The addition of fluoxetine to cognitive behavioural therapy for youth depression (YoDA-C): study protocol for a randomised control trial.

BACKGROUND: The aim of the Youth Depression Alleviation-Combined Treatment (YoDA-C) study is to determine whether antidepressant medication should be started as a first-line treatment for youth depression delivered concurrently with psychotherapy. Doubts about the use of medication have been raised by meta-analyses in which the efficacy and safety of antidepressants in young people have been questioned, and subsequent treatment guidelines for youth depression have provided only qualified support. METHODS/DESIGN: YoDA-C is a double-blind, randomised controlled trial funded by the Australian government's National Health and Medical Research Council. Participants between the ages of 15 and 25 years with moderate to severe major depressive disorder will be randomised to receive either (1) cognitive behavioural therapy (CBT) and fluoxetine or (2) CBT and placebo. The treatment duration will be 12 weeks, and follow-up will be conducted at 26 weeks. The primary outcome measure is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) after 12 weeks of treatment. The MADRS will be administered at baseline and at weeks 4, 8, 12 and 26. Secondary outcome measures will address additional clinical outcomes, functioning, quality of life and safety. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ID: ACTRN12612001281886 (registered on 11 December 2012).

Long-term follow-up of all-cause and unnatural death in young people with first-episode psychosis.

OBJECTIVE: To determine mortality-related estimates and causes of death in young people with first-episode psychosis (FEP), and to identify baseline predictors of mortality. METHOD: Mortality outcomes in 723 young people presenting to an early psychosis service were prospectively ascertained up to 20 years. Predictors of all-cause and unnatural death were investigated using survival techniques. RESULTS: Forty-nine participants died by study end. Most deaths (n=41) occurred within 10 years of service entry. All-cause mortality was 5.5% at 10 years, rising to 8.0% after 20 years. Unnatural death rates at 10 and 20 years were 5.0% and 5.9%, respectively. Three risk factors consistently predicted all-cause mortality and unnatural deaths. CONCLUSION: A substantial proportion of excess mortality was due to non-suicide unnatural death, and, later, natural deaths. This suggests that mental health services should expand their current focus on suicide to incorporate strategies to prevent accidental death and promote healthier lifestyles.

Is there a gap between recommended and 'real world' practice in the management of depression in young people? A medical file audit of practice.

BACKGROUND: Literature has shown that dissemination of guidelines alone is insufficient to ensure that guideline recommendations are incorporated into every day clinical practice. METHODS: We aimed to investigate the gaps between guideline recommendations and clinical practice in the management of young people with depression by undertaking an audit of medical files in a catchment area public mental health service for 15 to 25 year olds in Melbourne, Australia. RESULTS: The results showed that the assessment and recording of depression severity to ensure appropriate treatment planning was not systematic nor consistent; that the majority of young people (74.5%) were prescribed an antidepressant before an adequate trial of psychotherapy was undertaken and that less than 50% were monitored for depression symptom improvement and antidepressant treatment emergent suicide related behaviours (35% and 30% respectively). Encouragingly 92% of first line prescriptions for those aged 18 years or under who were previously antidepressant-naïve was for fluoxetine as recommended. CONCLUSIONS: This research has highlighted the need for targeted strategies to ensure effective implementation. These strategies might include practice system tools that allow for systematic monitoring of depression symptoms and adverse side effects, particularly suicide related behaviours. Additionally, youth specific psychotherapy that incorporates the most effective components for this age group, delivered in a youth friendly way would likely aid effective implementation of guideline recommendations for engagement in an adequate trial of psychotherapy before medication is initiated.

Does engagement with an intensive outreach service predict better treatment outcomes in 'high-risk' youth?

AIM: Engagement is critical in ensuring that the most 'at risk' clients receive care from psychiatric services, but the relationship between engagement and treatment outcomes remains unclear. This study investigated possible improvements in client engagement and the relationship between engagement and treatment outcomes in a group of difficult-to-engage, 'high-risk' young people seen by the Intensive Mobile Youth Outreach Service (IMYOS) in Western Metropolitan Melbourne, Australia. METHODS: Data from standardized outcome measures on client engagement, suicidality, hostility, well-being and functioning obtained at referral, after initial assessment and at discharge, were analysed retrospectively. RESULTS: Improved engagement was achieved after initial assessment and remained steady at discharge. All outcome measures showed significant improvement at discharge. Higher overall engagement following assessment was associated with decreased hostility risk and greater well-being and functioning at discharge. The engagement dimensions 'collaboration', 'perceived usefulness' and 'client-therapist interaction' were most consistently associated with better treatment outcomes. CONCLUSION: Engagement at an early stage of treatment can be a useful predictor for later hostility risk, well-being and functioning. To promote better outcomes for difficult-to-engage youth, service delivery needs to focus on collaborative client involvement, the development of a 'strong' therapeutic alliance and individualization of treatment in regard to client needs.

Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02.

PURPOSE: To report the impact of radiotherapy quality on outcome in a large international phase III trial evaluating radiotherapy with concurrent cisplatin plus tirapazamine for advanced head and neck cancer. PATIENTS AND METHODS: The protocol required interventional review of radiotherapy plans by the Quality Assurance Review Center (QARC). All plans and radiotherapy documentation underwent post-treatment review by the Trial Management Committee (TMC) for protocol compliance. Secondary review of noncompliant plans for predicted impact on tumor control was performed. Factors associated with poor protocol compliance were studied, and outcome data were analyzed in relation to protocol compliance and radiotherapy quality. RESULTS: At TMC review, 25.4% of the patients had noncompliant plans but none in which QARC-recommended changes had been made. At secondary review, 47% of noncompliant plans (12% overall) had deficiencies with a predicted major adverse impact on tumor control. Major deficiencies were unrelated to tumor subsite or to T or N stage (if N+), but were highly correlated with number of patients enrolled at the treatment center (< five patients, 29.8%; > or = 20 patients, 5.4%; P < .001). In patients who received at least 60 Gy, those with major deficiencies in their treatment plans (n = 87) had a markedly inferior outcome compared with those whose treatment was initially protocol compliant (n = 502): -2 years overall survival, 50% v 70%; hazard ratio (HR), 1.99; P < .001; and 2 years freedom from locoregional failure, 54% v 78%; HR, 2.37; P < .001, respectively. CONCLUSION: These results demonstrate the critical importance of radiotherapy quality on outcome of chemoradiotherapy in head and neck cancer. Centers treating only a few patients are the major source of quality problems.

Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group.

PURPOSE: Promising results in a randomized phase II trial with the hypoxic cytotoxin tirapazamine (TPZ) combined with cisplatin (CIS) and radiation led to this phase III trial. PATIENTS AND METHODS: Patients with previously untreated stage III or IV (excluding T1-2N1 and M1) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either CIS (100 mg/m(2)) on day 1 of weeks 1, 4, and 7 or CIS (75 mg/m(2)) plus TPZ (290 mg/m(2)/d) on day 1 of weeks 1, 4, and 7 and TPZ alone (160 mg/m(2)/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS). The primary end point was overall survival (OS). The planned sample size was 850, estimated to result in 334 deaths, which would provide 90% power to detect a difference in 2-year survival rates of 60% v 70% for CIS versus TPZ/CIS, respectively (hazard ratio = 0.69). RESULTS: Eight hundred sixty-one patients were accrued from 89 sites in 16 countries. In an intent-to-treat analysis, the 2-year OS rates were 65.7% for CIS and 66.2% for TPZ/CIS (TPZ/CIS--CIS: 95% CI, -5.9% to 6.9%). There were no significant differences in failure-free survival, time to locoregional failure, or quality of life as measured by Functional Assessment of Cancer Therapy-Head and Neck. CONCLUSIONS: We found no evidence that the addition of TPZ to chemoradiotherapy, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improves OS.

Prospective trial to evaluate staged neck dissection or elective neck radiotherapy in patients with CT-staged T1-2 N0 squamous cell carcinoma of the oral tongue.

BACKGROUND: A prospective study was undertaken to evaluate a policy of selective, single-modality elective neck treatment in T1-2, node-negative oral tongue squamous cell carcinoma. METHODS: Where the primary tumor showed 1 of the 4 key pathological criteria (greater than 7 mm of muscle invasion, less than 5 mm of resection margin, perineural or lymphovascular invasion), radiotherapy was delivered to the primary site and the at-risk undissected neck. Otherwise patients underwent ipsilateral neck dissection within 4 weeks of initial resection. Prospective quality of life assessments were performed. RESULTS: The study was closed after accrual of 25 patients, because the high locoregional recurrence rate met early stopping criteria. With a median follow-up of 3.4 years, the locoregional recurrence rate was 23%. The 4-year overall and disease-free survival rates were 71% and 64%, respectively. CONCLUSION: The poor disease-free survival reflects the need for better prognostic markers and more aggressive treatment in these patients.

Long-term survival following chemoradiation for inoperable non-small cell lung cancer.

OBJECTIVE: To measure long-term survival following combined chemotherapy and radiotherapy for inoperable non-small cell lung cancer. DESIGN AND SETTING: Two prospective Phase I/II studies in the multidisciplinary Lung Service of a dedicated cancer hospital in Victoria, commencing in 1996 and 1997-1998. PATIENTS: 33 patients referred for treatment of histologically or cytologically proven inoperable non-small cell lung cancer, who had no evidence of distant metastases, Karnofsky performance status > 70%, weight loss < 10%, and no prior treatment for lung cancer. Patients were followed until death or for a minimum of 9 years. INTERVENTIONS: Patients in both studies were treated concomitantly with chemotherapy and radiotherapy 60 Gy in 30 fractions over 6 weeks. Chemotherapy in the first study (LURTCE) consisted of cisplatin and etoposide; in the second study (LURTCF), chemotherapy consisted of escalating doses of carboplatin and fluorouracil. MAIN OUTCOME MEASURE: Overall survival. RESULTS: Six of 33 patients were still alive 9 years after commencement of treatment. Median survival for the whole group was 2.1 years (95% CI, 1.3-3.1 years), with 18% (95% CI, 8%-35%) of patients still alive at 5 years (plateau). CONCLUSION: Long-term survival can be achieved in some patients with inoperable non-small cell lung cancer treated by radical chemoradiation alone, suggesting the possibility of cure.

A prospective study to evaluate the impact of FDG-PET on CT-based radiotherapy treatment planning for oesophageal cancer.

BACKGROUND AND PURPOSE: This prospective study sought to determine how the use of combined PET/CT for radiotherapy treatment planning of oesophageal cancer would alter the delineation of tumour volumes compared to CT alone if PET/CT is assumed to more accurately represent true disease extent. PATIENTS AND METHODS: All patients underwent FDG-PET/CT scanning in the radiotherapy treatment position. For each patient, two separate gross tumour volumes (GTV) were defined, one based on CT images alone (GTV-CT) and another based on combined PET/CT data (GTV-PET). Corresponding planning target volumes (PTV) were generated, and separate treatment plans were then produced. For each patient, volumetric analysis of GTV-CT, PTV-CT and GTV-PET was performed to quantify the proportion of PET-avid disease that was not included in the GTV and PTV (geographic miss) if CT data alone were used for radiotherapy planning. Assessment of the cranial and caudal extent of the primary oesophageal tumour as defined by CT alone vs PET/CT was also compared. RESULTS: The addition of PET information altered the clinical stage in 8 of 21 eligible patients enrolled on the study (38%); 4 patients had distant metastatic disease and 4 had unsuspected regional nodal disease. Sixteen patients proceeded to the radiotherapy planning phase of the study and received definitive chemoradiation planned with the PET/CT data set. The GTV based on CT information alone excluded PET-avid disease in 11 patients (69%), and in five patients (31%) this would have resulted in a geographic miss of gross tumour. The discordance between CT and PET/CT was due mainly to differences in defining the longitudinal extent of disease in the oesophagus. The cranial extent of the primary tumour as defined by CT vs PET/CT differed in 75% of cases, while the caudal extent differed in 81%. CONCLUSIONS: This study demonstrates that if combined PET/CT is used for radiotherapy treatment planning, there may be alterations to the delineation of tumour volumes when compared to CT alone, with the potential to avoid a geographic miss of tumour.

Long-term outcome after radiotherapy alone for lymphocyte-predominant Hodgkin lymphoma: a retrospective multicenter study of the Australasian Radiation Oncology Lymphoma Group.

BACKGROUND: The curative potential of radiotherapy (RT) alone as initial treatment for patients with Stage I-II lymphocyte-predominant Hodgkin lymphoma (LPHL) has not been defined well. METHODS: Two hundred two patients who were treated between 1969 and 1995 were evaluated in a retrospective, multicenter study. RESULTS: Patient characteristics were as follows: The median age was 31 years, 75% of patients were male, 80% of patients had Ann Arbor Stage I disease, 1% of patients had bulky disease, 3% of patients had B symptoms, 1% of patients had extranodal involvement, and 80% of patients had supradiaphragmatic disease. The RT fields were a full mantle field in 52% of patients, less than a full mantle field in 24% of patients, an inverted-Y field in 17% of patients, less than an inverted-Y field in 3% of patients, and total lymph node irradiation in 3% of patients. The median dose was 36 Gray. The median follow-up was 15 years. The overall survival (OS) rate at 15 years was 83%, and freedom from progression (FFP) was observed in 82% of patients, including 84% of patients with Stage I disease and 73% of patients with Stage II disease. No recurrent LPHL and only 1 patient with non-Hodgkin lymphoma (NHL) were reported after 15 years. Adverse prognostic factors that were identified on multifactor analysis were as follows: for OS, age 45 years or older (P < 0.0005), the presence of B symptoms (P = 0.002), increasing number of sites (P = 0.015); for FFP, increasing number of sites (P = 0.002). No significant difference was found in FFP in a comparison of patients who received elective mediastinal RT with patients who did not receive mediastinal RT (P = 0.11). Causes of death at 15 years were LPHL in 3% of patients, NHL in 2% of patients, in-field malignancy in 2% of patients, in-field cardiac/respiratory in 4% of patients, and other in 6% of patients. CONCLUSIONS: The current data suggested that RT potentially may be curative for patients with Stage I-II LPHL and raise the possibility that limited-field RT may be used without loss of treatment efficacy. Involved-field RT warrants further investigation for patients with early-stage LPHL.

A randomized cross-over trial to determine the effect of Cremophor EL on the pharmacodynamics and pharmacokinetics of carboplatin chemotherapy.

PURPOSE: Paclitaxel, when combined with carboplatin, exhibits a platelet-sparing effect. Paclitaxel is formulated in Cremophor EL (CrEL), which has been shown in preclinical models to reduce haematological toxicity from radiotherapy and chemotherapy. We sought to determine the effect of a 3-h infusion of 20 ml/m2 (equivalent to 175 mg/m2 paclitaxel) CrEL on myelosuppression following carboplatin chemotherapy, and the effect of CrEL on carboplatin pharmacokinetics. METHODS: A total of 16 patients with locally advanced or metastatic cancer were randomized to receive either CrEL or saline over 3 h prior to carboplatin (area under the curve, AUC, 5-7). Each patient was subsequently crossed over to the other treatment. Blood samples were collected at selected time-points for estimation of platinum AUC and 24-h platinum levels. Full blood counts were obtained three times per week. RESULTS: Of the 16 patients randomized, 15 were evaluable. Myelosuppression was measured by percentage fall at nadir and nadir levels. No significant differences were obtained when comparing CrEL and saline with respect to the above end-points after adjusting for multiple testing. There was no evidence to indicate that CrEL altered the pharmacokinetics of carboplatin. CONCLUSION: CrEL at this dose and schedule does not appear to be a major contributory factor to the platelet-sparing effect of paclitaxel when combined with carboplatin, nor does it alter the pharmacokinetics of carboplatin.

Cyclin d1 overexpression sensitizes breast cancer cells to fenretinide.

PURPOSE: Fenretinide has shown promise in the chemoprevention of breast cancer, a tumor type in which the oncogene cyclin D1 is overexpressed frequently. We aimed at determining the effect of cyclin D1 level on the response to fenretinide treatment. EXPERIMENTAL DESIGN: Stable clones of T47-D cells were created to overexpress cyclin D1 or a mutant of cyclin D1, injected in nude mice for xenograft formation, and the rate of tumor growth and tumor regression determined. RESULTS: We show here that cells overexpressing cyclin D1 are significantly more sensitive to fenretinide than genetically matched cells that express low levels of cyclin D1, and that fenretinide prevents tumor formation arising from cyclin D1-overexpressing cells. Furthermore, we show that fenretinide is also able to promote the regression of cyclin D1-positive tumors. We also show that cells expressing a mutant of cyclin D1 that cannot bind to cdk4 are also more sensitive to fenretinide. CONCLUSIONS: These results suggest that fenretinide may be particularly useful in the treatment of cyclin D1-positive breast cancers, and that the interaction between cyclin D1 and fenretinide is independent of cyclin D1 binding to cdk4.

Overexpression of wild-type p53 in lichen sclerosus adjacent to human papillomavirus-negative vulvar cancer.

Human papillomavirus is a risk factor for vulvar cancer, whereas human papillomavirus-negative late onset vulvar carcinoma is associated with the dermatologic condition, lichen sclerosus. Human papillomavirus E6 protein targets TP53 for degradation and by inference it has been assumed that human papillomavirus-negative vulvar cancer is dependent upon the acquisition of p53 somatic mutations and subsequent allelic loss. To investigate this, TP53 expression, loss of heterozygosity, and p53 genomic sequence were examined in 29 cases of human papillomavirus-negative vulvar carcinoma with adjacent lichen sclerosus. We examined 37 cases of lichen sclerosus without vulvar carcinoma, 10 cases of nongenital lichen sclerosus, and 12 cases of normal vulvar epithelium served as controls. TP53 was evident in 72% of vulvar carcinoma, 48% in epithelium adjacent to vulvar carcinoma, but was minimal in normal samples. When lichen sclerosus cases were selected to exclude samples with absolutely no TP53 expression through probable failed antigen retrieval or homozygous p53 loss the number of epithelial cells expressing TP53 increased progressively from nongenital lichen sclerosus to lichen sclerosus without vulvar carcinoma, then to lichen sclerosus with vulvar carcinoma (p<0.0001). These data suggest elevated TP53 is a feature of vulvar lichen sclerosus. Seventy-four percent of vulvar carcinoma had chromosome 17p-linked loss of heterozygosity, whereas 47% of adjacent lichen sclerosus featured loss of heterozygosity, but only 31% of vulvar carcinoma had p53 mutations, a frequency less than reported previously. Seven percent of adjacent lichen sclerosus had mutations, showing for the first time the presence of an identical mutation to the matched vulvar carcinoma. These data, however, implicate p53 mutations as a later event in vulvar carcinoma and in marked contrast to the original expectation, our loss of heterozygosity data are consistent with loss of another locus (not p53) on 17p operating as a tumor suppressor in lichen sclerosus destined to develop vulvar carcinoma.