Examining temporal trends in psychological distress and the co-occurrence of common substance use in a population-based sample of grade 7-12 students from 2013 to 2019.

PURPOSE: Characterizing trends and correlates of adolescent psychological distress is important due to observed global increases over the last 20 years. Substance use is a commonly discussed correlate, though we lack an understanding about how co-occurrence of these concerns has been changing over time. METHODS: Data came from repeated, representative, cross-sectional surveys of grade 7-12 students across Ontario, Canada conducted biennially from 2013 to 2019. Poisson regression with robust standard errors was used to examine changes in the joint association between psychological distress (operationalized as Kessler-6 [K6] scores ≥ 13) and substance use over time. Weighted prevalence ratios (PR) and their 99% confidence intervals were estimated, where p < 0.01 denotes statistical significance. RESULTS: The prevalence of psychological distress doubled between 2013 and 2019, with adjusted increases of about 1.2 times each survey year. This biennial increase did not differ based on sex, perceived social standing, school level, or any substance use. Students using substances consistently reported a higher prevalence of psychological distress (between 1.2 times and 2.7 times higher). There were similarly no differential temporal trends based on substance use for very high distress (K6 ≥ 19) or K6 items explored individually. CONCLUSION: Psychological distress steeply increased among adolescents and substance use remains important to assess and address alongside distress. However, the magnitude of temporal increases appears to be similar for adolescents reporting and not reporting substance use.

Playing for more than winning: Exploring sports participation, physical activity, and belongingness and their relationship with patterns of adolescent substance use and mental health.

BACKGROUND: Promoting adolescent sports participation and physical activity may be effective low-barrier prevention strategies for co-occurring adolescent substance use (SU) and mental health symptoms (MH). The objectives of this study were to: 1) explore associations between profiles of SU/MH and sports participation; and 2) determine whether physical activity and belongingness account for these associations. METHODS: Data came from a representative sample of 11,994 grade 9-12 Ontarian students (ages ~14-18) previously grouped into five SU/MH profiles based on patterns of use and symptoms. A series of multinomial logistic regressions, adjusted for socio-demographics and school clustering, were used to predict the risks of students belonging to SU/MH profiles based on: 1) school sports participation (>=weekly), 2) sports and physical activity (>=60minutes; 0-7 days), and 3) sports, physical activity, and school belongingness. RESULTS: Greater school sports participation, physical activity, and belongingness were each associated with reduced risks of belonging to most profiles with elevations in SU and/or MH symptoms relative to the low SU/MH profile (Relative Risk Ratios: sports=0.62-0.87, physical activity=0.78-0.98, belonging=0.75-0.83). Frequency of physical activity accounted for ~32-60% of the associations between sports and SU/MH profiles, while school belongingness accounted for the remaining associations. Physical activity and belongingness remained independently associated with SU/MH profiles. CONCLUSIONS: Findings suggest possible indirect associations between school sports participation and SU/MH profiles through physical activity and school belongingness, which may be promising prevention targets that have independent associations over and above sports. School sports participation may be one of a number of ways to achieve these goals.

Unmet needs, quality of life and psychological distress: insights regarding head and neck cancer patients in a rural setting.

OBJECTIVE: This study aimed to evaluate the perceived quality of life, unmet needs and psychological distress in patients with head and neck cancer in a rural setting in New Zealand. METHOD: Patients presenting with head and neck cancer in Northland, New Zealand, were asked to complete questionnaires on quality of life, unmet needs, and anxiety or depression together with a free-text option. RESULTS: About one quarter of respondents (27 per cent) scored high in the anxiety and depression scale, with corresponding diminished quality of life scores and increased needs. Over half of respondents (54 per cent) found it challenging to travel for treatment. Financial difficulties were encountered more frequently with indigenous patients. Rurality alone does not lead to significant differences in quality of life or needs. CONCLUSION: After treatment for head and neck cancer, it is important to monitor and manage patients' psychological distress and ease of access to health services to improve quality of life.

Validity of the PROMIS depression and anxiety common metrics in an online sample of Australian adults.

PURPOSE: Recent US-based studies have utilised item response theory (IRT) to equate several self-report scales for depression and anxiety using the PROMIS depression and anxiety common metrics. The current study reports on the validity of the US-based equating procedures for the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7) and Kessler 6 psychological distress scale (K6) to equate scores in a large online sample of Australian adults. METHODS: Data comprised 3175 Australians recruited online. Each participant provided responses to the PROMIS depression and anxiety item banks, the PHQ-9, the GAD-7 and the K6. Two scoring methods were used to convert the scores on the PHQ-9, GAD-7 and K6 to the PROMIS depression and anxiety metrics. The converted scores were compared to the PROMIS depression and anxiety scores using intraclass correlations, mean difference, mean of absolute differences and Bland-Altman limits of agreement. RESULTS: Statistically significant mean differences were identified in five out of eight equated scores, albeit the effect sizes were small (Cohen's dz ≤ 0.25). The correlations were uniformly high (ICC ≥ 0.86). The mean of absolute differences between observed and equated scores for each metric and across scoring methods ranged between 4.23 and 5.33. CONCLUSIONS: The results demonstrate the validity of generating PROMIS depression and anxiety scores from the PHQ-9, GAD-7 and K6 in an independent sample of Australians. The agreement between equated scores provides some assurance that researchers and clinicians can utilise the converted PHQ-9, GAD-7 and K6 scores on the PROMIS metrics without a substantial decrease in accuracy and precision at the group level.

Assessing distress in the community: psychometric properties and crosswalk comparison of eight measures of psychological distress.

BACKGROUND: Many measures are available for measuring psychological distress in the community. Limited research has compared these scales to identify the best performing tools. A common metric for distress measures would enable researchers and clinicians to equate scores across different measures. The current study evaluated eight psychological distress scales and developed crosswalks (tables/figures presenting multiple scales on a common metric) to enable scores on these scales to be equated. METHODS: An Australian online adult sample (N = 3620, 80% female) was administered eight psychological distress measures: Patient Health Questionnaire-4, Kessler-10/Kessler-6, Distress Questionnaire-5 (DQ5), Mental Health Inventory-5, Hopkins Symptom Checklist-25 (HSCL-25), Self-Report Questionnaire-20 (SRQ-20) and Distress Thermometer. The performance of each measure in identifying DSM-5 criteria for a range of mental disorders was tested. Scale fit to a unidimensional latent construct was assessed using Confirmatory Factor Analysis (CFA). Finally, crosswalks were developed using Item Response Theory. RESULTS: The DQ5 had optimal performance in identifying individuals meeting DSM-5 criteria, with adequate fit to a unidimensional construct. The HSCL-25 and SRQ-20 also had adequate fit but poorer specificity and/or sensitivity than the DQ5 in identifying caseness. The unidimensional CFA of the combined item bank for the eight scales showed acceptable fit, enabling the creation of crosswalk tables. CONCLUSIONS: The DQ5 had optimal performance in identifying risk of mental health problems. The crosswalk tables developed in this study will enable rapid conversion between distress measures, providing more efficient means of data aggregation and a resource to facilitate interpretation of scores from multiple distress scales.

Perceived needs for mental health care and barriers to treatment across age groups.

PURPOSE: This study aimed to assess responses to a structured measure of perceived need for treatment to understand whether differences in treatment uptake across age groups are related to differences in: (1) perceived need for mental health care; (2) perceptions of treatment needs being met; and/or (3) perceived attitudinal and structural treatment barriers. METHODS: Data from a nationally representative sample of the Australian population (2007 National Survey of Mental Health and Wellbeing) were analysed using logistic and multinomial regression. All participants potentially benefiting from mental health services were included in analyses; including those reporting symptoms of mental disorders, using mental health services, or self-reporting significant mental health problems in the past 12 months (n = 5733). All regression analyses were adjusted for gender, the presence of chronic physical health conditions, disorder type, and disorder severity. RESULTS: Older adults were the least likely to report any perceived need for mental health care, and specifically reported lower needs for psychotherapy, information about available services, and support improving their ability to work. Older adults perceiving a need for mental health care were also the most likely to report having these needs met. There were no differences in attitudinal and structural barriers to treatment across age groups. CONCLUSIONS: These results highlight that age needs to be considered in strategies for improving engagement and efficacy of mental health services, as well as the need for further research to understand what drives age differences in perceived need for mental health care.

The structure of adolescent psychopathology: a symptom-level analysis.

BACKGROUND: Most empirical studies into the covariance structure of psychopathology have been confined to adults. This work is not developmentally informed as the meaning, age-of-onset, persistence and expression of disorders differ across the lifespan. This study investigates the underlying structure of adolescent psychopathology and associations between the psychopathological dimensions and sex and personality risk profiles for substance misuse and mental health problems. METHOD: This study analyzed data from 2175 adolescents aged 13.3 years. Five dimensional models were tested using confirmatory factor analysis and the external validity was examined using a multiple-indicators multiple-causes model. RESULTS: A modified bifactor model, with three correlated specific factors (internalizing, externalizing, thought disorder) and one general psychopathology factor, provided the best fit to the data. Females reported higher mean levels of internalizing, and males reported higher mean levels of externalizing. No significant sex differences emerged in liability to thought disorder or general psychopathology. Liability to internalizing, externalizing, thought disorder and general psychopathology was characterized by a number of differences in personality profiles. CONCLUSIONS: This study is the first to identify a bifactor model including a specific thought disorder factor. The findings highlight the utility of transdiagnostic treatment approaches and the importance of restructuring psychopathology in an empirically based manner.

Examining the shared and unique relationships among substance use and mental disorders.

BACKGROUND: Co-morbidity among use of different substances can be explained by a shared underlying dimensional factor. What remains unknown is whether the relationship between substance use and various co-morbid mental disorders can be explained solely by the general factor or whether there remain unique contributions of specific substances. METHOD: Data were from the 2007 Australian National Survey of Mental Health and Wellbeing (NSMHWB). A unidimensional latent factor was constructed that represented general substance use. The shared and specific relationships between lifetime substance use indicators and internalizing disorders, suicidality and psychotic-like experiences (PLEs) were examined using Multiple Indicators Multiple Causes (MIMIC) models in the total sample. Additional analyses then examined the shared and specific relationships associated with substance dependence diagnoses as indicators of the latent trait focusing on a subsample of substance users. RESULTS: General levels of latent substance use were significantly and positively related to internalizing disorders, suicidality and psychotic-like experiences. Similar results were found when examining general levels of latent substance dependence in a sample of substance users. There were several direct effects between specific substance use/dependence indicators and the mental health correlates that significantly improved the overall model fit but they were small in magnitude and had relatively little impact on the general relationship. CONCLUSIONS: The majority of pairwise co-morbid relationships between substance use/dependence and mental health correlates can be explained through a general latent factor. Researchers should focus on investigating the commonalities across all substance use and dependence indicators when studying mental health co-morbidity.

Reductions in the internalising construct following internet-delivered treatment for anxiety and depression in primary care.

Depressive and anxiety disorders are different manifestations of a latent internalising construct. To date, efficacy studies have tended to focus on disorder-specific outcomes, rather than underlying dimensions. This study examined the effect of a transdiagnostic internet-delivered cognitive behavioural therapy (iCBT) on the internalising construct in a primary care sample. Participants included 635 patients aged 18 years or over who were prescribed a six lesson transdiagnostic iCBT program for anxiety and depression by their primary healthcare professional. All patients completed the Patient Health Questionnaire 9, the Generalised Anxiety Disorder 7-Item Scale, the Mini Social Phobia Inventory and the Panic Disorder Severity Self-Report Scale at baseline. 325 of these patients completed the program and provided data on each of these scales during the final lesson. Reductions in the latent internalising construct were assessed within a longitudinal factor analysis framework that compared internalising factor means before and after treatment. The within group mean reduction in the latent internalising construct was large (ES = 1.23, SE = 0.09; p < 0.001). Due to the lack of a control group, between group reductions in the latent internalising construct could not be investigated. This study demonstrated that there are clinically significant reductions in the latent internalising construct following transdiagnostic iCBT for anxiety and depression.

An examination of generalized anxiety disorder and dysthymic disorder by latent class analysis.

BACKGROUND: The nosological status of generalized anxiety disorder (GAD) versus dysthymic disorder (DD) has been questioned. The aim of this study was to examine qualitative differences within (co-morbid) GAD and DD symptomatology. METHOD: Latent class analysis was applied to anxious and depressive symptomatology of respondents from three population-based studies (2007 Australian National Survey of Mental Health and Wellbeing; National Comorbidity Survey Replication; and Netherlands Mental Health Survey and Incidence Study-2; together known as the Triple study) and respondents from a multi-site naturalistic cohort [Netherlands Study of Depression and Anxiety (NESDA)]. Sociodemographics and clinical characteristics of each class were examined. RESULTS: A three-class (Triple study) and two-class (NESDA) model best fitted the data, reflecting mainly different levels of severity of symptoms. In the Triple study, no division into a predominantly GAD or DD co-morbidity subtype emerged. Likewise, in spite of the presence of pure GAD and DD cases in the NESDA sample, latent class analysis did not identify specific anxiety or depressive profiles in the NESDA study. Next, sociodemographics and clinical characteristics of each class were examined. Classes only differed in levels of severity. CONCLUSIONS: The absence of qualitative differences in anxious or depressive symptomatology in empirically derived classes questions the differentiation between GAD and DD.

Psychotic-like experiences in a community sample of 8000 children aged 9 to 11 years: an item response theory analysis.

BACKGROUND: Psychotic-like experiences (PLEs) in the general population are common, particularly in childhood, and may constitute part of a spectrum of normative development. Nevertheless, these experiences confer increased risk for later psychotic disorder, and are associated with poorer health and quality of life. METHOD: This study used factor analytic methods to determine the latent structure underlying PLEs, problem behaviours and personal competencies in the general child population, and used item response theory (IRT) to assess the psychometric properties of nine PLE items to determine which items best represented a latent psychotic-like construct (PSY). A total of 7966 children aged 9-11 years, constituting 95% of eligible children, completed self-report questionnaires. RESULTS: Almost two-thirds of the children endorsed at least one PLE item. Structural analyses identified a unidimensional construct representing psychotic-like severity in the population, the full range of which was well sampled by the nine items. This construct was discriminable from (though correlated with) latent dimensions representing internalizing and externalizing problems. Items assessing visual and auditory hallucination-like experiences provided the most information about PSY; delusion-like experiences identified children at more severe levels of the construct. CONCLUSIONS: Assessing PLEs during middle childhood is feasible and supplements information concerning internalizing and externalizing problems presented by children. The hallucination-like experiences constitute appropriate items to screen the population to identify children who may require further clinical assessment or monitoring. Longitudinal follow-up of the children is required to determine sensitivity and specificity of the PLE items for later psychotic illness.

Investigating differential symptom profiles in major depressive episode with and without generalized anxiety disorder: true co-morbidity or symptom similarity?

BACKGROUND: Large community-based epidemiological surveys have consistently identified high co-morbidity between major depressive episode (MDE) and generalized anxiety disorder (GAD). Some have suggested that this co-morbidity may be artificial and the product of the current diagnostic system. Because of the added direct and indirect costs associated with co-morbidity, it is important to investigate whether methods of diagnostic classification are artificially increasing the level of observed co-morbidity. METHOD: The item response theory (IRT) log-likelihood ratio procedure was used to test for differential item functioning (DIF) of MDE symptoms between respondents with and without a diagnosis of GAD in the 2001-2002 National Epidemiological Survey on Alcohol and Related Conditions (NESARC). RESULTS: The presence of GAD significantly increased the chances of reporting any symptom of MDE, with odds ratios ranging from 2.54 to 5.36. However, there was no indication of significant DIF of MDE symptoms in respondents with and without GAD. CONCLUSIONS: The lack of any significant DIF indicates that cases with GAD do not present with a distinct MDE symptom profile, one that is consistent with the endorsement of symptoms that are conceptually similar in nature between the two disorders, compared to cases without GAD. This does not support the hypothesis that co-morbidity between MDE and GAD is artificially inflated because of the similar symptom criteria required by the current diagnostic system. Instead, MDE and GAD may be thought of as two distinct diagnostic entities that frequently co-occur because of a shared underlying trait.

Neurocognitive disorders: cluster 1 of the proposed meta-structure for DSM-V and ICD-11.

BACKGROUND: In an effort to group mental disorders on the basis of aetiology, five clusters have been proposed. In this paper, we consider the validity of the first cluster, neurocognitive disorders, within this proposal. These disorders are categorized as 'Dementia, Delirium, and Amnestic and Other Cognitive Disorders' in DSM-IV and 'Organic, including Symptomatic Mental Disorders' in ICD-10. METHOD: We reviewed the literature in relation to 11 validating criteria proposed by a Study Group of the DSM-V Task Force as applied to the cluster of neurocognitive disorders. RESULTS: 'Neurocognitive' replaces the previous terms 'cognitive' and 'organic' used in DSM-IV and ICD-10 respectively as the descriptor for disorders in this cluster. Although cognitive/organic problems are present in other disorders, this cluster distinguishes itself by the demonstrable neural substrate abnormalities and the salience of cognitive symptoms and deficits. Shared biomarkers, co-morbidity and course offer less persuasive evidence for a valid cluster of neurocognitive disorders. The occurrence of these disorders subsequent to normal brain development sets this cluster apart from neurodevelopmental disorders. The aetiology of the disorders is varied, but the neurobiological underpinnings are better understood than for mental disorders in any other cluster. CONCLUSIONS: Neurocognitive disorders meet some of the salient criteria proposed by the Study Group of the DSM-V Task Force to suggest a classification cluster. Further developments in the aetiopathogenesis of these disorders will enhance the clinical utility of this cluster.

Neurodevelopmental disorders: cluster 2 of the proposed meta-structure for DSM-V and ICD-11.

BACKGROUND: DSM-IV and ICD-10 are atheoretical and largely descriptive. Although this achieves good reliability, the validity of diagnoses can be increased by an understanding of risk factors and other clinical features. In an effort to group mental disorders on this basis, five clusters have been proposed. We now consider the second cluster, namely neurodevelopmental disorders. METHOD: We reviewed the literature in relation to 11 validating criteria proposed by a DSM-V Task Force Study Group. RESULTS: This cluster reflects disorders of neurodevelopment rather than a 'childhood' disorders cluster. It comprises disorders subcategorized in DSM-IV and ICD-10 as Mental Retardation; Learning, Motor, and Communication Disorders; and Pervasive Developmental Disorders. Although these disorders seem to be heterogeneous, they share similarities on some risk and clinical factors. There is evidence of a neurodevelopmental genetic phenotype, the disorders have an early emerging and continuing course, and all have salient cognitive symptoms. Within-cluster co-morbidity also supports grouping these disorders together. Other childhood disorders currently listed in DSM-IV share similarities with the Externalizing and Emotional clusters. These include Conduct Disorder, Attention Deficit Hyperactivity Disorder and Separation Anxiety Disorder. The Tic, Eating/Feeding and Elimination disorders, and Selective Mutisms were allocated to the 'Not Yet Assigned' group. CONCLUSION: Neurodevelopmental disorders meet some of the salient criteria proposed by the American Psychiatric Association (APA) to suggest a classification cluster.

Classification of anxiety and depressive disorders: problems and solutions.

The American Psychiatric Association and the World Health Organization have begun to revise their classifications of mental disorders. Four issues related to these revisions are discussed in this study: the structure of the classifications, the relationship between categories and dimensions, the sensitivity of categorical thresholds to definitions, and maximizing the utility and validity of the diagnostic process. There is now sufficient evidence to consider replacing the present groupings of disorders with an empirically based structure that reflects the actual similarities among disorders. For example, perhaps the present depression and anxiety disorders would be best grouped as internalizing disorders. Most mental disorders exist on a severity dimension. The reliability and validity of the classification might be improved if we accepted the dimensional nature of disorders while retaining the use of categorical diagnoses to enhance clinical utility. Definitions of the thresholds that define categories are very susceptible to detail. In International Classification of Diseases-11(ICD-11) and Diagnostic and Statistical Manual of Mental Disorders-V (DSM-V), disorders about which there is agreement should be identically defined, and disorders in which there is disagreement should be defined differently, so that research can identify which definition is more valid. The present diagnostic criteria are too complex to have acceptable clinical utility. We propose a reduced criterion set that can be remembered by clinicians and an enhanced criterion set for use with decision support tools.

Vitiligo and Graves' disease following treatment of malignant melanoma with recombinant human interleukin 4.

This report describes a patient with metastatic malignant melanoma treated with recombinant human interleukin 4 who developed vitiligo and severe Graves' Disease after therapy. The patient has experienced complete remission of melanoma for 49+ months. The association of antitumor response, vitiligo and thyroid disorders is reviewed.

Phase I/II trial of continuous infusion vinorelbine for advanced breast cancer.

PURPOSE: A phase I/II trial of vinorelbine (VRL) administered by continuous infusion (CIV) was conducted in advanced breast carcinoma (ABC) patients to determine the maximum-tolerated dose (MTD) and to evaluate the toxicity pattern and antitumor activity of this alternative administration schedule to the currently recommended weekly short intravenous (IV) administration. PATIENTS AND METHODS: Between February 1990 and July 1991, 64 consecutive, eligible patients with ABC were treated; 33 had received one or two previous palliative chemotherapy combinations and 31 had not received chemotherapy for metastatic disease. VRL was administered, after an initial IV bolus of 8 mg/m2 on day 1, by a 4-day CIV at five different 24-hour dose levels (DLs) to be repeated every 21 or 28 days: DL1, 5.5 mg/m2; DL2, 7 mg/m2; DL3, 8 mg/m2, DL4, 9 mg/m2; and DL5, 10 mg/m2. RESULTS: The limiting noncumulative toxicity was neutropenia, with the MTD established at 8 mg/m2 bolus plus 10 mg/m2/d for 4 days (total dose per cycle, 48 mg/m2). At DL3 and DL4, we observed mucositis (14% of patients; five percent of cycles > grade 2), alopecia, and asthenia. By contrast, neurotoxicity was minor. The toxicity was otherwise predictable and manageable. Pharmacokinetic data obtained at DL1 and DL3 showed a mean VRL plasma concentration of 967 +/- 331 ng/mL after the initial 8 mg/m2 IV bolus dose, which declined rapidly thereafter to reach mean steady-state levels of 12 ng/mL (n = 5) for the 30-mg/m2 dose and 8 ng/mL (n = 2) for the 40-mg/m2 dose. These levels were maintained over the 96-hour CIV. The mean residence time (MRT) was 29 +/- 7 hours (terminal half-life [t1/2], 23 hours), the total-body clearance (CL) was 24 +/- 11 L/hr/m2, and the volume of distribution at steady-state (Vss) was high at 1,832 +/- 359 L/m2. Two patients achieved a complete response (CR) and 21 a partial response (PR), for an objective response rate of 36% (95% confidence interval [Cl], 23 to 49). The median duration of response was 6 months. The median survival duration was 24 months (range, 3 to 37). A relationship between given dose-intensity and objective response rate was found, with an overall response (OR) rate of 13.3% (two of 15) for 8 to 10 mg/m2/wk, 35.4% (11 of 31) for 10 to 12 mg/m2/wk, and 55.5% (10 of 18) for 12 to 14.5 mg/m2/wk. CONCLUSION: This trial, while confirming VRL activity in ABC, shows the feasability of a CIV administration schedule. A decrease of the administrated total dose per 3- to 4-week cycle to less than the weekly schedule with the same therapeutic activity suggests a better therapeutic index. The data are also suggestive of a dose-response relationship and a dose-intensity/activity correlation.

Phase II studies of recombinant human interleukin-4 in advanced renal cancer and malignant melanoma.

Interleukin (IL-4) is a pluripotent cytokine that stimulates proliferation of activated T-cells and has antineoplastic activity against human renal tumors in animal systems. In phase I trials, IL-4 could be tolerated at doses up to 20 micrograms/kg, with dose-limiting toxicities consisting of fever, fluid retention, nasal congestion, and mucositis. We report the results of two separate Phase II trials of IL-4 in 30 patients with metastatic malignant melanoma and 19 patients with advanced renal cancer. IL-4 was administered intravenously every 8 h for 14 doses in two 5-day courses separated by a 9-day interval. The first 27 patients were treated at a dose of 800 micrograms/m2, but after three of these patients developed cardiac toxicities, the dose was decreased to 600 micrograms/m2. One complete response occurred in a patient with metastatic melanoma (duration > or = 30 months). No responses were seen among the patients with renal cancer. The most frequent side effects were fever, nausea, malaise, nasal congestion, and diarrhea. Reversible hepatic and renal dysfunction were also common. Hypotension was infrequent, but transient weight gain due to fluid retention was common. The major life-threatening toxicities were cardiac and gastrointestinal. Suspected cardiac ischemia was observed in two patients, pericarditis in one, and arrhythmias in two. Three patients had major upper gastrointestinal bleeding without evidence of local tumor. We conclude that IL-4, when given as a single agent on this schedule at maximum tolerated dose, does not possess meaningful activity in renal cancer or melanoma.

Failure of GM-CSF to permit dose-escalation in an every other week dose-intensive regimen for advanced breast cancer.

BACKGROUND: In an attempt to improve dose intensity and therapeutic effectiveness in breast cancer, GM-CSF was incorporated into a multi-drug every other week chemotherapy regimen that had been previously reported to have promising activity, but whose dose-limiting toxicity was neutropenia. PATIENTS AND METHODS: A Phase I-II study in patients with locally advanced or metastatic breast cancer was initiated using GM-CSF and a 5-drug chemotherapy regimen employing oral cyclophosphamide daily for 7 days and doxorubicin, vincristine, methotrexate, 5-fluorouracil, and leucovorin IV every 2 weeks for 10 courses. In the first 8 patients, GM-CSF in escalating doses (1-20 micrograms/kg s.c. per day) was given on days 8-13 of each 2 week cycle. In the last 12 patients, GM-CSF was given on days 3-14 of each cycle in an attempt to improve its effectiveness by prolonging treatment duration. RESULTS: The regimen was poorly tolerated. Only 10 patients completed all 10 courses of treatment, and most of those required dose delays and/or reductions. GM-CSF failed to reduce neutropenia when given by either schedule. Furthermore, thrombocytopenia was severe and progressive, especially with the more prolonged GM-CSF schedule in which the mean lowest nadir platelet count was 15,000/microliters. Anemia, fatigue, mucositis, and neutropenic fevers were also common, and dose escalations were not possible in any patient. Central venous catheter complications were also common. Complete or partial remissions were observed in 15 of 20 patients, but response durations were brief. CONCLUSIONS: GM-CSF in two different schedules failed to ameliorate myelosuppression when used in combination with this multiple drug, every other week regimen. Neutropenia and, especially, thrombocytopenia remained dose limiting.