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Background and purpose The aim of this study was to correlate clinical and dosimetric variables with acute esophageal toxicity (AET) following Intensity Modulated Radiotherapy (IMRT) with concurrent chemotherapy for locally advanced non-small cell lung cancer (NSCLC). In addition, timeline of AET was reported. Material and methods 153 patients with locally advanced NSCLC treated with 66Gy/2.75Gy/24 fractions of radiotherapy and concurrent daily low dose cisplatin were selected. Medical records and treatments of these patients were retrospectively reviewed. Maximum AET grade ⩾2 and maximum grade 3 were the endpoints of this study. Dates for onset, maximum and recovery (to baseline) of AET were reported. Univariate and multivariate analysis were applied to correlate clinical, tumor, dosimetric and chemotherapy dose variables to AET grade ⩾2 and grade 3. Results AET grade 2 occurred in 37% and grade 3 in 20% of the patients. The median onset of AET was around day 15 for all grades. The median onset of the maximum grade was day 30 for both grades 2 and 3. The median duration was 43days for grade 1, 50days for grade 2 and >80days for grade 3. Of the grade 3 AET patients, 48% recovered within 3months. Esophagus V50, ethnic background, and the number of cisplatin administrations were significantly correlated with grade 3 AET. Conclusions For NSCLC patients treated with concurrent chemotherapy and IMRT A higher number of cisplatin administrations, non-Caucasian background and higher V50oes were associated with grade 3 AET. The median onset of AET grade 3 is 15days after the start of treatment, maximized at day 30, with a median duration of >80days.

If all initially node-positive patients undergo axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NAC), overtreatment may occur in patients with complete response. Positron emission tomography-computed tomography (PET/CT) during NAC may predict axillary response and select patients appropriate for less invasive treatment after NAC. We evaluated the value of sequential (18)F fluorodeoxyglucose (FDG) PET/CTs during NAC for axillary response monitoring in stage II-III breast cancer.A total of 219 PET/CTs were performed in 80 patients with cytology-proven, node-positive disease at baseline (PET/CT1, n = 80) and twice during NAC (PET/CT2 n = 62, PET/CT3, n = 77). The relative changes in maximum standardized uptake value (SUVmax) of axillary nodes were examined for their ability to assess pathological response. All patients underwent ALND after chemotherapy, and complete axillary response (pCR), defined as absence of isolated tumor cells and of micro- and macrometastases, served as the reference standard.A total of 32 (40 %) patients experienced axillary pCR. The relative decrease in SUVmax was significantly higher in patients with pCR than in those without, both on PET/CT2 (p0.001) and PET/CT3 (p = 0.025). The area under the receiver operating characteristic curve values for PET/CT2 and PET/CT3 were 0.80 (95 % confidence interval 0.68-0.92) and 0.65 (95 % confidence interval 0.52-0.79), respectively. A relative decrease of ≥60 % on PET/CT2 had an excellent specificity (35 of 37, 95 %), a high positive predictive value (12 of 14, 86 %), and a sensitivity of 48 %-that is, it accurately identified histologic pCR in 12 of 25 patients with disease that responded to therapy.(18)F-FDG PET/CT early during NAC is useful for axillary response monitoring in cytology-proven node-positive breast cancer because it identifies pathological response, thus permitting ALND to be spared.

Background Response monitoring with MRI during neoadjuvant chemotherapy (NAC) in breast cancer is promising, but knowledge of breast cancer subtype is essential. The aim of the present study was to evaluate the relevance of breast cancer subtypes for monitoring of therapy response during NAC with 18F-FDG PET/CT. Methods Evaluation included 98 women with stages II and III breast cancer. PET/CTs were performed before and after six or eight weeks of NAC. FDG uptake was quantified using maximum standardized uptake values (SUVmax). Tumors were divided into three subtypes: HER2-positive, ER-positive/HER2-negative, and triple negative. Tumor response at surgery was assessed dichotomously (presence or absence of residual disease) and ordinally (breast response index, representing relative change in tumor stage). Multivariate regression and receiver operating characteristic (ROC) analyses were employed to determine associations with pathological response. Results A (near) complete pathological response was seen in 19 (76%) of 25 HER2-positive, 7 (16%) of 45 ER-positive/HER2-negative, and 20 (71%) of 28 triple negative tumors. Multivariate regression of pathological response indicated a significant interaction between change in FDG uptake and breast cancer subtype. The area under the ROC curve was 0.35 (0.12–0.64) for HER2-positive, 0.90 (0.76–1.00) for ER-positive/HER2-negative, and 0.96 (0.86–1.00) for triple negative tumors. We found no association between age, stage, histology, or baseline SUVmax and pathological response. Conclusion Response monitoring with PET/CT during NAC in breast cancer seems feasible, but is dependent on the breast cancer subtype. PET/CT may predict response in ER-positive/HER2-negative and triple negative tumors, but seems less accurate in HER2-positive tumors.

Background The purpose of this investigation was to present 5-years of quality-of-life (QOL) results of a multicenter randomized phase III trial, assessing intra-arterial (IA) versus standard intravenous (IV) chemoradiation for inoperable stage IV head and neck cancer. Methods Evaluation of 71 patients through European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core Module (EORTC QLQ-C30) and Head and Neck Module (QLQ-H&N35), and trial-specific questionnaires. Treatment consisted of standard radiotherapy with 4 weekly IA or 3 weekly IV cisplatin infusions. Results No significant differences in treatment-related QOL problems between 1 and 5 years posttreatment were observed, except for dry mouth (gradually improving; p = .004). Survivors have lower fatigue levels (p = .04), better voice (p = 0.3), and swallowing (p = .03) than patients who could not complete all subsequent follow-up questionnaires. Conclusions Most treatment-related QOL issues deteriorate during treatment, improve in the first year, and then remain stable, except xerostomia, improving up to the 5-year assessment point. Survivors show more positive scores for fatigue, voice, and swallowing. QOL issues at 1 year, thus, for most already represent those after 5-year follow-up. (c) 2011 Wiley Periodicals, Inc. Head Neck, 2012

We studied the use of internal anatomical surrogates (carina and diaphragm) for the purpose of predicting the 3D position of lung tumours in 41 patients, in whom repeat 4DCT scans were available. Despite using two surrogates, significant prediction errors were observed, which varied depending on tumour position, baseline tumour motion and respiratory phase.

PurposeTo investigate whether time-trends of enhanced [(18)F]Fluoromethylcholine ([(18)F]FCH) in lymph nodes (LN) of prostate cancer (PCa) patients can help to discriminate reactive from malignant ones, and whether single time point standardized uptake value (SUV) measurements also suffice.Procedures25 PCa patients with inguinal (presumed benign) and enlarged pelvic LN (presumed malignant) showing enhanced [(18)F]FCH uptake at dual-phase PET-CT were analyzed. Associations between LN status (benign versus malignant) and SUV(max) and SUV(meanA50), determined at 2 min (early) and 30 min (late) post injection, were assessed. We considered two time-trends of [(18)F]FCH uptake: type A (SUV early > SUV late) and type B (SUV late ≥ SUV early). Histopathology and/or follow-up were used to confirm the assumption that LN with type A pattern are benign, and LN with type B pattern malignant.ResultsAnalysis of 54 nodes showed that LN status, time-trends, and 'late' (30 min p.i.) SUV(max) and SUV(meanA50) parameters were strongly associated (PConclusionsTime-trends of enhanced [(18)F]FCH uptake can help to characterize lymph nodes in prostate cancer patients. Single time-point SUV measurements, 30 min p.i., may be a reasonable alternative for predicting benign versus malignant status of lymph nodes, but this remains to be validated in non-enlarged pelvic lymph nodes.

Purpose To compare efficacy of pemetrexed versus pemetrexed plus carboplatin in pretreated patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with advanced NSCLC, in progression during or after first-line platinum-based chemotherapy, were randomly assigned to receive pemetrexed (arm A) or pemetrexed plus carboplatin (arm B). Primary end point was progression-free survival (PFS). A preplanned pooled analysis of the results of this study with those of the NVALT7 study was carried out to assess the impact of carboplatin added to pemetrexed in terms of overall survival (OS). Results From July 2007 to October 2009, 239 patients (arm A, n = 120; arm B, n = 119) were enrolled. Median PFS was 3.6 months for arm A versus 3.5 months for arm B (hazard ratio [HR], 1.05; 95% CI, 0.81 to 1.36; P = .706). No statistically significant differences in response rate, OS, or toxicity were observed. A total of 479 patients were included in the pooled analysis. OS was not improved by the addition of carboplatin to pemetrexed (HR, 90; 95% CI, 0.74 to 1.10; P = .316; P heterogeneity = .495). In the subgroup analyses, the addition of carboplatin to pemetrexed in patients with squamous tumors led to a statistically significant improvement in OS from 5.4 to 9 months (adjusted HR, 0.58; 95% CI, 0.37 to 0.91; P interaction test = .039). Conclusion Second-line treatment of advanced NSCLC with pemetrexed plus carboplatin does not improve survival outcomes as compared with single-agent pemetrexed. The benefit observed with carboplatin addition in squamous tumors may warrant further investigation.

This paper investigates criminal sentencing in the Australian State of Victoria in particular the intuitive nature of the decision making and the difficulties of representing intuitive knowledge. In order for decision systems to be useful for the purposes of training novice practitioners and law students in the complex area of sentencing they must be constructed with an authentic cognitive model that faithfully represents the sentencing process and also the decision-making process. In this paper a pre-cognitive model of the sentencing process is presented.

UNLABELLED:In Indonesia, Nasopharyngeal Carcinoma (NPC) is the most frequent cancer of the head and neck region. At first presentation in the hospital most patients already have advanced NPC. Our previous study showed that general practitioners (GPs) working in Yogyakarta, Indonesia lack the knowledge necessary for early detection of NPC. By providing training on early symptoms of NPC we hope that the diagnosis and referral will occur at an earlier stage. Here we assess the current NPC knowledge levels of GPs in Jakarta, evaluate improvement after training, compare the effectiveness of two training formats, and estimate the loss of recall over a two week period. METHODS:Two Indonesian GPs visited 31 Primary Health Care Centres (PHCCs) and provided a lecture on NPC. The alternative format consisted of a symposium at the Universitas Indonesia, Jakarta, presented by local head and neck surgeons, with all GPs in the region being invited. To evaluate the effect of both formats a questionnaire was conducted before and after. RESULTS:The lecture in the PHCCs was attended by 130 GPs. Sixty-six GPs attended the training in the university hospital and 40 GPs attended both. Pre training the NPC knowledge level was poor with an average of 1.6 symptoms being correctly identified out of a potential maximum of 12, this was increased to 4.9 post training (p

Chromogranin A (CgA) is the most important tumour marker for well-differentiated neuroendocrine tumours (NET) and neuron specific enolase (NSE) for poorly differentiated neuroendocrine carcinoma (NEC). This study investigated whether the markers progastrin-releasing peptide (proGRP) and cytokeratin fragments (CKfr) CK8, CK18 and CK19 (MonoTotal) can be of additional value to the histological classification and help predict survival in these patients.CgA, NSE, proGRP and CKfr were measured in 242 patients with grade 1 NET (G1NET), 38 with grade 2 NET (G2NET), 42 with large cell NEC (LCNEC), 251 with small cell NEC (SCNEC) and in 282 healthy persons. Results were compared with tumour characteristics and survival by means of Receiver Operating Characteristics (ROC) curves and Cox regression analyses.The largest area under the ROC curve was for CgA (0.86, 0.91 and 0.90, respectively) when comparing patients with G1NET, G2NET and LCNEC with healthy persons. ProGRP showed the highest sensitivity (73%) at 95% specificity in patients with SCNEC. In a multivariate survival analysis, only CKfr was associated with survival (P0.0001) for patients with well-differentiated NET (G1NET and G2NET). For patients with poorly differentiated NEC, both CKfr and NSE were associated with survival (P0.0001 and P=0.003, respectively).Within all histological groups a combination of tumour markers proved to be more informative as diagnostic and prognostic marker than each marker alone. In patients with well-differentiated NET and LCNEC we recommend the use of CgA and CKfr, whilst in patients with SCNEC, proGRP and CKfr are preferred.

BACKGROUND: Understanding the molecular biology of colorectal cancer (CRC) provides opportunities for effective personalised patient management. We evaluated whether chromosomal aberrations, mutations in the PI(3)K signalling pathway and the CpG-island methylator phenotype (CIMP) in primary colorectal tumours can predict liver metastases.METHODS: Formalin-fixed paraffin-embedded material from primary colorectal tumours of three different groups were investigated: patients with CRC without metastases (M0, n = 39), patients who were treated with hyperthermal intraperitoneal chemotherapy for CRC metastases confined to the peritoneum (PM, n = 46) and those who had isolated hepatic perfusion for CRC metastases confined to the liver (LM, n = 48).RESULTS: All samples were analysed for DNA copy number changes, PIK3CA, KRAS, BRAF mutations, CIMP and microsatellite instability. The primary CRCs of the LM group had significantly higher frequency of amplified chromosome 20q (P = 0.003), significantly fewer mutations in the PI(3)K signalling pathway (P = 0.003) and fewer CIMP high tumours (P = 0.05). There was a strong inverse correlation between 20q and the PI(3)K pathway mutations.CONCLUSION: The development of CRC liver metastases is associated with amplification of chromosome 20q and not driven by mutations in the PI(3) K signalling pathway. British Journal of Cancer (2011) 105, 281-287. doi: 10.1038/bjc.2011.184 www.bjcancer.com Published online 14 June 2011 (C) 2011 Cancer Research UK

Purpose: To explore the effect of dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (SNP) and haplotypes on outcome of capecitabine. Experimental Design: Germline DNA was available from 568 previously untreated patients with advanced colorectal cancer participating in the CAIRO2 trial, assigned to capecitabine, oxaliplatin, and bevacizumab ± cetuximab. The coding region of dihydropyrimidine dehydrogenase gene (DPYD) was sequenced in 45 cases with grade 3 or more capecitabine-related toxicity and in 100 randomly selected controls (cohort). Most discriminating (P < 0.1) or frequently occurring (>1%) nonsynonymous SNPs were analyzed in all 568 patients. SNPs and haplotypes were associated with toxicity, capecitabine dose modifications, and survival. Results: A total of 29 SNPs were detected in the case–cohort analysis, of which 8 were analyzed in all 568 patients. Of the patients polymorphic for DPYD IVS14+1G>A, 2846A>T, and 1236G>A, 71% (5 of 7), 63% (5 of 8), and 50% (14 of 28) developed grade 3 to 4 diarrhea, respectively, compared with 24% in the overall population. All patients polymorphic for IVS14+1G>A developed any grade 3 to 4 toxicity, including one possibly capecitabine-related death. Because of toxicity, a mean capecitabine dose reduction of 50% was applied in IVS14+1G>A and 25% in 2846A>T variant allele carriers. Patients were categorized into six haplotype groups: one predicted for reduced (10%), and two for increased risks (41% and 33%) for severe diarrhea. Individual SNPs were not associated with overall survival, whereas one haplotype was associated with overall survival [HR (95% CI) = 0.57 (0.35–0.95)]. Conclusions: DPYD IVS14+1G>A and 2846A>T predict for severe toxicity to capecitabine, for which patients require dose reductions. Haplotypes assist in selecting patients at risk for toxicity to capecitabine. Clin Cancer Res; 17(10); 3455–68. ©2011 AACR.

Background Progastrin-releasing peptide (proGRP) is a recently identified biomarker of small-cell lung cancer. In well-differentiated neuroendocrine tumours (WDNETs), this study investigates the association between proGRP and tumour characteristics and the prognostic value of proGRP levels compared with chromogranin A (CgA) levels. Patients and methods Serum samples were obtained in 282 patients with WDNET. The receiver operating characteristic (ROC) curve technique was used to assess specificity and sensitivity in the identification of a primary tumour location. Cox proportional hazards models and Kaplan–Meier curves were constructed to determine the association of patients’ characteristics and tumour markers with survival. Results For proGRP, the ROC curve indicated a cut-off level of 90 ng/l (approximately twice the upper reference value), with a specificity of 99% and a sensitivity of 43% in distinguishing primary pulmonary tumours from other sites. In the multivariate Cox model, both proGRP and CgA were strongly associated with survival (P Conclusions A high-risk proGRP level (more than twice the upper reference value) in patients with WDNETs is a strong indication for a primary tumour in the lung. Besides CgA, proGRP is a complementary tumour marker for prognosis and treatment monitoring in patients with neuroendocrine tumour.

Objective: To assess the endotracheal temperature and humidity and clinical effects of 2 modelsof a new heat and moisture exchanger (HME): Rplus, which has regular breathing resistance, andLplus, which has lower breathing resistance. Methods: We measured endotracheal temperature and humidity in 10 laryngectomized patients, for 10 min each, with and without the HMEs. We sequentially tested 4 HME models (all Atos Medical, Ho¨rby, Sweden), in randomized order: Rplus, Lplus, Provox Normal (the HME we regularly use and which we considered the reference HME), and Stomvent (an older HME model). We also assessed the short-term clinical and practical effects of the Rplus and Lplus in a prospective 3-week trial with 13 laryngectomized patients. Results: Rplus and Lplus had better humidification than Provox Normal (6.8 mg H2O/L, 4.3 mg H2O/L, and 3.7 mg H2O/L, respectively, P < .001), and no significant temperature difference. During the 3-weekstudy period, 7 of the 13 patients reported noticeably lower mucus production with Rplus and Lplus.Conclusions: Rplus and Lplus had better heating and humidification than Provox Normal. Although Stomvent also performed well, its design is less convenient for laryngectomized patients. Further HME improvement is still warranted and should focus on improving the HME’s heating capacity.

Background Data collection by Electronic Medical Record (EMR) systems have been proven to be helpful in data collection for scientific research and in improving healthcare. For a multi-centre trial in Indonesia and the Netherlands a web based system was selected to enable all participating centres to easily access data. This study assesses whether the introduction of a Clinical Trial Data Management service (CTDMS) composed of electronic Case Report Forms (eCRF) can result in effective data collection and treatment monitoring. Methods Data items entered were checked for inconsistencies automatically when submitted online. The data were divided into primary and secondary data items. We analysed both the total number of errors and the change in error rate, for both Primary and Secondary items, over the first five month of the trial. Results In the first five months 51 patients were entered. The Primary data error rate was 1.6%, whilst that for Secondary data was 2.7% against acceptable error rates for analysis of 1% and 2.5% respectively. Conclusion The presented analysis shows that after five months since the introduction of the CTDMS the Primary and Secondary data error rates reflect acceptable levels of data quality. Furthermore, these error rates were decreasing over time. The digital nature of the CTDMS, as well as the online availability of that data, gives fast and easy insight in adherence to treatment protocols. As such, the CTDMS can serve as a tool to train and educate medical doctors and can improve treatment protocols.

Background: Elderly patients with advanced non-small-cell lung cancer (NSCLC) may derive similar benefit from platinum-based chemotherapy as younger patients. Quality of life (QoL) and comprehensive geriatric assessment (CGA) is often advocated to assess benefits and risks. Patients and methods: A total of 181 chemotherapy-naive patients [‡70 years, performance score (PS) of 0‐2] with stage III‐IV NSCLC received carboplatin and gemcitabine (CG) (n = 90) or carboplatin and paclitaxel (CP) (n = 91) every 3 weeks for up to four cycles. Primary end point was change in global QoL from baseline compared with week 18. Pretreatment CGA and mini geriatric assessment during and after treatment were undertaken. A principal component (PC) analysis was carried out to determine the underlying dimensions of CGA and QoL and subsequently related to survival. Results: There were no changes in QoL after treatment. The number of QoL responders (CG arm, 12%; CP arm, 5%) was not significantly different. CGA items were only associated with neuropsychiatric toxicity. Quality-adjusted survival was not different between treatment arms. The PC analysis derived from nine CGA, six QoL and one PS score indicated only one dominant dimension. This dimension was strongly prognostic, and physical and role functioning, Groningen Frailty Indicator and Geriatric Depression Scale were its largest contributors. Conclusions: Paclitaxel or gemcitabine added to carboplatin did not have a differential effect on global QoL. CGA was associated with toxic effects in a very limited manner. CGA and QoL items measure one underlying dimension, which is highly prognostic.

To evaluate the long-term attachment of two types of endoclips in the human gastrointestinal tract.In this prospective observational study, endoclips were placed and followed-up during endoscopies or using fluoroscopic images as part of a prospective feasibility study evaluating external beam radiotherapy (EBRT, wk 1-3) followed by high dose rate brachytherapy (HDRBT with an endoluminal applicator once a week for 3 wk, wk 9-11) in medically inoperable rectal cancer patients. Initially, the type and number of endoclips were chosen randomly and later refined to 1 Resolution(®) clip (Microvasive) proximal and 2 Quickclips(®) (Olympus) distal to the tumor. Nine consecutive patients, included between September 2007 and August 2008 were analyzed. Retention rates were evaluated over three different observational periods [period 1: pre-HDRBT (wk -2-8), period 2: during HDRBT (wk 9-11) and period 3: post-HDRBT (wk 12-16)].In this study, a total of 44 clips were placed during endoscopy, either at the beginning or at the end of period 1. The Resolution clip had a higher overall retention rate than the Quickclip (P = 0.01). After a median period of 81 d after placement (in period 1), long-term retention rates for the Resolution clip and Quickclip clip were 67% and 35% respectively.The Resolution clip has a high retention rate and is useful in situations where long-term attachment to the human gastrointestinal mucosa is warranted.

Background. The aim of this study was to assess the heat and moisture exchange (HME) capacity of the upper respiratory tract and the effect of tracheotomy breathing on endotracheal climate in patients with head and neck cancer. Methods. We plotted the subglottic temperature and humidity measurements in 10 patients with head and neck cancer with a temporary precautionary tracheotomy during successive 10-minute periods of nose, mouth, and tracheotomy breathing in a randomized sequence. Results. End-inspiratory temperatures of nose, mouth, and tracheotomy breathing were 31.1, 31.3, and 28.3 degrees C, respectively. End-inspiratory humidity measurements of nose, mouth, and tracheotomy breathing were 29.3, 28.6, and 21.1 mgH(2)O/L, respectively. There was a trend toward lower end-inspiratory humidity in patients with radiotherapy or with large surgery-induced oropharyngeal mucosal defects, whereas temperatures were similar. Conclusion. This study gives objective information about the HME capacity of the upper respiratory tract in patients with head and neck cancer with precautionary tracheotomy, and thus provides target values for HMEs for laryngectomized and tracheotomized patients. (C) 2010 Wiley Periodicals, Inc. Head Neck 33: 117-124, 2011

Objective. To predict clinical outcome by classification of peritoneal metastases (PM) of colorectal or appendiceal origin.Background. This study investigates whether standardized histological classification can predict outcome for PM of colorectal or appendiceal origin treated with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC).Methods. Histology of PM (n = 269) was evaluated by analysis of mitotic activity, atypia, cellularity, and mucinous component. For overall survival (OS) and disease-free survival (DFS) Cox proportional-hazard models were constructed. Covariates included tumor, patient, and treatment characteristics.Results. PM could be categorized into four groups: low-grade, well-differentiated mucinous tumor (DPAM); intermediated-grade mucinous carcinoma (PMCA-i); high-grade mucinous carcinoma (PMCA); and high-grade nonmucinous carcinoma (PCA). Multivariate analysis showed that histological classification, gender, number of segments affected, completeness of cytoreduction, and HIPEC as primary treatment were significant related to OS and DFS. The 5-year OS was 64% in the DPAM group, 36% in the PMCA group, and 24% in the PCA group. Of PM originating from an appendix tumor, 29% were of non-DPAM type. Of primary colorectal tumors, 37% resulted in mucinous PM, and another 26% of PM of colorectal origin had partly mucinous histology.Conclusion. Histology is a significant predictive factor of OS and DFS in PM treated with surgical cytoreduction and HIPEC. Low-grade PM (DPAM) should be regarded as a separate entity because of its clearly different clinical course. High-grade mucinous PM has significant better prognosis than nonmucinous PM and should thus be distinguished.

Colorectal cancer (CRC) is the second most common cause of cancer related death. Prognosis is highly dependent on stage at diagnosis making early detection mandatory. This study aimed to identify novel disease specific biomarkers of CRC, validate our previously identified biomarkers of CRC and identify serum biomarkers predicting treatment response and for monitoring. Serum of patients with metastatic CRC was collected, according to a predefined schedule, prior to start of standard first-line chemotherapy with oxaliplatin and capecitabine and serially before each 3 weekly treatment cycle and analyzed for proteomic profile by standardized SELDI-TOF MS. Serum proteomic mass spectrometry data of all subjects were processed using the tbimass R-package and proteomic profiles of CRC patients were compared with those of matched normal control subjects. Furthermore, changes in proteomic profiles during the course of chemotherapy were recorded according to treatment response. In total, 42 patients with advanced CRC were treated and mean follow-up was 13.5 months. The response rate was 50% and the median overall survival 19.5 months (95% CI: 16-23). By comparing CRC patients and healthy controls we identified 13 potential biomarkers of CRC (m/z 2.0-31.9 kDa) whereas two proteins, m/z 14060 and 28100 Da (apolipoprotein A-I), were highly significant (p

However,pemetrexed is still costly and is considered an expensive drug by theDutch Healthy Authority, as it amounts to a cost of approximately€14,000 per patient and a total of €19 to 24 million per year in theNetherlands. Therefore, every effort should be undertaken to addi-tionally individualize lung cancer treatment with pemetrexed, andpharmacogenetictraitsareprimecandidates.ThestudybyAdjeietal

Aim To determine the difference in survival after cystectomy between patients presenting with primary muscle infiltrating bladder cancer and patients with progression to muscle infiltration after treatment for initial non-muscle-invasive bladder cancer (NMIBC). Patients and Methods We retrospectively analyzed the files of 188 patients who underwent cystectomy for transitional cell carcinoma between 1987 and 2005. Two groups were defined: patients presenting with muscle-invasive tumours and those progressing to muscle invasion after initial treatment. This second group was further divided into low-intermediate and high risk according to the EAU grouping for NMIBC. Results The 5-year disease specific survival (95% confidence intervals) for all patients was 50%(42–59%); 49%(40–60%) in the primary muscle infiltrating group and 52%(37–74%) in the progressive group ( p = ns). The 5-year disease specific survival in the progressive group according to EAU risk groups was 75%(58–97%) for the initially diagnosed low-intermediate risk tumours and 35%(17–71%) for the initially diagnosed high-risk tumours ( p = 0.015). The percentage of patients with non-locally confined tumours (pT3/4-N0//any pT-N+) was 31%//45% and 24%//46% in the primary muscle infiltrating and progressive group, respectively. Conclusions Despite close observation of patients treated for non-muscle-invasive bladder cancer, the survival of patients who progress to muscle invasion is not better than survival of patients presenting with primary muscle infiltrating cancer. Patients with high-risk non-invasive tumours (EAU risk-categories) who progress to muscle-invasive disease have a worse prognosis compared to patients with low or intermediate risk tumours.

Purpose We performed a randomized phase II trial comparing pemetrexed with pemetrexed plus carboplatin (PC) in patients experiencing relapse after platinum-based chemotherapy. Patients and Methods Main eligibility criteria were histologic or cytologic proof of advanced non–small-cell lung cancer (NSCLC), relapse more than 3 months after platinum-based chemotherapy, normal organ function, and Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned to pemetrexed 500 mg/m2 (arm A) or carboplatin area under the curve 5 and pemetrexed 500 mg/m2 (arm B), both administered intravenously every 3 weeks. Response assessment was performed every 6 weeks; toxicity assessment was performed every 3 weeks. Primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), overall survival (OS), and toxicity. The study was designed to detect a 33% decrease in the hazard of disease progression in the combination arm (α = 0.05, two-sided log-rank test). Polymorphisms of thymidylate synthase, the reduced folate carrier, γ-glutamyl hydrolase, and methylenetetrahydrofolate reductase (MTHF) were investigated in peripheral WBCs of consenting patients. Results Two hundred forty patients were enrolled. Median TTP was 2.8 months for arm A versus 4.2 months for arm B (hazard ratio, 0.67; 95% CI, 0.51 to 0.89; P = .005). Median OS was 7.6 months and 8.0 months and ORR was 4% and 9% for arms A and B, respectively. Subgroup analyses found adenocarcinoma to be associated with favorable outcome. Toxicities in both arms was negligible, with one potential toxic death in arm A. Patients with MTHFR C677T homozygous mutation had increased progression-free survival compared with patients with wild-type or heterozygous mutations (P = .03). Conclusion PC as second-line treatment for relapsed NSCLC resulted in a significant 33% reduction of the hazard of disease progression as compared with pemetrexed alone.

Purpose: Both carina and diaphragm positions have been used as surrogates during respiratory-gated radiotherapy. We studied the correlation of both surrogates with three-dimensional (3D) tumor position. Methods and Materials: A total of 59 repeat artifact-free four-dimensional (4D) computed tomography (CT) scans, acquired during uncoached breathing, were identified in 23 patients with Stage I lung cancer. Repeat scans were co-registered to the initial 4D CT scan, and tumor, carina, and ipsilateral diaphragm were manually contoured in all phases of each 4D CT data set. Correlation between positions of carina and diaphragm with 3D tumor position was studied by use of log-likelihood ratio statistics. Models to predict 3D tumor position from internal surrogates at end inspiration (EI) and end expiration (EE) were developed, and model accuracy was tested by calculating SDs of differences between predicted and actual tumor positions. Results: Motion of both the carina and diaphragm significantly correlated with tumor motion, but log-likelihood ratios indicated that the carina was more predictive for tumor position. When craniocaudal tumor position was predicted by use of craniocaudal carina positions, the SDs of the differences between the predicted and observed positions were 2.2 mm and 2.4 mm at EI and EE, respectively. The corresponding SDs derived with the diaphragm positions were 3.7 mm and 3.9 mm at EI and EE, respectively. Prediction errors in the other directions were comparable. Prediction accuracy was similar at EI and EE. Conclusions: The carina is a better surrogate of 3D tumor position than diaphragm position. Because residual prediction errors were observed in this analysis, additional studies will be performed using audio-coached scans. (C) 2009 Elsevier Inc

OBJECTIVE: The incidence of pulmonary complaints, severe tracheitis and lung function deterioration is increased during wintertime in laryngectomized individuals. We analyzed how a heat and moisture exchanger (HME) performs in cold and dry ambient circumstances, and how its efficiency in this environmental climate might be improved. STUDY DESIGN: Randomized crossover. METHODS: Intra-tracheal temperature and humidity were measured in 10 laryngectomized patients with and without HME, in a cold (mean, 4.7 degrees C) and dry (mean, 4.5 mgH2O/L) room. RESULTS: Presence of an HME causes the intra-tracheal mean humidity minima and maxima to increase with 4.2 mgH2O/L (95%CI: 3.3-5.0 mgH2O/L; p

Purpose Respiratory gating can mitigate the effect of tumor mobility in radiotherapy (RT) for lung cancer. Because the tumor is generally not visualized, external surrogates of tumor position are used to trigger respiration-gated RT. We evaluated the suitability of the carina position as a surrogate in respiration-gated RT. Methods and Materials A total of 30 four-dimensional (4D) computed tomography (CT) scans from 14 patients with lung cancer were retrospectively analyzed. Both uncoached (free breathing) and audio-coached 4D-CT scans were acquired from 9 patients, and 12 uncoached 4D-CT scans were acquired from 5 other patients during a 2–4-week period of stereotactic RT. The repeat scans were co-registered. The carina position was identified on the coronal cut planes in all 4D-CT phases. The correlation between the carina position and the total lung volume for each phase was determined, and the reproducibility of the carina position was studied in the 5 patients with repeat uncoached 4D-CT scans. Results The mean extent of carina motion in 21 uncoached scans was 5.3 ± 1.6 mm in the craniocaudal (CC), 2.3 ± 1.4 mm in the anteroposterior, and 1.5 ± 0.7 mm in the mediolateral direction. Audio coaching resulted in a twofold increase in carina mobility in all directions. The CC carina position correlated with changes in the total lung volume (R = 0.89 ± 0.14), but the correlation was better for the audio-coached than for the uncoached 4D-CT scans (R = 0.93 ± 0.08 vs. R=0.85 ± 0.17; paired t test, p = 0.034). Preliminary data from the 5 patients indicated that the CC carina motion correlated better with tumor motion than did the motion of the diaphragm. Conclusions The CC position of the carina correlated well with the total lung volume, indicating that the carina is a good surrogate for verifying the total lung volume during respiration-gated RT.

Background: Chemo-radiotherapy for thoracic tumors can result in high-grade radiation esophagitis. Treatment planning to reduce esophageal irradiation requires organ motion to be accounted for. In this study, esophageal mobility was assessed using four-dimensional computed tomography (4DCT). Methods and Materials: Thoracic 4DCT scans were acquired on a 16-slice CT scanner in 29 patients. The outer esophageal wall was contoured in two extreme phases of respiration in 9 patients with nonesophageal malignancies. The displacement of the center of contour was measured at 2-cm intervals. In 20 additional patients with Stage I lung cancer, the esophagus was contoured in all 10 phases of each 4DCT at five defined anatomic levels. Both approaches were then applied to 4DCT scans of 4 patients who each had two repeat scans performed. A linear mixed effects model was constructed with fixed effects: measurement direction, measurement type, and measurement location along the cranio-caudal axis. Results: Measurement location and direction were significant descriptive parameters (Wald F-tests, p < 0.001), and the interaction term between the two was significant (p = 0.02). Medio-lateral mobility exceeded dorso-ventral mobility in the lower half of the esophagus but was of a similar magnitude in the upper half. Margins that would have incorporated all movement in medio-lateral and dorso-ventral directions were 5 mm proximally, 7 mm and 6 mm respectively in the mid-esophagus, and 9 mm and 8 mm respectively in the distal esophagus. Conclusions: The distal esophagus shows more mobility. Margins for mobility that can encompass all movement were derived for use in treatment planning, particularly for stereotactic radiotherapy.

BACKGROUND: Activation of the PI3K pathway as an adaptive change in response to estrogen depletion results in acquired endocrine therapy resistance in vitro. Metastatic breast cancer patients with previous exposure to endocrine therapy do derive substantial benefit from the addition of an mTOR inhibitor to endocrine therapy compared to endocrine therapy alone. This suggests that compensatory PI3K pathway activation might play a role in the development of clinical resistance to endocrine therapy. We evaluated the activation of the downstream PI3K pathway protein mTOR in primary breast tumors and matched metastatic lesions. METHODS: From a previously described series of breast cancer patients from whom both primary tumor tissue as well as metastatic tumor tissue was collected, we selected estrogen receptor α (ERα) positive patients who had received endocrine therapy (N = 34) and who did not receive endocrine therapy (N = 37). The difference in expression of phosphorylated mTOR (p-mTOR) between primary and metastatic tumor was assessed by immunohistochemistry, which was scored by using the proportion of tumor cells with sub-membranous p-mTOR expression. We assessed whether this p-mTOR difference between primary and metastatic tumor was associated with clinico-pathological factors (location of metastasis, lymph node status, T-stage, grade, progesterone receptor status) or varied between patients who did and did not receive endocrine therapy, using Mann-Whitney tests. In addition we performed a linear regression model including the same clinico-pathological factors. RESULTS: In patients who had received endocrine therapy we observed an increase in p-mTOR expression in metastatic tumor lesions compared to the primary tumor (median difference 45%). This was significantly different from the mTOR changes observed in patients who did not receive endocrine therapy (median difference between metastatic and primary lesion 0 %) (p = 0.003). The difference remained significant in the multivariate regression model (p = 0.001). None of the other factors was significantly associated with a differential p-mTOR change. CONCLUSION: In patients who received previous adjuvant endocrine therapy, the increase in p-mTOR expression in metastatic tumor lesions compared to the primary tumor is significantly higher than in patients who did not receive endocrine therapy. Compensatory activation of the PI3K pathway might therefore be a clinically relevant resistance mechanism resulting in secondary endocrine therapy resistance. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD01-02.

Purpose A prediction model for progression free survival (PFS) in patients with non-small cell lung cancer (NSCLC) and treated with concurrent chemoradiation (CCRT), would help optimizing customized treatment planning. We analysed several patient factors related to PFS in patients with medically inoperable stage II and III treated with CCRT. Patients & methods Consecutive patients with locally advanced NSCLC treated with CCRT between 2008 and 2011 were included. Treatment consisted of intensity modulated radiotherapy up to 66 Gy (24 x 2.75Gy), and concurrent daily low dose cisplatin (6mg/m2). Age, gender, performance status, weight loss, TNM, tumor volume, involved lymph nodes, histology, metabolic activity of the primary (SUVmax), and a series of lab values including CYFRA, CEA, CA125, SCC, NSE, MT, Leukocytes, Neutrophils, HB, LD and platelets, were assessed before the start of treatment. All patients had a response evaluation by PET-CT scan six weeks after treatment followed by three-monthly X-rays or CT-scans. PFS was defined as the time from start of treatment until progression or death of any cause. Kruskal-Wallis and spearman correlation tests were used to assess associations between factors. Univariate, multivariate Cox proportional hazard models were used to identify high and low risk groups [Fig], defined using linear predictor tertiles. Results Out of the 230 patients, 227 were eligible for analysis. With a median FU of 23 months the median PFS was 15 months (95% CI 12-21 months), and a 2 years overall survival of 55% (95% CI 48%-64%). At the time of analysis 134 PFS events had occurred. The primary factors associated with PFS were tumor volume and SCC, with the pairwise interactions between SCC and both gender and histology also being potentially important. A full Cox regression model including the interactions and a reduced model only including only SCC and tumor volume were constructed. In both models a difference in PFS at 24 months of roughly 40% was observed between the high-and low risk groups. Conclusion A model prognostic for PFS using SCC and tumor volume, was developed that identified stage II-III patients at high risk for progressive disease after CCRT. Validation of this model is ongoing. Disclosure All authors have declared no conflicts of interest.

544 Background: Elevated insuline-like growth factor 1 receptor (IGF-1R) signaling activates the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways and result...

8089 Background: NTG increases tumor blood flow and thereby may augment drug delivery to the tumor and inhibits HIF-1a, a major regulator of hypoxia. In mouse models addition of HIF-1α inhibitors t...

e22128 Background: For FDG PET to qualify as a biomarker of response to cancer therapy beyond proof of principle, the evidence should be aggregated. Methods: A systematic literature search (Jan 1995-May 2011) for studies in solid extracerebral tumors with distinct cohorts of n≥10 patients, PET before and after cytotoxic neoadjuvant systemic therapy (with or without radiotherapy), dichotomized histopathological (PA) response. For model development we selected studies reporting individual or dichotomous aggregated level data, and performed bivariate SROC meta-regression. Results: 52 studies were identified, comprising data from 1,710 patients: rectal (32%), esophageal (21%), sarcoma (20%), breast (13%) and other cancers (14%). Most PET measures were SUVmax (65%) and other SUV measures (32%). Treatment type ChT (38%) and ChRT (62%); 46% were PA responders. The meta-regression indicated a weak increase in specificity for chemotherapy studies over chemoradiotherapy studies (p=0.08), however this disappeared after adjusting for publication bias. High baseline uptake rates improved diagnostic sensitivity (p=0.01). The SROC-AUC after adjusting for publication bias was 0.77. Maximal sensitivity and specificity was achieved with a PET reduction of 60%. Conclusions: There is a moderate association between FDG-PET change and histopathological response. This relation appears to be a function of baseline uptake, which may (at least in part) relate to repeatability issues.

7528 Background: Since standard chemotherapy treatment does not lead to long-term survival, new treatment approaches are required. MPM is known for a high vessel count and high levels of vascular growth factors. Suppression of the neo-vasculature by adding the oral VEGF-TKI axitinib to standard chemotherapy may lead to improvement. This study had both clinical and translational objectives. We here report the secondary endpoints response, PFS, OS and toxicity. Methods: Treatment naïve patients with suspected or proven malignant mesothelioma and medically suitable for limited surgical intervention were eligible after informed consent. Patients were treated with pemetrexed (500mg/m2q3wk) and cisplatin (75mg/m2q3wk) and were randomised to daily axitinib (2x5mg tablets). Before treatment a thoracosopy was performed to confirm the diagnosis. After 3 cycles of chemotherapy a palliative pleurectomy was performed. During both interventions material was obtained for research purposes. Patients could receive an additional 2 cycles of chemotherapy. Results: From July 2009 until October 2012, 26 patients were randomised. Six consecutive patients who received chemotherapy plus axitinib to demonstrate the feasibility and safety of the study design, were also included. In total twenty patients received axitinib. There was one protocol violation in the control arm. Median age: 61 yrs (35 yrs – 75 yrs), 84% epithelial type, 94% WHO 0-1 and 6% WHO 2. Median follow up was 18 months. Toxicity: There was more grade 3, 4 toxicity in the axitinib group concerning neutropenia (40% vs. 9%; p=0.11). One patient in the axitinib group developed a CVA, one patient pulmonary emboli. No thromboembolic events occurred in the control arm. Partial response was observed in 35% of patients in the experimental arm vs. 27% in the control group (p=0.99). Median PFS was 8 months in the experimental arm vs. 8.3 months in the control arm. There was also no difference in overall survival 17 vs 18 months, respectively. Conclusions: Axitinib was well tolerated in combination with cisplatin and pemetrexed. There was no evidence of benefit in response rate, progression free or overall survival. Clinical trial information: NCT01211275.

Introduction Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with chemotherapy did not improve outcome. However, in preclinical models and early phase non-comparative studies pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect. All patients Squamous Non squamous Mono Combi Mono Combi Mono Combi male/female(%) 65/35 63/37 74/26 77/23 60/40 56/44 age (med. range 64 (38-81) 63 (40-81) 66 (53-81) 64 (51-80) 62 (38-79) 62 (40-82) ECOG PS 0/1/2/ (%) 34/58/8 43/50/8 31/64/5 37/57/6 36/55/10 45/46/9 PFS months (median; 95% CI). 4.9 (4.2-6.3) 6.1 (4.8-7.9) 4.9 (3.8-8.0) 4.1 (2.9-8.2) 4.9 (3.9 - 7.6 7.2 (5.3-9.1) OS months (median; 95% CI). 5.5 (4.5-8.5) 7.8 (6.5-10.4) 6.2 (4.5-9.8 6.1 (4.1-11.7) 5.5 (4.3-9.4) 8.7 (7.2-13.7) Methods A randomized open label phase II study was performed in pts with advanced NSCLC who had progressed on or following first-line platinum containing chemotherapy. Pts received E monotherapy 150 mg daily (Arm A) or E 150 mg from day 2 to 16 of the 21 day cycle during 4 cycles of docetaxel for squamous (SQ) or pemetrexed for non-squamous (NSQ) pts (Arm B). After completion of chemotherapy E was continued as a daily regimen until PD. Primary endpoint is progression-free survival (PFS). Secondary endpoints include toxicity and overall survival (OS). Subgroup analysis for the SQ and NSQ was preplanned. The study was designed with 80% power to detect a 33% decrease in the hazard of progression (alpha = 0.05 two sided log rank test). Results Between March 2009 and December 2011, 231 patients were randomized, 115 in arm A (42 SQ, 73 NSQ) and 116 in arm B (35 SQ, 81 NSQ). The adjusted HR for PFS for all patients is 0.80 (95% CI 0.60 - 1.06), p = 0.12, for OS 0.68 (95% CI 0.50 - 0.94), p = 0.02. Toxicity gr 3+ occurred in 19% (arm A) and 55% (arm B), most frequent rash (7 vs 15%, resp). Febrile neutropenia was 0 vs 6%, resp. Conclusion PFS as primary endpoint was not significantly different between arms. OS was significantly improved in the combination arm and was restricted to non squamous histology. Disclosure All authors have declared no conflicts of interest.

7019 Background: Modest benefits from concurrent chemoradiotherapy (CRT) in patients with locally advanced NSCLC warrant more effective treatment regimen. Cetuximab, a monoclonal antibody against the epidermal growth factor receptor has shown activity in NSCLC. Feasibility data and toxicity have been published previously. We report treatment outcome of a multicenter phase II study of the combination of high dose accelerated RT and daily dose cisplatin with or without weekly cetuximab. Methods: Patients with locally advanced NSCLC received accelerated RT (66 Gy in 24 fractions) and concurrent daily cisplatin (6 mg/m2) with (Arm A) or without (Arm B) additional weekly cetuximab (400 mg/m2 loading dose one week prior to the RT start followed by weekly 250 mg/m2). The Objective Local Response Control (OLRC) was determined at 6 and 24 weeks after treatment using response evaluation criteria in solid tumours criteria. Results: Between Feb 2009 and May 2011, 102 patients were included. Median follow-up was 13 months. Patients and tumor characteristics are shows in the Table. Stage distribution was: II (8%), IIIa (51%), and IIIb (40%). The CRT was well tolerated. The OLRC at 24 weeks was 79% in Arm A and 80% in Arm B. The one-year progression free survival and overall survival were 58% (45%-76%) and 76% (64%-91%) for Arm A and 49% (35%-68%) and 72% (58%-89%) for Arm B respectively. Conclusions: The addition of cetuximab to low dose cisplation CRT does not improve OLRC in an unselected patient cohort but data on longterm disease control and survival are to be awaited. [Table: see text]

562 Background: The sensitivity of the estrogen receptor (ERα) to anti-estrogen therapy can be affected by phosphorylation events. In premenopausal breast cancer patients, phosphorylation of the ERα at serine 118 (ERαS118-p) is predictive for benefit from adjuvant tamoxifen. Since ERαS118-p represents the common hallmark of different signaling cascades that differ in E2 dependency, the resulting effect on estrogen sensitivity may differ between pre- and postmenopausal patients. Phosphorylation of serine 167 (ERαS167-p) has been associated with favorable disease outcome, but whether ERαS167-p can predict tamoxifen sensitivity is currently unknown. We tested the predictive value of both ERαS118-p and ERαS167-p for benefit from adjuvant tamoxifen in postmenopausal breast cancer patients. Methods: We collected primary tumor blocks from 563 ERα positive (stage I-III) postmenopausal patients who had been randomized between tamoxifen (1 to 3 years) vs. no adjuvant therapy (IKA trial). The median follow-up of patients without a recurrence event was 9.4 years. Immunohistochemistry was performed on a TMA using monoclonal antibodies for ERαS118-p and ERαS167-p. The percentage of positive nuclei was scored and a score of ≥ 10 % was considered as positive. Multivariate Cox models were used to assess hazard ratios (HRs) for recurrence free interval and the interaction between these phosphorylations and tamoxifen treatment. Results: We did not find a significant interaction between either ERαS118-p (p=0.99) or ERαS167-p (p=0.44) and tamoxifen, suggesting that the relative benefit from adjuvant tamoxifen in postmenopausal patients is not dependent on the presence of one of these phosphorylations. Both tamoxifen treated patients as well as control patients had a better prognosis when their tumor was positive for ERαS118-p (adjusted HR 0.60 p=0.02) or ERαS167-p (adjusted HR 0.62, p=0.02) compared to patients whose tumor did not express these ERα phosphorylations. Conclusions: In postmenopausal patients ERαS118-p and ERαS167-p are both associated with better prognosis, but do not predict differential benefit from tamoxifen.

7006 Background: Standard chemotherapy treatment does not lead to long-term survival; new treatment approaches are required. MPM is known for its high vessel count and levels of vascular growth factors. Suppression of the neo-vasculature by adding thalidomide in the maintenance setting might lead to improved progression free survival (PFS). We here report the final results of PFS, overall survival (OS) and toxicity. Methods: Patients with pemetrexed (500 mg/m2) and carboplatin (AUC 5) or cisplatin (75mg/m2)(q3) for ≥ 4 courses and no signs of progression were eligible. After obtaining informed consent patients were randomized to receive thalidomide 200 mg/day orally (A) or no treatment (B). CT scanning of the thorax and physical examination was performed every 2 months or earlier. PFS and OS were calculated from start of randomization. A number of 190 events were required to show an improvement of 50% in PFS. Results: From 05/2004 until 12/2009 222 patients from 8 Dutch and 4 Australian centers were inclu...

576 Background: Three endocrine response classes are defined in the St. Gallen guidelines: highly endocrine responsive (ER-H) (expression of both ER and progesterone receptor (PgR) in >50% of tumor...

7536 Background: We assessed the impact of gene polymorphisms on clinical outcome in advanced non-small cell lung cancer (NSCLC) patients receiving platinum-gemcitabine chemotherapy (PG). Methods: ...

Background: Therapies for breast cancer may result in symptoms as hot flashes, genitourinary atrophy and psychological distress. Hot flashes are common symptoms that can interfere with quality of life. We undertook a double-blind, placebo controlled trial to assess the efficacy of venlafaxine and clonidine during 12 weeks of treatment. Methods: 102 patients with a history of breast cancer with at least two hot flashes per day were randomly assigned (2:2:1) to venlafaxine 75 mg/d, clonidine 0.1 mg/d or placebo. Daily hot flash scores were recorded at baseline and during treatment. Questionnaires at baseline and during week 4 and 12 assessed sexual function (SAQ), sleep quality (GSQ), anxiety and depression (HADS). The primary endpoint was differences in the average daily hot flash score in the twelfth week between venlafaxine, clonidine and placebo. Secondary objectives were to determine the effect of both drugs on sexual function, sleep quality, anxiety, depression and treatment side effects. Analyses were by intention to treat. Results: 80 patients had evaluable data over the whole study period of 12 weeks. At week 12, treatment was associated with a decrease in the occurrence of hot flashes by 45% versus placebo (p=0.03). There was no significant difference between venlafaxine and clonidine treatment however, over the course of 12 weeks hot flash scores were reduced by 41% in the venlafaxine group and by 26% in the clonidine group (Figure 1). The differences between both treatments and placebo over the 12 week period were significant (p=0.0004 venlafaxine versus placebo, p=0.045 clonidine versus placebo, p=0.002 both treatments versus placebo). Sexual function and sleep quality were not significantly different between the two treatment groups. Adjusting for baseline scores, the week 12 anxiety scores were higher in the clonidine group than in the venlafaxine group (p=0.04) and the depression scores were higher in the venlafaxine group than in the clonidine group (p=0.03). Frequencies of treatment-related side effects, nausea (p=0.02) and constipation (p=0.04) were significantly higher in the venlafaxine group. Only appetite loss (p=0.003) occurred more frequently in the venlafaxine group as severe side effect. Premature discontinuation for adverse events occurred in 2 (5%) patients in the venlafaxine group and 6 (15%) patients in the clonidine group (p=0.26). 41 patients (40%) continued the study treatment after the end of the study. Figure 1. Hot flash score over 12 weeks (blue=placebo, red=clonidine, green=venlafaxine; Discussion: Venlafaxine and clonidine are effective treatments in the management of hot flashes. Venlafaxine treatment resulted in a swifter reduction in the hot flash score in comparison to clonidine. Venlafaxine is more effective than clonidine over the 12 week period of treatment, but at the cost of more side effects. These findings suggest that venlafaxine is to be preferred above clonidine. In case of intolerance clonidine is a realistic treatment alternative. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD08-04.