Pre-eclampsia during pregnancy and risk of endometrial cancer: a systematic review and meta-analysis.

BACKGROUND: Pre-eclampsia may be associated with the development of endometrial cancer; however, previous findings have been conflicting. OBJECTIVES: To investigate if pre-eclampsia is associated with an increased risk of endometrial cancer. METHOD: Two independent reviewers screened titles and abstracts of studies identified in MEDLINE, Embase, and Web of Science databases from inception until March 2022. Studies were included if they investigated pre-eclampsia and subsequent risk of endometrial cancer (or precursor lesions). Random-effects meta-analysis was used to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between pre-eclampsia during pregnancy and endometrial cancer risk. MAIN RESULTS: There were seven articles identified which investigated endometrial cancer, of which one also investigated endometrial cancer precursors. Overall, the studies include 11,724 endometrial cancer cases. No association was observed between pre-eclampsia and risk of endometrial cancer with moderate heterogeneity observed (pooled HR 1.07, 95% CI 0.79-1.46, I2 = 34.1%). In sensitivity analysis investigating risk of endometrial neoplasia (atypical hyperplasia, carcinoma in situ, or cancer), there was some evidence that pre-eclampsia was associated with an increased risk (HR 1.34, 95% CI 1.15-1.57, I2 = 29.6%). CONCLUSIONS: Pre-eclampsia was not associated with an increased risk of endometrial cancer. Additional large studies with information on pre-eclampsia sub-type aiming to investigate endometrial cancer precursor conditions are merited.

Dominant Power and the Concept of Caste: Implications for Dentistry and Oral Health Inequality.

This paper explores the issues of caste and casteism in the U.S. as described by Pulitzer Prize winning journalist Isabel Wilkerson in her 2020 book "Caste: The Origin of Our Discontents". Wilkerson argues that a caste system not only exists in the U.S. but operates as a hidden force affecting social inequality. The paper draws on Wilkerson's work to explore caste as an analytical concept. It begins by defining caste and casteism in contrast with racism, the eight pillars of a caste system, the consequences of casteism, and the psychological drivers of casteism. The paper then applies to concept of caste to understanding power, dentistry, and oral health inequality. The paper concludes by emphasizing that the concept of caste and its relationship to oral health inequality must be understood it if we want to create real social change.

Neoliberalism and Indigenous oral health inequalities: a global perspective.

Neoliberalism is the dominant ideology underpinning the operation of many governments. Its tenets include policies of economic liberalization such as privatization, deregulation, free trade and reduced public expenditures on infrastructure and social services. Champions of neoliberalism claim that expansion of global trade has rescued millions from abject poverty and that direct foreign investment successfully transfers technology to developing economies. However, critics have urged governments to pay greater attention to how neoliberalism shapes population health. Indigenous populations experience inequalities in ways that are unique and distinct from the experiences of other marginalised groups. This is largely due to colonial influences that have resulted in sustained loss of lands, identity, languages and the control to live life in a traditional, cultural way that is meaningful. Oral health is simultaneously a reflection of material circumstances, structural inequities and access to health services. Indigenous populations carry a disproportionate burden of oral health inequalities at a global level. In this commentary, we contend that neoliberalism has overwhelmingly contributed to these inequities in three ways: (1) increased dominance of transnational corporations; (2) privatization of health and; (3) the neoliberal emphasis on personal responsibility.

Social media for dissemination and public engagement in neurosurgery-the example of Brainbook.

BACKGROUND: Public engagement has become one of the most effective tools in gaining feedback and perspectives from members of the public, involving patients with decisions, and inspiring young people to carry the medical profession forwards. Brainbook is a multi-platform, social media-based resource that was created specifically to enhance public engagement in neurosurgery and results from one of its case discussions will be reported in this paper. METHODS: A Brainbook case was created in collaboration with the NIHR Global Health Research Group on Neurotrauma and presented over 3 days (23-25 February 2018). YouTube videos were created depicting the management of an acute subdural haematoma using patient interviews, medical illustration, consultant-led discussion and operative footage. Content was shared across all Brainbook social media platforms and analytics were gathered through social media applications. RESULTS: Over a 72-hour time period, and across multiple social media accounts, 101,418 impressions were achieved (defined as penetrance onto individual media feeds and total views of the content), with active discussion on social media. CONCLUSIONS: Neurosurgical content published across multiple social media outlets represents an encouraging and exciting potential for global engagement across multiple audiences. Social media can be an effective method of not only disseminating neurosurgical knowledge, but activating and engaging the public, allied healthcare professionals, medical students and neurosurgeons.

Transnational corporations and oral health: examples from the sugar industry.

This paper seeks to describe the political behavior of transnational corporations (TNCs) related to sugars and dental caries. The paper begins by exploring dental caries as a political issue. It then provides a brief overview of key actors (expanders--e.g. public health advocates working to make policy action on sugar likely, and containers--e.g. TNC's working to prevent policy action on sugar) and the importance of problem definition in public policy making. The paper then compares how expanders and containers frame the problem of sugars and dental caries. Based upon a policy analysis framework, categories used to frame problems include incidence, causality, severity, crisis, characteristics of the problem population, values, and solutions. These categories are discussed with application to debates about public policy solutions to the problem of dental caries. It then concludes by highlighting some tensions that remain in tackling dental caries through legislation and regulation.

The interdigitating Y-plasty procedure for the correction of transverse vaginal septa.

Transverse vaginal septa are rare congenital abnormalities of the female genital tract, the surgical management of which is hardly described in the literature. While thicker septa might require complex reconstructive surgery, this paper proposes a simple technique for the surgical management of thin septa, utilising two interdigitating Y-plasties, without the need for excision of any septal tissue. The authors also present their series of eight consecutive cases where this technique was used, with no major complications or any cases of vaginal re-stenosis. This technique can also be used in imperforate hymen correction, therefore it might also be of interest to the general gynaecologist. TWEETABLE ABSTRACT: Interdigitating Y-plasties in transverse vaginal septa: presentation of a new technique.

Harmonizing influenza primary-care surveillance in the United Kingdom: piloting two methods to assess the timing and intensity of the seasonal epidemic across several general practice-based surveillance schemes.

General Practitioner consultation rates for influenza-like illness (ILI) are monitored through several geographically distinct schemes in the UK, providing early warning to government and health services of community circulation and intensity of activity each winter. Following on from the 2009 pandemic, there has been a harmonization initiative to allow comparison across the distinct existing surveillance schemes each season. The moving epidemic method (MEM), proposed by the European Centre for Disease Prevention and Control for standardizing reporting of ILI rates, was piloted in 2011/12 and 2012/13 along with the previously proposed UK method of empirical percentiles. The MEM resulted in thresholds that were lower than traditional thresholds but more appropriate as indicators of the start of influenza virus circulation. The intensity of the influenza season assessed with the MEM was similar to that reported through the percentile approach. The MEM pre-epidemic threshold has now been adopted for reporting by each country of the UK. Further work will continue to assess intensity of activity and apply standardized methods to other influenza-related data sources.

Age-specific vaccine effectiveness of seasonal 2010/2011 and pandemic influenza A(H1N1) 2009 vaccines in preventing influenza in the United Kingdom.

An analysis was undertaken to measure age-specific vaccine effectiveness (VE) of 2010/11 trivalent seasonal influenza vaccine (TIV) and monovalent 2009 pandemic influenza vaccine (PIV) administered in 2009/2010. The test-negative case-control study design was employed based on patients consulting primary care. Overall TIV effectiveness, adjusted for age and month, against confirmed influenza A(H1N1)pdm 2009 infection was 56% (95% CI 42-66); age-specific adjusted VE was 87% (95% CI 45-97) in <5-year-olds and 84% (95% CI 27-97) in 5- to 14-year-olds. Adjusted VE for PIV was only 28% (95% CI -6 to 51) overall and 72% (95% CI 15-91) in <5-year-olds. For confirmed influenza B infection, TIV effectiveness was 57% (95% CI 42-68) and in 5- to 14-year-olds 75% (95% CI 32-91). TIV provided moderate protection against the main circulating strains in 2010/2011, with higher protection in children. PIV administered during the previous season provided residual protection after 1 year, particularly in the <5 years age group.

California Dentists' Engagement in Media Advocacy for Sugar Restriction Policies.

OBJECTIVES: Increasing dentists' visibility in the media to make the case for sugary beverage taxes can help advance public policy that improves oral health outcomes. We assessed California dentists' media engagement behaviors related to sugar restriction policies for dental caries prevention and correlates of engaging in such behavior. METHODS: Survey items related to sugar policies and media engagement were embedded in an electronically distributed statewide survey of dentists' tobacco cessation counseling behaviors. Descriptive statistics were calculated for respondent characteristics, perceived professional responsibility to discuss selected topics with patients, and attitudes and behaviors related to sugar restriction policy and media communication. Multivariable models identified independent correlates of media engagement. RESULTS: Of 624 respondents, most had never talked to traditional media (78%) or posted to social media (64%) about sugar or sugar policies for dental caries prevention. Respondents with the highest level of media engagement were more likely to agree that sugary beverage taxes are effective at reducing dental caries, that they had support from dental professional organizations to talk to the media, that it is realistic for patients to reduce their sugar consumption, and that sugar and sugary drinks are extremely harmful to health. CONCLUSIONS: Efforts to increase dentists' media engagement related to sugar restriction policies for dental caries prevention should address dentists' negative attitudes toward the effectiveness of sugar restriction policies and may require increased support from dental professional societies. KNOWLEDGE TRANSFER STATEMENT: Study findings identify dentists' low engagement in media advocacy to support sugar restriction policy adoption. The results identify correlates of media engagement and of dentists' willingness and confidence to act, which could serve to inform interventions to support and enhance engagement.

Neurosciences intensive care medicine in initial neurosurgical training.

The authors describe a novel 4-month clinical placement in neurosciences intensive care medicine (NICM) undertaken in the first specialty registrar (ST1) year of neurosurgical training as part of a clinical neurosciences themed training year. Neurosurgery is unique among British surgical specialties in having pioneered themed early years in run-through training to replace basic surgical training in general surgical specialties as part of Modernising Medical Careers. After describing events leading to the new neurosurgical training, the knowledge, skills and attitudes acquired in NICM are highlighted alongside discussion of logistic aspects and future directions from an inaugural experience.

Paclitaxel disposition in plasma and central nervous systems of humans and rats with brain tumors.

BACKGROUND: Paclitaxel (Taxol) has been shown to sensitize some malignant cells to the effects of radiation. A number of clinical protocols, combining paclitaxel with radiation therapy, have been designed to exploit this phenomenon. The radiation-potentiating effect of paclitaxel is likely dependent on the ability of the drug to penetrate the tissue being radiated. Paclitaxel is known to have limited access to the central nervous system (CNS) of rats and mice, but its ability to penetrate malignant tissue in the CNS is inadequately documented. PURPOSE: Our purpose was to examine the concentrations of paclitaxel in the cerebrospinal fluid (CSF) of patients with CNS malignancies and in normal and malignant tissues from the brains of Fischer rats bearing the C6 rat glioma and then to compare those paclitaxel concentrations with concomitant paclitaxel concentrations in the plasma of those same patients and animals. METHODS: Four patients were treated with 3-hour infusions of paclitaxel at doses between 90 and 200 mg/m2. Plasma and CSF were sampled at 0.33, 1.5, 3.25, 5, 6, and 24 hours after initiation of the paclitaxel infusion. Four Fischer rats had 20,000 C6 glioma cells stereotactically implanted into their right frontal lobes; 28 days later, they were given 3-hour infusions of paclitaxel at 10 mg/kg. Plasma was sampled during the paclitaxel infusion. At the completion of the infusion, rats were killed, and portions of their normal and malignant CNS tissues were removed for histologic assessment. Concentrations of paclitaxel in plasma, CSF, and brain tissue were determined with high-pressure liquid chromatography. RESULTS: Plasma pharmacokinetics of paclitaxel in patients with brain tumors were comparable to those previously described in patients with other malignancies. Paclitaxel could be measured in CSF of all patients, but concentrations were very low. Peak paclitaxel concentrations in CSF ranged between 5 and 83 nM and occurred between 3.25 and 5 hours after initiation of the paclitaxel infusion. Peak paclitaxel concentrations in CSF were between 0.12% and 8.3% of those present in concomitant plasma samples. Paclitaxel was not detectable in the normal or malignant CNS tissue of any rat, despite the fact that plasma concentrations of paclitaxel at the time of tissue acquisition ranged from 0.62 to 153 microM. CONCLUSIONS: Paclitaxel has only limited access to the CSF of patients with CNS malignancies and to normal and malignant CNS tissues of rats bearing brain tumors. IMPLICATIONS: The utility of combining paclitaxel with radiation therapy to treat CNS malignancies should be considered in light of the documented limited access of paclitaxel to the CNS.

Pharmacokinetics of cladribine (2-chlorodeoxyadenosine) in children with acute leukemia.

Cladribine is a synthetic purine nucleoside with demonstrated activity in hairy cell leukemia and acute myeloid leukemia. We have studied the pharmacokinetics of this drug in 25 pediatric patients with acute leukemia treated with cladribine as a single agent, 8.9 mg/m2/24 h, for 5 days by continuous i.v. infusion. Twelve patients were in relapse, and acute myeloid leukemia was newly diagnosed in 13 patients. Plasma, urine, and cerebrospinal fluid cladribine concentrations were determined by a radioimmunoassay with a limit of detection of 1 nM. An open two-compartment model was fit to the plasma concentration data. The mean (SD) clearance was 39.4 (12.4) liters/h/m2 and ranged from 14.4-55.4 liters/h/m2. When clearance was normalized to body weight (liters/h/kg) it was negatively correlated with age, with older patients having slower clearances per unit of body weight. However, when clearance was normalized to body surface area, no significant correlation with age was observed. The mean (SD) steady-state plasma concentration (predicted 120-h concentration) was 37.7 (17.3) nM and ranged from 23.2-84.5 nM. The terminal phase half-life in 22 patients ranged from 14.3-25.8 h, with a mean (SD) of 19.7 (3.4) h. The volume of distribution at steady state was highly variable, with a mean (SD) of 356.6 (225.2) liters/m2. None of these parameters was significantly different between patients in relapse and patients with newly diagnosed disease. Renal clearance was determined in 7 patients and ranged from 34.6-643.6 ml/min/m2, with a mean (SD) of 317.9 (208.7) ml/min/m2. Renal clearance as a percentage of total systemic clearance ranged from 11.0-85.1%, with a mean of 51.0%. In 11 patients, the mean (SD) cerebrospinal fluid concentration was 6.1 (3.97) nM, a mean of 18.2% of the steady-state plasma concentration. The CSF:plasma concentration ratio was significantly higher on day 5 (22.7% in 7 patients) than on day 4 (7.6% in 3 patients; P = 0.03). Additional studies are needed to further define the metabolic fate of cladribine. In this paper we provide the first comprehensive description of the pharmacokinetics of this drug in children and provide data which suggest that cladribine may be useful in the treatment of patients with meningeal leukemia or malignancies of the central nervous system.

2-Chlorodeoxyadenosine produces a high rate of complete hematologic remission in relapsed acute myeloid leukemia.

PURPOSE: The purine analog 2-chlorodeoxyadenosine (2-CDA) was well tolerated and showed promising anti-leukemic activity in a phase I trial conducted at St Jude Children's Research Hospital. To substantiate and extend this result, we performed a phase II trial in a representative group of children and young adults with relapsed acute leukemia. PATIENTS AND METHODS: Twenty-four patients (median age, 11 years) with acute myeloid or lymphoid leukemia in first or later relapse (acute myeloid leukemia [AML], 17; acute lymphoid leukemia [ALL], seven) were given continuous infusion 2-CDA for 5 days at 8.9 mg/m2/d. Patients with residual blast cells 10 days after treatment received a second course of 2-CDA that was identical to the first. Detailed pharmacokinetic studies were performed on plasma collected from five patients. RESULTS: Eight (47%) of the 17 patients with AML had complete hematologic remissions (four after the initial course of 2-CDA), and two (12%) had partial remissions, for a total response rate of 59%. Only one child with ALL achieved remission. Seven of the responding patients underwent allogeneic or autologous bone marrow transplantation, with six remaining free of leukemia for a median of 7 months (range, 1 to 11 months). The major form of drug-induced toxicity was hematologic, with severe neutropenia and thrombocytopenia (National Cancer Institute [NCI] grade 3 or 4) developing in 34 of the 36 courses of 2-CDA. In responding patients, the median times to recovery of neutrophil counts greater than 0.5 x 10(9)/L and platelet counts greater than 50 x 10(9)/L were 18 and 21 days, respectively. There were no deaths due to toxicity. The mean steady-state plasma concentration of 2-CDA was 34.6 nmol/L (range, 20 to 54 nmol/L). CONCLUSION: 2-CDA given by prolonged continuous infusion has clinically significant activity against AML and merits further testing in multidrug regimens for this disease.

Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans.

PURPOSE: To characterize and model the disposition of paclitaxel in humans and define a pharmacodynamic relationships between paclitaxel disposition and its toxicity and efficacy. PATIENTS AND METHODS: Paclitaxel pharmacokinetics were studied in 55 courses of therapy in 30 patients. Paclitaxel was administered at 135 mg/m2 or 175 mg/m2 by either a 3- or a 24-hour infusion schedule to patients with advanced ovarian cancer (n = 15), or at 225 mg/m2 by 3-hour infusion to patients with advanced breast cancer (n = 15). Paclitaxel and 6 alpha-hydroxylpaclitaxel were quantified by high-performance liquid chromatography (HPLC). Pharmacokinetics were assessed by noncompartmental and model-dependent methods. Pharmacodynamic correlations were evaluated statistically and by regression models. RESULTS: Paclitaxel disposition is nonlinear in humans and, on the 3-hour schedule, 6 alpha-hydroxylpaclitaxel was identified in the plasma of all patients treated. The plasma disposition of paclitaxel and 6 alpha-hydroxylpaclitaxel was well described by a model that featured multiple nonlinear processes. Neutropenia was not related to the areas under the curves (AUCs) of paclitaxel or 6 alpha-hydroxylpaclitaxel, or to palitaxel peak concentrations (Cmax). Neutropenia was related to the duration that plasma concentrations were > or = 0.05 mumol/L, a relationship that is well described by a sigmoid maximum response (Emax) model. CONCLUSION: The disposition of paclitaxel in humans is nonlinear. Paclitaxel metabolism to 6 alpha-hydroxylpaclitaxel is likely an important detoxification pathway. Myelosuppression is related to the duration that plasma paclitaxel concentrations are > or = 0.05 mumol/L. Trials of new doses and schedules of paclitaxel should take into account its nonlinear disposition to rule out adverse clinical consequences, especially if the drug is administered by short infusion. Our pharmacokinetic model should prove to be a powerful tool in predicting paclitaxel disposition, regardless of dose and schedule, and should facilitate further pharmacodynamic investigations.

Phase I study of weekly outpatient paclitaxel and concurrent cranial irradiation in adults with astrocytomas.

PURPOSE: Astrocytomas are extremely resistant to currently available treatments. Cranial irradiation is a mainstay of frontline therapy, but tumor recurrence is nearly universal. Paclitaxel has shown antitumor efficacy against astrocytoma cell lines, and is a potent radiosensitizer. For these reasons, we conducted a phase I study of weekly paclitaxel and concurrent cranial irradiation in patients with newly diagnosed astrocytomas. PATIENTS AND METHODS: Patients with astrocytomas were eligible for this study following initial surgery if they had a Karnofsky performance score (KPS) > or = 60%; normal hematologic, liver, and renal function; and could give informed consent. Beginning on day 1 of treatment, patients received paclitaxel by 3-hour infusion once weekly for 6 weeks, concurrent with standard cranial irradiation. Pharmacokinetic studies were performed on 10 patients. RESULTS: Sixty patients were enrolled; 56 were fully assessable. Forty-eight had glioblastomas (GBMs), 10 anaplastic astrocytomas (AAs), and two astrocytomas. Age ranged from 21 to 81 years (median, 55); KPS ranged from 60 to 100 (median, 70). The paclitaxel dose was escalated from 20 mg/m2 to 275 mg/m2. No clinically significant anemia or thrombocytopenia occurred. Only one patient (175 mg/m2) became neutropenic. Sensory neuropathy was dose-limiting. The maximum tolerated dose (MTD) was 250 mg/m2. Paclitaxel pharmacokinetic profiles in study patients were identical to those of previously reported patients with other solid tumors. CONCLUSION: The MTD of paclitaxel administered weekly for 6 weeks by 3-hour infusion is 250 mg/m2. Since patients with brain tumors often have preexisting neurologic deficits, we suggest 225 mg/m2 as the optimum dose for phase II trials in this group of patients.

Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264.

PURPOSE: To characterize the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of paclitaxel in patients with abnormal liver function. PATIENTS AND METHODS: Adults with tumors appropriate for paclitaxel therapy who had abnormal liver function tests were eligible. Patients were assigned to one of three treatment cohorts: I, AST level twofold normal and bilirubin level less than 1.5 mg/dL; II, bilirubin level 1.6 to 3.0 mg/dL; and III, bilirubin level greater than 3.0 mg/dL. Doses were explored in at least three patients within each cohort. Although designed to assess a 24-hour infusion schedule, the trial was extended to also assess a 3-hour regimen. Pharmacokinetics were to be studied in all patients. RESULTS: Eighty-one patients were assessable for toxicity. Patients with bilirubin levels greater than 1.5 mg/dL had substantial toxicity at all doses explored, whereas the toxicity for patients with elevated AST levels occurred at doses that ranged from 50 to 175 mg/m2 administered over 24 hours. In most patients, the DLT was myelosuppression. The pharmacokinetic data were insufficient to adequately evaluate the relationship between pharmacokinetics and toxicity in patients who received 24-hour infusions but provided evidence of a longer exposure to paclitaxel than anticipated for the doses used in this study in the 3-hour infusion group. CONCLUSION: If paclitaxel is used for patients with elevated levels of AST or bilirubin, dose reductions are necessary, and an increase in toxicity can be anticipated. The increased myelosuppression observed is at least partially because of altered paclitaxel pharmacokinetics in such patients.

Phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose of paclitaxel with carboplatin with and without filgrastim support in patients with metastatic non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of paclitaxel and carboplatin and correlate these with the pharmacodynamic effects. PATIENTS AND METHODS: Thirty-six chemotherapy-naive patients with metastatic NSCLC were entered into this phase I dose-escalation and pharmacokinetic study. Paclitaxel was initially administered as a 24-hour infusion at a fixed dose of 135 mg/m2, and the carboplatin dose was escalated in cohorts of three patients, using Calvert's formula [dose(mg) = area under the concentration time curve (glomerular filtration rate + 25)], to target areas under the concentration time curve (AUCs) of 5, 7, 9, and 11 mg/mL x minute. A measured 24-hour urinary creatinine clearance was substituted for the glomerular filtration rate. Once the maximum-tolerated AUC (MTAUC) of carboplatin was reached, the paclitaxel dose was escalated to 175, 200, and 225 mg/m2. When the paclitaxel dose escalation began, the AUC of carboplatin was reduced to one level below the MTAUC. RESULTS: Myelosuppression was the major dose-limiting toxicity. Thrombocytopenia was observed at a carboplatin AUC of 11 mg/mL x minute after course 2 and thereafter. End-of-infusion plasma paclitaxel concentrations and median duration of time above 0.05 microM were similar in course 1 versus course 2 at the 135 and 175 mg/m2 dose levels. The neutropenia experienced by patients was consistent with that observed in patients who had received paclitaxel alone. Measured carboplatin AUCs were approximately 12% (20% v 3% with course 1 v course 2, respectively) below the desired target, with a standard deviation of 34% at all dose levels. A sigmoid-maximum effect model describing the relationship between relative thrombocytopenia and measured free platinum exposure indicated that patients who received the combination of carboplatin with paclitaxel experienced less severe thrombocytopenia than would be expected from carboplatin alone. Of the 36 patients entered onto the study, one experienced a complete response and 17 had partial responses, for an overall response rate of 50%. The recommended doses of paclitaxel (24-hour infusion) and carboplatin for future phase II studies of this combination are (1) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute without filgrastim support; (2) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 9 mg/mL x minute with filgrastim support; and (3) paclitaxel 225 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute with filgrastim support. CONCLUSION: The regimen of paclitaxel and carboplatin is well-tolerated and has promising activity in the treatment of NSCLC. There is no pharmacokinetic interaction between paclitaxel and carboplatin, but there is a pharmacodynamic, platelet-sparing effect on this dose-limiting toxicity of carboplatin.

Considerations regarding the less-than-expected thrombocytopenia encountered with combination paclitaxel/carboplatin chemotherapy.

Whenever drugs are given in combination for the treatment of a disease, the potential for synergistic, additive, or antagonistic effects exists. Evaluation of the effects of drugs in combination requires that the effect of each drug as a single agent be well described. Recently, combination chemotherapy with carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has met with much clinical interest. Toxicity expectations of the combination were based on the established pharmacokinetic/pharmacodynamic relationships of each drug as a single agent. In several independent studies, investigators have noted that carboplatin-associated thrombocytopenia was less than expected in patients treated with combination carboplatin/paclitaxel. Although the mechanism underlying this observation has not been identified, carboplatin underdosing, variation in analytic or computational techniques, and pharmacokinetic interactions can be ruled out as contributing factors.

Paclitaxel pharmacokinetics and pharmacodynamics.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) displays nonlinear pharmacokinetics in humans. Both peak plasma paclitaxel concentrations and areas under the curve (AUCs) of the concentration versus time profiles will change disproportionately to changes in dose. Models that accurately describe the plasma paclitaxel profile contain two separate saturable processes, both described by Michaelis-Menten kinetics. Pharmacokinetic models using only linear components ultimately fail to describe adequately the disposition of paclitaxel in the body. The major toxicity of paclitaxel, neutropenia, appears to be related to the duration of time that plasma paclitaxel concentrations are at or above a threshold value. This relationship is well described by a sigmoid-Emax (maximum effect) model. Neutropenia is not directly related to either peak paclitaxel plasma concentration or to paclitaxel areas under the curve. A relationship between therapeutic efficacy and paclitaxel disposition is, as yet, undefined.