to be curative with tumor recurrence or malignant transformation being relatively rare. However, there have been very few studies specifically looking at the prognosis for adult patients diagnosed with pilocytic astrocytoma. To evaluate the frequency of recurrence and malignant transformation of pilocytic astrocytoma in adults, we performed a retrospective analysis of all adult patients who underwent surgical resection for this tumor at our institution over a period of 10 years. In our cohort of 20 patients, there were 6 (30%) recurrences with four patients requiring repeat surgery due to symptomatic progression. Relatively rapid recurrences were noted with the median time to recurrence being 16.5 months. All recurrences occurred within 4 years of initial surgery while patients requiring repeat surgery presented within 17 months of initial surgery. Based on this study estimated rates of freedom from recurrence (FFR) at 12 and 24 months after initial surgery are 94 +/- 5% and 76 +/- 10%, respectively. A high rate of malignant transformation was observed in the patients that underwent repeat surgery with 75% (3/4) progressing to anaplastic astrocytoma on pathological examination. This study provides further evidence that the clinical course of a subset of adult patients with pilocytic astrocytoma will not be benign. The potential for rapid tumor recurrence and malignant transformation necessitates careful post-operative follow-up for adult patients with this tumor.

The prognostic value of tumor markers in newly diagnosed patients with primary central nervous system germ cell tumors.

BACKGROUND: To determine the impact of diagnostic serum and/or cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (b-HCG) elevations on survival in newly diagnosed patients with central nervous system germ cell tumors (CNS GCT) treated with chemotherapy with the intent to avoid irradiation. PROCEDURE: Seventy-five patients with newly diagnosed CNS GCT enrolled in two sequential internationally conducted clinical trials with serum and CSF AFP and b-HCG levels available from initial diagnosis were retrospectively analyzed. Subjects received platinum based chemotherapy and were followed with serial imaging and tumor marker evaluations. RESULTS: The 5-year overall survival (OS) and event free survival (EFS) for patients with normal tumor markers compared with those with elevated markers at diagnosis was 78% (95% CI 51-91%) versus 60% (95% CI 46-72%) (P = 0.08) and 22% (95% CI 7-43%) versus 28% (95% CI 16-40%) (P = 0.68). The hazard ratio of death for patients with elevated markers was 1.9 times as high as that for those with normal markers (95% CI 0.58-6.5) after adjusting for other baseline characteristics. There was no observed difference in survival among patients with histologically confirmed germinomas, irrespective of level of b-HCG. CONCLUSIONS: Patients with elevated tumor markers appear to have poorer OS independent of tumor histology, although these differences do not reach statistical significance (P < or = 0.05). No differences were observed in EFS between groups likely due to the poor response of chemotherapy only approach to patients with normal markers. b-HCG elevations in biopsy proven germinomas do not seem to alter a patient's prognosis.

Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas.

BACKGROUND: The prognosis for patients with recurrent high-grade gliomas is poor and treatment options are limited. Current chemotherapeutic regimens can improve clinical outcomes, but extend survival by only a few months. Temozolomide is a methylating agent that is typically administered once daily. Because preclinical studies suggested that a twice-daily dosing schedule might be more effective, the safety and efficacy of twice-daily dosing of temozolomide were studied in patients with recurrent gliomas at their first, second, or third recurrence. METHODS: This multi-institutional trial enrolled 120 patients with recurrent glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), or anaplastic oligodendroglioma (AO). An initial oral dose of 200 mg/m(2) of temozolomide was followed by 9 consecutive doses of 90-mg/m(2) every 12 hours. Treatment cycles were repeated every 28 days. Doses were escalated to 100 mg/m(2) twice daily in the absence of unacceptable toxicity or were reduced if unacceptable toxicity occurred. RESULTS: For GBM, AA, and AO patients, respectively, the median progression-free survival (PFS) was 4.2 months, 5.8 months, and 7.7 months, whereas the median overall survival (OS) was 8.8 months, 14.6 months, and 18 months. The overall response rate (partial and complete) for the GBM, AA, and AO patients was 31%, 46%, and 46%, respectively. Grade 3/4 toxicities included neutropenia (1.1%), thrombocytopenia (3.6%), and anemia (0.3%) (graded according to the World Health Organization grading system). CONCLUSIONS: Twice-daily dosing may enhance the efficacy of temozolomide in the treatment of recurrent gliomas without increasing toxicity. This regimen compares favorably with other dosing schedules of temozolomide reported in the literature.

Randomized study of paclitaxel and tamoxifen deposition into human brain tumors: implications for the treatment of metastatic brain tumors.

PURPOSE: Drug resistance in brain tumors is partially mediated by the blood-brain barrier of which a key component is P-glycoprotein, which is highly expressed in cerebral capillaries. Tamoxifen is a nontoxic inhibitor of P-glycoprotein. This trial assessed, in primary and metastatic brain tumors, the differential deposition of paclitaxel and whether tamoxifen could increase paclitaxel deposition. EXPERIMENTAL DESIGN: Patients for surgical resection of their primary or metastatic brain tumors were prospectively randomized to prior paclitaxel alone (175 mg/m(2)/i.v.) or tamoxifen for 5 days followed by paclitaxel. Central and peripheral tumor, surrounding normal brain and plasma, were analyzed for paclitaxel and tamoxifen. RESULTS: Twenty-seven patients completed the study. Based on a multivariate linear regression model, no significant differences in paclitaxel concentrations between the two study arms were found after adjusting for treatment group (tamoxifen versus control). However, in analysis for tumor type, metastatic brain tumors had higher paclitaxel concentrations in the tumor center (1.93-fold, P = 0.10) and in the tumor periphery (2.46-fold, P = 0.039) compared with primary brain tumors. Pharmacokinetic analyses showed comparable paclitaxel areas under the serum concentration between treatment arms. CONCLUSIONS: Paclitaxel deposition was not increased with this tamoxifen schedule as the low plasma concentrations were likely secondary to concurrent use of P-450-inducing medications. However, the statistically higher paclitaxel deposition in the periphery of metastatic brain tumors provides functional evidence corroborating reports of decreased P-glycoprotein expression in metastatic versus primary brain tumors. This suggests that metastatic brain tumors may respond to paclitaxel if it has proven clinical efficacy for the primary tumor's histopathology.

Tamoxifen paradoxically decreases paclitaxel deposition into cerebrospinal fluid of brain tumor patients.

BACKGROUND: P-glycoprotein (Pgp) mediates, in part, resistance to natural product chemotherapy drugs which constitute over half of the available drugs for cancer treatment. Tamoxifen (TAM) enhances intracellular deposition of natural product chemotherapy in human cell lines by inhibition of Pgp. Pgp is highly expressed in the choroid plexus and is thought to be a key component of the blood-cerebrospinal fluid barrier (BCSFB). We conducted a prospective, randomized study to assess if Pgp inhibition by TAM alters deposition of paclitaxel in cerebrospinal fluid (CSF). METHODS: Ten patients with either primary or metastatic brain tumors were randomized to: paclitaxel alone (175 mg/m2/IV) or a course of TAM (160 mg/m2 PO BID on Days 1-5) followed by paclitaxel (175 mg/m2/IV on Day 5). CSF and plasma samples were obtained following paclitaxel infusion; paclitaxel and TAM concentrations were measured by high-performance liquid chromatography assays. RESULTS: Paclitaxel was detected in the CSF of six of the 10 patients. Peak CSF paclitaxel concentrations of the paclitaxel and paclitaxel-TAM groups ranged between 3.5-57.4 and 2.3-24.6 nM, respectively. Though there was a 2.4-fold higher mean CSF paclitaxel concentration and a 3.7-fold higher median peak CSF:plasma paclitaxel ratio for those who received paclitaxel alone as compared to combined paclitaxel-TAM, it was not statistically significant (P = 0.22). In one patient enrolled to both arms, higher CSF concentrations of paclitaxel and higher paclitaxel CSF: plasma ratios were observed when given paclitaxel alone. CONCLUSIONS: The trend towards lower paclitaxel CSF concentrations when given with TAM is consistent with the published finding that Pgp's localization in the endothelial cells of the choroid plexus works in an opposite direction and keeps drugs in the CSF. Thus, agents which inhibit Pgp, such as TAM, may increase efflux of Pgp substrates out of the BCSFB and may paradoxically lower CSF concentrations of natural product chemotherapy drugs. Conceptually, this finding implies that the Pgp in the BBB and BCSFB keeps natural toxins such as paclitaxel, from entering the brain (BBB) and, if they do enter the brain, keeps them in the CSF (BCSFB) where they may be less harmful than if they re-entered the brain. Thus, our work supports this novel idea and adds to the understanding of the functions of the BCSFB.

Multisection 1H magnetic resonance spectroscopic imaging assessment of glioma response to chemotherapy.

This study evaluated the role of proton magnetic resonance spectroscopic imaging (1H MRSI) in assessing the response of low-grade brain tumors to a chemotherapy-only treatment regimen. Specifically, it was of interest to assess if 1H MRSI could detect early tumor response to therapy prior to magnetic resonance imaging (MRI) changes, and to establish which spectral markers were sensitive to regional changes within and around a heterogeneous tumor mass. A total of 14 patients with lower-grade gliomas were evaluated by multislice 1H MRSI, MRI and clinical examination. Changes associated with chemotherapy were assessed by longitudinal comparisons of regional levels of choline (Cho), N-acetyl-L-aspartate (NAA), and lactate (Lac) relative to total creatine. These changes were, in turn, compared to changes on pre- and post-contrast MR images and to each patient's clinical status. In enhancing tumor regions, there was a significant association between an increase in Lac/Cr during treatment and decreased progression-free survival time. At baseline, a low NAA/Cr in normal-appearing brain tissue adjacent to non-enhancing tumor was associated with decreased progression-free survival time, as was an increase in Cho/Cr during chemotherapy. An increase in Cho/Cr and Lac/Cr in normal-appearing brain regions next to non-enhancing tumor in one patient was noted 2 months before MRI showed progressive disease. These results suggest that 1H MRSI can be a powerful adjunct to MRI in the assessment of tumor response to chemotherapy, and that Cho/Cr and Lac/Cr appear to be the most reliable markers of tumor progression and may predict response prior to MRI changes.

Osseous metastasis of pineoblastoma: a case report and review of the literature.

PURPOSE: To review the literature on the occurrence of osseous metastases in recurrent pineoblastoma, and to report upon the feasibility and efficacy of treatment using intensive conventional chemotherapy to achieve a remission, followed by consolidation with marrow ablative chemotherapy and autologous hemopoietic stem cell rescue. PATIENT AND METHODS: An adult with isolated extraneural, osseous and bone marrow metastases from a pineoblastoma, received conventional cyclical chemotherapy, followed by consolidation with marrow ablative chemotherapy (thiotepa, carboplatin and temozolomide) and autologous hemopoietic stem cell rescue. RESULTS: A complete radiographic and histopathologic response was achieved after almost one year of conventional chemotherapy that was tolerated without significant sequelae. Following successful harvesting of peripheral blood stem cells, the patient underwent myeloablative chemotherapy with autologous stem cell rescue, without difficulty in hemopoietic reconstitution and without serious or permanent side effects. CONCLUSIONS: Osseous metastases from pineoblastoma are an extremely rare occurrence. We conclude that conventional chemotherapy can achieve a complete response, and subsequent consolidation with marrow ablative chemotherapy and autologous hemopoietic stem cell rescue is feasible and well tolerated.

Thiotepa-based high-dose chemotherapy with autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell tumors.

PURPOSE: To evaluate the efficacy and toxicity of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in patients with relapsed or progressive CNS germ cell tumors (GCTs). PATIENTS AND METHODS: Twenty-one patients with CNS GCTs who experienced relapse or progression despite having received initial chemotherapy and/or radiotherapy were treated with thiotepa-based HDC regimens followed by ASCR. RESULTS: Estimated overall survival (OS) and event-free survival (EFS) rates for the entire group 4 years after HDC were 57% +/- 12% and 52% +/- 14%, respectively. Seven of nine (78%) patients with germinoma survived disease-free after HDC with a median survival of 48 months. One patient died as a result of progressive disease (PD) 39 months after HDC, and another died as a result of pulmonary fibrosis unrelated to HDC 78 months after ASCR without assessable disease. However, only four of 12 patients (33%) with nongerminomatous germ cell tumors (NGGCTs) survived without evidence of disease, with a median survival of 35 months. Eight patients with NGGCTs died as a result of PD, with a median survival of 4 months after HDC (range, 2 to 17 months). Patients with germinoma fared better than those with NGGCTs (P =.016 and.014 for OS and EFS, respectively). Patients with complete response to HDC also had significantly better outcome (P <.001 for OS and EFS) compared with patients with only a partial response or stable disease. There were no toxic deaths because of HDC. CONCLUSION: Dose escalation of chemotherapy followed by ASCR is effective therapy for patients with recurrent CNS germinomas and might be effective in patients with recurrent NGGCTs with a low tumor burden.

Current advances in the diagnosis and management of intracranial germ cell tumors.

Central nervous system (CNS) germ cell tumors (GCT) account for less than 5% of primary brain tumors in children and young adults, but they continue to attract much attention. Over the past decade, two advances have led to re-evaluation of what constitutes conventional therapy for CNS GCT. For pure germinomas, the challenge remains the determination of the optimal field and dose of irradiation and whether or not the use of chemotherapy can lead to a reduced dose or elimination of irradiation altogether without compromising disease control or survival. For non-germinomatous germ cell tumors, an improvement in the current dismal prognosis is imperative.

Chemotherapy-induced parkinsonism responsive to levodopa: an underrecognized entity.

Parkinsonism is a rare neurological complication of cancer treatment. Although individual case reports of this syndrome have been reported, the clinical features and prevalence of this syndrome are unknown. We present 3 patients, encountered over 6 months at one institution, who developed parkinsonism after treatment with various chemotherapeutic agents. Parkinsonism was severe in 2 patients, affecting postural reflexes, speech, and swallowing. All 3 patients responded dramatically to treatment with levodopa, and parkinsonism spontaneously improved or remitted over months. This unusual complication of cancer therapy is treatable and may be underappreciated.

Leptomeningeal relapse of multiple myeloma following allogeneic stem cell transplantation.

Progressive multiple myeloma may manifest features of 'de-differentiation', including a plasmablastic appearance, failure to secrete paraprotein, extramedullary involvement, and resistance to treatment. A 44-year-old woman with kappa-light chain myeloma underwent allogeneic stem cell transplantation (SCT). Twenty months later she developed paraspinal plasmablastic myeloma in the absence of paraprotein in urine or myeloma in the marrow. The paraspinal masses responded to chemotherapy. At 30 months she developed myelomatous meningitis, which proved resistant to intrathecal chemotherapy, irradiation, and donor lymphocyte infusion (DLI). The leptomeningeal disease led to death at 38 months. This is the first report of leptomeningeal relapse of myeloma after allografting.