Postoperative Concurrent Chemoradiotherapy Versus Postoperative Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: The Randomized Phase III TROG 05.01 Trial.

Purpose To report the results of the Trans Tasman Radiation Oncology Group randomized phase III trial designed to determine whether the addition of concurrent chemotherapy to postoperative radiotherapy (CRT) improved locoregional control in patients with high-risk cutaneous squamous cell carcinoma of the head and neck. Patients and Methods The primary objective was to determine whether there was a difference in freedom from locoregional relapse (FFLRR) between 60 or 66 Gy (6 to 6.5 weeks) with or without weekly carboplatin (area under the curve 2) after resection of gross disease. Secondary efficacy objectives were to compare disease-free survival and overall survival. Results Three hundred twenty-one patients were randomly assigned, with 310 patients commencing allocated treatment (radiotherapy [RT] alone, n = 157; CRT, n = 153). Two hundred thirty-eight patients (77%) had high-risk nodal disease, 59 (19%) had high-risk primary or in-transit disease, and 13 (4%) had both. Median follow-up was 60 months. Median RT dose was 60 Gy, with 84% of patients randomly assigned to CRT completing six cycles of carboplatin. The 2- and 5-year FFLRR rates were 88% (95% CI, 83% to 93%) and 83% (95% CI, 77% to 90%), respectively, for RT and 89% (95% CI, 84% to 94%) and 87% (95% CI, 81% to 93%; hazard ratio, 0.84; 95% CI, 0.46 to 1.55; P = .58), respectively, for CRT. There were no significant differences in disease-free or overall survival. Locoregional failure was the most common site of first treatment failure, with isolated distant metastases as the first site of failure seen in 7% of both arms. Treatment was well tolerated in both arms, with no observed enhancement of RT toxicity with carboplatin. Grade 3 or 4 late toxicities were infrequent. Conclusion Although surgery and postoperative RT provided excellent FFLRR, there was no observed benefit with the addition of weekly carboplatin.

Acute myeloid leukaemia relapsing after allogeneic haemopoietic stem cell transplantation: prognostic factors and impact of initial therapy of relapse.

BACKGROUND/AIMS: We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft-versus-host disease (GVHD) on OSR. METHODS: Data on 386 patients from nine Australian centres with relapsed AML post-alloHSCT were collected retrospectively. OSR was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the log-rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling. RESULTS: On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P < 0.001) and grade 3-4 acute GVHD preceding relapse (HR 2.0, P = 0.004), were associated with inferior OSR. Patients with 1-2 factors had inferior OSR compared to those with zero factors (all patients: HR 2.3, P < 0.001, patients given salvage: HR 1.8, P < 0.001). The first salvage therapy used post-relapse was donor cell therapy (DCT) (second alloHSCT or donor lymphocyte infusion) in 75, re-induction chemotherapy (CT) in 103, radiotherapy in 8 and interferon-α in 6. Although re-induction CT death rate was low (2%), survival after CT was inferior to DCT (HR 1.9, P < 0.001). No survival benefit was seen for patients who developed GVHD following salvage therapy (P = 0.405). CONCLUSION: Patients with AML who relapse beyond 6 months from alloHSCT without prior grade 3-4 acute GVHD have a better outcome from salvage therapy. Salvage treatments employing DCT as the initial treatment of AML relapse confer a survival advantage over CT.

Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era.

Acute promyelocytic leukemia (APL) is commonly complicated by a complex coagulopathy. Uncertainty remains as to which markers of bleeding risk are independent predictors. Drawing from 5 large clinical trials that included all-trans retinoic acid (ATRA) as part of induction, we assessed known determinants of bleeding at baseline and evaluated them as potential predictors of hemorrhagic death (HD) in the first 30 days of treatment. The studies included were ALLG APML3 (single arm of ATRA + idarubicin ± prednisone), ALLG APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone), CALGB C9710 (single arm of ATRA + cytarabine + daunorubicin), Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA), and SWOG S0521 (single-arm induction of ATRA + cytarabine + daunorubicin). A total of 1009 patients were included in the original trials, of which 995 had sufficient data to be included in our multivariate analysis. In this final cohort, there were 37 HD cases during the first 30 days following induction, for an estimated cumulative incidence of 3.7% (95% confidence interval [CI], 2.6% to 5.0%). Using multivariate Cox proportional hazards regression, the hazard ratio of HD in the first 30 days was 2.17 (95% CI, 0.84-5.62) for an ECOG performance status of 3-4 vs 0-2 and 5.20 (95% CI, 2.70-10.02) for a white blood cell count of ≥20 000/µL vs <20 000/µL. In this large cohort of APL patients, high white blood cell count emerged as an independent predictor of early HD.

Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial.

BACKGROUND: Initial treatment of acute promyelocytic leukaemia traditionally involves tretinoin (all-trans retinoic acid) combined with anthracycline-based risk-adapted chemotherapy, with arsenic trioxide being the treatment of choice at relapse. To try to reduce the relapse rate, we combined arsenic trioxide with tretinoin and idarubicin in induction therapy, and used arsenic trioxide with tretinoin as consolidation therapy. METHODS: Patients with previously untreated genetically confirmed acute promyelocytic leukaemia were eligible for this study. Eligibilty also required Eastern Cooperative Oncology Group performance status 0-3, age older than 1 year, normal left ventricular ejection fraction, Q-Tc interval less than 500 ms, absence of serious comorbidity, and written informed consent. Patients with genetic variants of acute promyelocytic leukaemia (fusion of genes other than PML with RARA) were ineligible. Induction comprised 45 mg/m(2) oral tretinoin in four divided doses daily on days 1-36, 6-12 mg/m(2) intravenous idarubicin on days 2, 4, 6, and 8, adjusted for age, and 0·15 mg/kg intravenous arsenic trioxide once daily on days 9-36. Supportive therapy included blood products for protocol-specified haemostatic targets, and 1 mg/kg prednisone daily as prophylaxis against differentiation syndrome. Two consolidation cycles with tretinoin and arsenic trioxide were followed by maintenance therapy with oral tretinoin, 6-mercaptopurine, and methotrexate for 2 years. The primary endpoints of the study were freedom from relapse and early death (within 36 days of treatment start) and we assessed improvement compared with the 2 year interim results. To assess durability of remission we compared the primary endpoints and disease-free and overall survival at 5 years in APML4 with the 2 year interim APML4 data and the APML3 treatment protocol that excluded arsenic trioxide. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12605000070639. FINDINGS: 124 patients were enrolled between Nov 10, 2004, and Sept 23, 2009, with data cutoff of March 15, 2012. Four (3%) patients died early. After a median follow-up of 4·2 years (IQR, 3·2-5·2), the 5 year freedom from relapse was 95% (95% CI 89-98), disease-free survival was 95% (89-98), event-free survival was 90% (83-94), and overall survival was 94% (89-97). The comparison with APML3 data showed that hazard ratios were 0·23 (95% CI 0·08-0·64, p=0·002) for freedom from relapse, 0·21 (0·07-0·59, p=0·001) for disease-free survival, 0·34 (0·16-0·69, p=0·002) for event-free survival, and 0·35 (0·14-0·91, p=0·02) for overall survival. INTERPRETATION: Incorporation of arsenic trioxide in initial therapy induction and consolidation for acute promyelocytic leukaemia reduced the risk of relapse when compared with historical controls. This improvement, together with a non-significant reduction in early deaths and absence of deaths in remission, translated into better event-free and overall survival. FUNDING: Phebra.

Safety and cost analysis of an (18)FDG-PET-CT response based follow-up strategy for head and neck cancers treated with primary radiation or chemoradiation.

BACKGROUND: Prognostic information can rationalise clinical follow-up after radical cancer treatment. This retrospective cohort study of radical head and neck (chemo)radiotherapy patients examines the clinical safety and cost implications of stratifying follow-up intensity by post-treatment (18)FDG-PET-CT response. METHODS: In 2008 clinical review after radical head and neck radiotherapy was reduced from 3- to 6-monthly for patients with complete (18)FDG-PET-CT response at 3months. 184 patients treated after this change ("PET Stratified", 2009-11) were compared to 178 patients treated before ("Standard", 2005-7). Clinical safety was assessed by the time to detection of recurrence, overall survival and potential for radical treatment of recurrence. A hospital cost analysis was performed using individual patient data. RESULTS: 127 of 178 Standard and 148 of 184 PET Stratified patients achieved complete response on post-treatment imaging. Baseline clinical characteristics were comparable. Median follow-up from response assessment was 4.8years in the Standard cohort and 2.1years for PET Stratified. PET Stratified patients had a mean 4.4 outpatient visits in 2years, compared to 7.0 among Standard patients. Over 90% of patients remained free of recurrence at 2years in both cohorts. Time to detection of recurrence was similar between two cohorts (HR1.05, 95%CI 0.45-2.52), as was overall survival (HR0.91, 95%CI 0.36-2.29). The proportion of radically treatable recurrences was also similar (42% Standard vs. 47% PET Stratified). The hospital cost savings per patient from reduced review were AUD$2606 over 2years, AUD$5012 over five. CONCLUSION: (18)FDG-PET-CT to stratify follow-up intensity after radical radiotherapy for head and neck cancer reduces costs with no apparent clinical detriment.

68Ga-EDTA PET/CT imaging and plasma clearance for glomerular filtration rate quantification: comparison to conventional 51Cr-EDTA.

UNLABELLED: Glomerular filtration rate (GFR) can accurately be determined using (51)Cr-ethylenediaminetetraacetic acid (EDTA) plasma clearance counting but is time-consuming and requires technical skills and equipment not always available in imaging departments. (68)Ga-EDTA can be readily available using an onsite generator, and PET/CT enables both imaging of renal function and accurate camera-based quantitation of clearance of activity from blood and its appearance in the urine. This study aimed to assess agreement between (68)Ga-EDTA GFR ((68)Ga-GFR) and (51)Cr-EDTA GFR ((51)Cr-GFR), using serial plasma sampling and PET imaging. METHODS: (68)Ga-EDTA and (51)Cr-EDTA were injected concurrently in 31 patients. Dynamic PET/CT encompassing the kidneys was acquired for 10 min followed by 3 sequential 3-min multibed step acquisitions from kidneys to bladder. PET quantification was performed using renal activity at 1-2 min (PETinitial), renal excretion at 2-10 min (PETearly), and, subsequently, urinary excretion into the collecting system and bladder (PETlate). Plasma sampling at 2, 3, and 4 h was performed, with (68)Ga followed by (51)Cr counting after positron decay. The level of agreement for GFR determination was calculated using a Bland-Altman plot and Pearson correlation coefficient (PCC). RESULTS: (51)Cr-GFR ranged from 10 to 220 mL/min (mean, 85 mL/min). There was good agreement between (68)Ga-GFR and (51)Cr-GFR using serial plasma sampling, with a Bland-Altman bias of -14 ± 20 mL/min and a PCC of 0.94 (95% confidence interval, 0.88-0.97). Of the 3 methods used for camera-based quantification, the strongest correlation was for plasma sampling-derived GFR with PETlate (PCC of 0.90; 95% confidence interval, 0.80-0.95). CONCLUSION: (68)Ga-GFR agreed well with (51)Cr-GFR for estimation of GFR using serial plasma counting. PET dynamic imaging provides a method to estimate GFR without plasma sampling, with the additional advantage of enabling renal imaging in a single study. Additional validation in a larger cohort is warranted to further assess utility.

A randomized trial of prophylactic palifermin on gastrointestinal toxicity after intensive induction therapy for acute myeloid leukaemia.

Gastrointestinal toxicity, including oral mucositis, is a frequent complication of intensive combination chemotherapy for acute myeloid leukaemia (AML) and contributes substantially to treatment-related mortality. We conducted a placebo-controlled randomized trial to evaluate the efficacy of palifermin (keratinocyte growth factor), given at 60 µg/kg per daily IV for 3 d before and after chemotherapy, for mucosal protection in adult patients with previously untreated AML receiving induction therapy with idarubicin, high-dose cytarabine and etoposide. Among 155 randomized patients, there was no statistically significant difference in the rate of grade 3 and 4 oral mucositis (primary study endpoint) between the two treatment arms (three in palifermin arm (4%), 8 in placebo arm (10%; P = 0·21); however, when considering the severity of oral mucositis (World Health Organization grade 0-4), there was evidence of reduced rates of higher grades of oral mucositis in the palifermin arm (P = 0·0007, test for trend). There was a statistically significantly lower rate of grades 3 and 4 gastrointestinal adverse events in the palifermin arm (21% vs. 44% in placebo arm; P = 0·003), mainly due to a reduction in severe diarrhoea (8% palifermin, 26% placebo; P = 0·01). Palifermin has activity as a mucosal protectant in AML patients receiving intensive chemotherapy. This trial is registered at ACTRN012605000095662.

Weight and fat distribution in patients taking valproate: a valproate-discordant gender-matched twin and sibling pair study.

OBJECTIVES: Chronic treatment with valproate (VPA) is commonly associated with weight gain, which potentially has important health implications, in particular increased central fat distribution. We utilized a VPA-discordant same-sex, twin and matched sibling pair study design to primarily examine for differences in fat distribution between patients with epilepsy treated with VPA compared to their matched twin or sibling control. Weight, blood pressure, and leptin levels were assessed. METHODS: Height, weight, waist and hip measurements, exercise, blood pressure (BP), and serum leptin levels were measured. Body composition was measured using dual-energy x-ray absorptiometry (DXA). Abdominal fat was expressed as a percentage of the abdominal region (AFat%); and of whole body fat (WBF); (AFat%WBF). Mean within-pair differences were assessed (VPA-user and nonuser). Restricted maximum likelihood (REML) linear mixed model analysis was fitted to examine associations of anthropometrics, zygosity, gender, menopausal status, VPA dose and duration, with weight and AFat%. RESULTS: We studied 19 pairs of VPA-discordant, gender-matched (five male, 14 female) twins and siblings. Mean (standard deviation, SD) duration of therapy for VPA users was 11.0 (7.4) years. There were no statistically significant within-pair differences in age, height, weight, body mass index (BMI), BP, leptin level, WBF, AFat%, or AFat%WBF. For pairs in which VPA-user was treated for >11 years there were statistically significant mean within-pair differences in AFat%, (+7.1%, p = 0.03, n = 10 pairs), mean BP (+11.0 mm Hg, p = 0.006, n = 8 pairs); but not in AFat%WBF. VPA duration was positively associated with weight (estimate +0.98 kg/per year of VPA, p = 0.03); VPA treatment duration and dose were not significantly associated with AFat%. SIGNIFICANCE: This study demonstrated a relationship between long-term VPA use and abdominal adiposity (AFat%), which could have significant health implications. We recommend ongoing monitoring of weight, BMI, and blood pressure for patients taking VPA.

Differential (18)F-FDG and (18)F-FLT Uptake on Serial PET/CT Imaging Before and During Definitive Chemoradiation for Non-Small Cell Lung Cancer.

UNLABELLED: We aimed to prospectively observe cellular metabolism and proliferation in patients with non-small-cell lung cancer (NSCLC) during radical chemoradiation therapy using serial PET/CT with (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT). METHODS: Twenty patients with stage I-III NSCLC and candidates for radical chemoradiation therapy (60 Gy in 30 fractions over 6 wk) were recruited. (18)F-FDG and (18)F-FLT PET/CT were performed at baseline and during therapy (weeks 2 and 4). Tumor response was assessed semiquantitatively and using visual response criteria. RESULTS: The median and range for primary tumor volume (cm(3)) at baseline on (18)F-FDG were 28 and 2-241, respectively, and on (18)F-FLT 31 and 2-184, respectively. At week 2, (18)F-FDG was 26 (range, 2-164), and (18)F-FLT was 11 (range, 0-111). At week 4, (18)F-FDG was 19 (1-147), and (18)F-FLT was 7 (0-48). The median and range of maximum standardized uptake value (SUVmax) at baseline on (18)F-FDG were 14 and 4-31, respectively, and on (18)F-FLT 6 and 2-12, respectively. Week 2 (18)F-FDG median SUVmax was 10 (2-31), and (18)F-FLT median SUVmax was 3 (1-15); week 4 (18)F-FDG median SUVmax was 10 (2-15), and (18)F-FLT median SUVmax was 2 (2-9). There was fair agreement between visual tumor response on (18)F-FDG and (18)F-FLT during therapy (Cohen's unweighted κ statistic, 0.27 at week 2 and 0.355 at week 4). Cerebral metastases were detected on 1 baseline (18)F-FLT scan, resulting in palliative management. Progressive disease was detected on week 2 scans in 3 patients, resulting in changes to radiation therapy (2 patients) and treatment intent (1 patient). CONCLUSION: This study demonstrates that (18)F-FLT PET/CT is a more sensitive tracer of early treatment response than (18)F-FDG PET/CT. The ability of these tracers to detect distinct biologic processes may lead to their use as biomarkers for personalized radiation therapy and prognosis in the future.

The operating surgeon is an independent predictor of chest tube drainage following cardiac surgery.

OBJECTIVES: Bleeding into the chest is a major cause of blood transfusion and adverse outcomes following cardiac surgery. The authors investigated predictors of bleeding following cardiac surgery to identify potentially correctable factors. DESIGN: Data were retrieved from the medical records of patients undergoing cardiac surgery over the period of 2002 to 2008. Multivariate analysis was used to identify the independent predictors of chest tube drainage. SETTING: Tertiary hospital. PARTICIPANTS: Two thousand five hundred seventy-five patients. INTERVENTIONS: Cardiac surgery. RESULTS: The individual operating surgeon was independently associated with the extent of chest tube drainage. Other independent factors included internal mammary artery grafting, cardiopulmonary bypass time, urgency of surgery, tricuspid valve surgery, redo surgery, left ventricular impairment, male gender, lower body mass index and higher preoperative hemoglobin levels. Both a history of diabetes and administration of aprotinin were associated with reduced levels of chest tube drainage. CONCLUSIONS: The individual operating surgeon was an independent predictor of the extent of chest tube drainage. Attention to surgeon-specific factors offers the possibility of reduced bleeding, fewer transfusions, and improved patient outcomes.

Differential mechanisms of CDKN2A (p16) alteration in oral tongue squamous cell carcinomas and correlation with patient outcome.

CDKN2A (p16) disruption is reported as a frequent event in head and neck squamous cell carcinomas that confers poor prognosis. We investigated the frequency of different potential mechanisms of CDKN2A inactivation in oral tongue squamous cell carcinomas (OTSCC) and their impact on patient outcome. From a cohort of 153 OTSCC patients, 131 formalin fixed paraffin embedded blocks of pre-treatment primary tumours were suitable for further molecular analysis. We assessed CDKN2A (p16) levels by immunohistochemistry (IHC), promoter methylation status by methylation-sensitive high resolution melting, mutation status by Sanger sequencing, gene copy number variation by fluorescence in situ hybridisation, and correlated these with patient outcome. We found that the majority of OTSCC did not overexpress p16 (110/116, 95%), assessed by IHC. The frequency of CDKN2A mutations was 20% (21/103), homozygous loss was 7% (7/97), hemizygous loss 31% (30/97), and promoter methylation was 18% (20/113). We found no evidence of these mechanisms in 24/106 (23%) p16 IHC negative tumours. No significant correlation was identified between any potential mechanism of CDKN2A inactivation and clinical features, including smoking status and age. There was a non-significant trend for worse overall survival for p16 IHC negative patients versus positive patients (HR = 1.81, 95% CI = 0.44-7.47, p = 0.40). No relationship was found between mechanisms of CDKN2A disruption and patient outcome. In conclusion, we demonstrate that CDKN2A alteration is a frequent event in OTSCC tumourigenesis. However, no correlation was identified between different potential mechanisms of CDKN2A disruption and clinical characteristics or patient outcome.

T4 squamous cell carcinoma of the oral tongue without mandibular involvement: surgery or chemoradiotherapy?

OBJECTIVE: To investigate disease control and functional outcomes in patients with T4 squamous cell carcinoma of the oral tongue who had undergone surgery or definitive chemoradiotherapy. STUDY DESIGN: Records of all consecutive patients with T4 squamous cell carcinoma of the oral tongue treated radically between 1999 and 2010 at the Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia, were retrospectively reviewed. RESULTS: Of 31 patients, 19 underwent surgery and 12 underwent definitive chemoradiotherapy. There were no significant differences between cohorts in terms of age, nodal involvement, or performance status. All patients had T4 disease on the basis of extrinsic muscle invasion; none had bone invasion. Disease outcomes at 5 years after surgery or chemoradiotherapy were not significantly different, including local control (61% vs 70%), progression-free rate (56% vs 55%), and overall survival (27% vs 40%). A higher proportion of patients in the chemoradiotherapy group had only mild impairment of speech and swallowing. CONCLUSIONS: Definitive chemoradiotherapy may be a reasonable alternative to surgery for patients with T4 squamous cell carcinoma of the oral tongue without bony invasion.

Quantitative methodology is critical for assessing DNA methylation and impacts on correlation with patient outcome.

BACKGROUND: DNA hypermethylation is reported as a frequent event and prognostic marker in head and neck squamous cell carcinomas (HNSCC). Methylation has been commonly assessed with non-quantitative methodologies, such as methylation-specific PCR (MSP). We investigated previously reported hypermethylated genes with quantitative methodology in oral tongue squamous cell carcinomas (OTSCC). RESULTS: The methylation status of 12 genes in 115 OTSCC samples was assessed by one or more of three quantitative analyses: methylation sensitive high resolution melting (MS-HRM), sensitive-melting analysis after real time-methylation specific PCR (SMART-MSP), and bisulfite pyrosequencing. In contrast to much of the literature, either no or infrequent locus-specific methylation was identified by MS-HRM for DAPK1, RASSF1A, MGMT, MLH1, APC, CDH1, CDH13, BRCA1, ERCC1, and ATM. The most frequently methylated loci were RUNX3 (18/108 methylated) and ABO (22/107 methylated). Interrogation of the Cancer Genome Atlas (TCGA) HNSCC cohort confirmed the frequency of significant methylation for the loci investigated. Heterogeneous methylation of RUNX3 (18/108) and ABO (22/107) detected by MS-HRM, conferred significantly worse survival (P = 0.01, and P = 0.03). However, following quantification of methylation levels using pyrosequencing, only four tumors had significant quantities (>15%) of RUNX3 methylation which correlated with a worse patient outcome (P <0.001), while the prognostic significance of ABO hypermethylation was lost. RUNX3 methylation was not prognostic for the TCGA cohort (P = 0.76). CONCLUSIONS: We demonstrated the critical need for quantification of methylation levels and its impact on correlative analyses. In OTSCC, we found little evidence of significant or frequent hypermethylation of many loci reported to be commonly methylated. It is likely that previous reports have overestimated the frequency of significant methylation events as a consequence of the use of non-quantitative methodology.

Intra-patient dose escalation in Ewing's sarcoma treated with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide: a retrospective review.

BACKGROUND: Data suggests that males experience less toxicity and poorer survival than females treated for Ewing's sarcoma. We instituted an intra-patient dose escalation (DE) policy with Vincristine/Doxorubicin/Cyclophosphamide (VDC) alternating with Ifosfamide/Etoposide (IE) based on hematological nadirs and report its feasibility and safety. METHODS: A retrospective review of adherence to DE guidelines and toxicities was conducted for patients who received DE with VDC/IE over 3 years at a single cancer center. Absolute neutrophil counts (ANC) was collected on days 8, 12 and 15 for cycles 1-6. DE of 10%/cycle was applied if ANC > 1.5×109/L and platelet > 100×109/L on all blood results. The primary endpoint was the proportion of patients who received appropriate DE. The secondary endpoint was to assess morbidity, changes in hematologic nadirs between gender and age and a comparison with a prior cohort of ESFT patients who did not receive DE. Gender comparisons were assessed via independent 2-sample t-tests assuming unequal variances. Within cycle changes in hematologic nadirs were assessed using repeated measures ANOVA. Relapse free survival and overall survival (OS) curves were estimated using the Kaplan-Meier method. RESULTS: 23 patients were identified (mean age: 27; range 17-54). 91 decisions for DE were made (1 decision excluded because of progressive disease) with 90% concordance with guidelines. No adverse outcomes occurred as a result of the inappropriate escalation. Grade 3/4 febrile neutropenia (FN) during VDC and IE was 26.1% (6/23 patients) and 17.4% respectively with no difference for those who were DE. Males were less neutropenic after C1 and C3 of VDC compared to females (P-value C1 = 0.003; C3 = 0.005). VDC was associated with greater neutropenia on day 8 whereas IE had greater neutropenia on day 12 (P-value <0.001). During VDC, a non statistical difference in neutropenia was seen for individuals aged 15-25 (n = 13) compared with older individuals (P-value = 0.09). OS comparison for those with localized disease with a prior cohort who were not DE showed similar outcomes (P-value = 0.37). CONCLUSIONS: DE is deliverable without increased adverse outcomes. Males have less myelosuppression during VDC, and should be especially considered for DE.

Patients treated with platinum-doublet chemotherapy for advanced non--small-cell lung cancer have inferior outcomes if previously treated with platinum-based chemoradiation.

INTRODUCTION: The standard of care for locoregionally advanced non-small-cell lung cancer is concurrent platinum-based chemoradiation. Many patients relapse, and subsequent systemic treatment may involve platinum-doublet chemotherapy. It is not known if prior platinum-based chemoradiation influences the response to platinum-based chemotherapy given subsequently for relapse. Therefore, we compared outcomes in these patients with those in patients without prior treatment. METHODS: A retrospective study of patients who had been treated with carboplatin and gemcitabine chemotherapy for de novo metastatic disease or recurrent non--small-cell lung cancer after receiving platinum-based chemoradiation. The primary outcome was progression-free survival (PFS). RESULTS: A total of 104 patients were analyzed. The median age was 63 years (range, 35-81 years), with 63 (61%) patients with newly diagnosed disease and with 41 (39%) who were previously treated. The response rate was significantly lower for those previously exposed to chemoradiation (10% vs. 29%: P = .001), as was the median PFS (3.6 months vs. 5.7 months; P = .002), and median overall survival (OS) (8.6 months vs. 12.1 months; P = .007). Only the treatment group was a significant predictor (P = .032) of PFS by univariate analysis. In univariate analysis; sex (men; P = .04), histology (squamous cell; P = .04), Eastern Cooperative Oncology Group Performance Status Scale (P = .002), and treatment group (P = .023) predicted significantly inferior OS. Multivariate analysis showed that performance status was the only significant predictor of inferior OS. CONCLUSION: Outcomes were inferior in patients previously exposed to platinum-based chemoradiation. An approach of stratifying such patients in future trials of chemotherapy should be adopted. Alternative options such as non--platinum-based agents or targeted therapies should be considered in this group.

Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis.

PURPOSE: The LIVESTRONG Young Adult Alliance has conducted a meta-analysis of individual patient data from prospective neoadjuvant chemotherapy osteosarcoma studies and registries to examine the relationships of sex, age, and toxicity on survival. PATIENTS AND METHODS: Suitable data sets were identified by a survey of published data reported in PubMed. The final pooled data set comprised 4,838 patients from five international cooperative groups. RESULTS: After accounting for important variables known at study entry such as tumor location and histology, females experienced higher overall survival rates than males (P = .005) and children fared better than adolescents and adults (P = .002). Multivariate landmark analysis following surgery indicated that a higher rate of chemotherapy-induced tumor necrosis was associated with longer survival (P < .001), as was female sex (P = .004) and the incidence of grade 3 or 4 mucositis (P = .03). Age group was not statistically significant in this landmark analysis (P = .12). Females reported higher rates of grade 3 or 4 thrombocytopenia relative to males (P < .001). Children reported the highest rates of grade 3 or 4 neutropenia (P < .001) and thrombocytopenia (P < .001). The achievement of good tumor necrosis was higher for females than for males (P = .002) and for children than for adults (P < .001). CONCLUSION: These results suggest fundamental differences in the way chemotherapy is handled by females compared with males and by children compared with older populations. These differences may influence survival in a disease in which chemotherapy is critical to overall outcomes.

A phase II study of induction carboplatin and gemcitabine followed by chemoradiotherapy for the treatment of locally advanced nasopharyngeal carcinoma.

OBJECTIVES: To investigate the tolerability and feasibility of induction gemcitabine and carboplatin chemotherapy followed by radiotherapy with concurrent cisplatin in patients with locally advanced nasopharyngeal carcinoma. PATIENTS AND METHODS: Twenty-eight patients with previously untreated non-keratinising nasopharyngeal carcinoma, with stage IIb to IV disease were enroled to receive three cycles of carboplatin AUC 5 and gemcitabine 1 g/m(2) day 1 and 8 every 21-days, followed by 70 Gy of radiotherapy with concurrent cisplatin 20 mg/m(2)/day for 5 days of weeks 1, 4 and 7. RESULTS: 26/28 (93.0%) patients received all three cycles of induction chemotherapy. All 27 patients who commenced chemoradiotherapy received 70 Gy in 35 fractions of radiotherapy with at least two cycles of concurrent cisplatin. The three-year time to locoregional failure rate was 92.9% (95% CI: 75.5-98.2%) and the three-year overall survival rate was 89.3% (95% CI: 71.6-96.5%). Induction chemotherapy was well tolerated with 5/28 (17.9%) patients experiencing grade 3 non-haematological toxicities and no reported episodes of febrile neutropenia or grade 4 toxicity. For the 27 patients who received radiotherapy, no acute grade 4 radiation toxicities and only 2/27 (7.4%) late grade 4 radiation adverse events were observed. CONCLUSION: The use of induction carboplatin and gemcitabine followed by chemoradiotherapy is feasible, with acceptable toxicity, and is a promising regimen for the treatment of locally advanced nasopharyngeal carcinoma.

Frequency of fibroblast growth factor receptor 1 gene amplification in oral tongue squamous cell carcinomas and associations with clinical features and patient outcome.

OBJECTIVES: Novel therapies are required for patients with recurrent or metastatic oral tongue squamous cell carcinoma (OTSCC). Fibroblast Growth Factor Receptor 1 (FGFR1) amplification frequently occurs in squamous cell carcinoma of the lung and represents a novel druggable therapeutic target in this and other malignancies. This study examined the frequency and clinical associations of FGFR1 amplification in OTSCC. MATERIALS AND METHODS: The frequency of FGFR1 amplification determined by fluorescence in situ hybridization was evaluated in a cohort of 123 OTSCC patients. Associations of FGFR1 amplification with clinical characteristics and outcome were determined. RESULTS: FGFR1 gene amplification was present in 9.3% (10/107) of cases and was significantly associated with smoking status (P = 0.03). FGFR1 amplification was seen more commonly in males (9/10 amplified cases male, P = 0.16) and there were no associations with age, stage, T stage, nodal status, alcohol history or performance status (all P>0.05). Outcome was not significantly different between FGFR1 amplified and non-amplified patients. CONCLUSIONS: Copy number variations of the FGFR1 gene occur in a subset of OTSCC with approximately 10% of cases showing amplification of the gene. FGFR1 amplification may represent a therapeutic target in OTSCC.