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Introduction. Colorectal cancer (CRC) and its treatments can cause distressing sequelae.We conducted amulticenter randomized controlled trial aiming to improve psychological distress, supportive care needs (SCNs), and quality of life (QOL) of patients with CRC. The intervention, called SurvivorCare (SC), comprised educational materials, needs assessment, survivorship care plan, end-of-treatment session, and three follow-up telephone calls. Methods. At the end of treatment for stage I-III CRC, eligible patients were randomized 1:1 to usual care (UC) or to UC plus SC. Distress (Brief Symptom Inventory 18), SCNs (Cancer Survivors' Unmet Needs measure), and QOL (European Organization for Research and Treatment of Cancer [EORTC] QOL questionnaires C30 and EORTC CRC module CR29) were assessed at baseline and at 2 and 6 months (follow-up 1 [FU1] and FU2, respectively). The primary hypothesis was that SC would have a beneficial effect on distress at FU1. The secondary hypotheses were that SC would have a beneficial effect on (a) SCN and QOL at FU1 and on (b) distress, SCNs, and QOL at FU2. A total of 15 items assessed experience of care. Results. Of 221 patients randomly assigned, 4 were ineligible for thestudyand1waslost toFU, leaving 110 in the UC group and 106 in the SC group. Patients' characteristics included the following: median age, 64 years; men,52%; colon cancer, 56%; rectal cancer, 35%; overlapping sites of disease, 10%; stage I disease, 7%; stage II, 22%; stage III, 71%. Baseline distress and QOL scores were similar to population norms. Between-group differences in distress at FU1 (primary outcome) and at FU2, and SCNs and QOL at FU1 and FU2 were small and non significant.Patients inthe SC group were more satisfied with survivorship care than those in the UC group (significant differences on 10 of 15 items). Conclusion. The addition of SC to UC did not have a beneficial effect on distress, SCNs, or QOL outcomes, but patients in the SC group were more satisfied w

Background: Liver metastases are the dominant site of disease in mCRC and the dominant cause of death. The SIRFLOX study was designed to assess the efficacy and safety of combining FOLFOX chemotherapy (+/- bevacizumab) with SIRT using yttrium-90 (Y-90) resin microspheres as first-line treatment of patients with liver metastases from mCRC. Method(s): SIRFLOX was an international, multi-centre, open-label, RCT in chemotherapy-naive patients with non-resectable, liver-only or liver-dominant (liver plus lung and/or lymph node metastases) mCRC. Arm A: mFOLFOX6 (+/- bevacizumab, at investigator discretion) was compared to arm B: mFOLFOX6 + SIRT (SIR-Spheres; Sirtex) administered once with cycle 1 (+/- bevacizumab, at investigator discretion) until disease progression. The primary endpoint was Progression-Free Survival (PFS) using RECIST v1.0 by independent central imaging review in the intention-to-treat (ITT) cohort. PFS in the liver, as defined by Cumulative Incidence of Liver Progression (Liver CIP), was assessed by Competing Risk analysis. Stratification variables included presence of extra-hepatic metastases (liver-only vs. liver-dominant), degree of liver involvement (<=25% vs. >25%), and ITT with bevacizumab (with vs. no bevacizumab). Result(s): From October 2006 to April 2013, 530 patients were randomised (arm A, n = 263; arm B, n = 267); 212 (40%) had extra-hepatic metastases; 292 (55%) were stratified to receive bevacizumab. Median follow-up was 36.1 months. The median overall PFS was 10.2 vs. 10.7 months in arms Avs. B, respectively (hazard ratio [HR]: 0.93; 95% CI 0.77-1.12; p = 0.429) by Kaplan-Meier analysis. The median Liver PFS was 12.6 vs. 20.5 months in arm Avs. B (HR: 0.69; 95% CI 0.55-0.90; p = 0.002). Median Liver PFS was 12.4 vs. 21.1 months in arm Avs. B (HR: 0.64; 95% CI 0.48-0.86; p = 0.003) for patients with liver-only metastases, and 12.6 vs. 16.7 months (HR: 0.77, 95% CI 0.54-1.09; p = 0.147) for those with liver and extra-hepatic metastases. M

Background: Colorectal cancer (CRC) and its treatments can cause distressing short and long-term side effects as well as significant functional consequences. Current models of follow-up do not adequately address these issues. We conducted a multi-center RCT of an innovative program (SurvivorCare (SC)); designed to have a beneficial effect on psychological distress, supportive care needs (SCN) and quality of life (QOL). Method(s): At the end of active treatment for stage I-III CRC, eligible patients ( =18 years, adequate English) were randomized 1:1 to usual care (UC) or to UC+SC. SC comprised educational materials, needs assessment, an individualized survivorship care plan, nurse-led end-oftreatment session and three follow up (FU) phone calls. Distress (BSI-18), SCN (CaSUN) and QOL (EORTC QLQ-C30, CR29) were assessed at baseline, 2 (FU1) and 6 (FU2) months. Primary hypothesis: SC would have a beneficial effect on distress at FU1. Secondary hypotheses: SC would have a beneficial effect on (1) SCN and QOL at FU1; and (2) distress, SCN and QOL at FU2. 15 items assessed satisfaction with survivorship care. Sample size of 180 (90/arm) was based on 80% power, 2-sided alpha of 0.05, to detect a between groups difference of 3.6 on BSI-18 at FU1. Outcome analysis was ITT. Result(s): Of 221 patients randomized (111 UC, 110 SC), 4 were ineligible and 1 lost to FU, leaving 110 UC, 106 SC. Groups appeared well balanced. Median age was 64, 52% male, 56% colon, 35% rectal cancer, 10% overlap. Stage I 7%, II 22%, III 71%. Intervention fidelity was acceptable. Baseline distress and QOL were similar to population norms. Between groups differences in distress at FU1 (primary outcome), distress at FU2 and SCN and QOL at FU1 and FU2 were small and non-significant. SC patients were more satisfied with survivorship care than UC patients (significant differences on 10 of 15 items). Conclusion(s): The addition of SC to UC did not have a beneficial effect on distress, SCN or QOL outcomes bu

BACKGROUND: This randomised phase II study evaluated the efficacy and safety of panitumumab added to docetaxel-based chemotherapy in advanced oesophagogastric cancer. METHODS: Patients with metastatic or locally recurrent cancer of the oesophagus, oesophagogastric junction or stomach received docetaxel and a fluoropyrimidine with or without panitumumab for 8 cycles or until progression. The primary end point was response rate (RECIST1.1). We planned to enrol 100 patients, with 50% expected response rate for combination therapy. RESULTS: A total of 77 patients were enrolled. A safety alert from the REAL3 trial prompted a review of data that found no evidence of adverse outcomes associated with panitumumab but questionable efficacy, and new enrolment was ceased. Enrolled patients were treated according to protocol. Response rates were 49% (95% CI 34-64%) in the chemotherapy arm and 58% (95% CI 42-72%) in the combination arm. Common grade 3 and 4 toxicities included infection, anorexia, vomiting, diarrhoea and fatigue. At 23.7 months of median follow-up, median progression-free survival was 6.9 months vs 6.0 months and median overall survival was 11.7 months vs 10.0 months in the chemotherapy arm and the combination arm, respectively. CONCLUSIONS: Adding panitumumab to docetaxel-based chemotherapy for advanced oesophagogastric cancer did not improve efficacy and increased toxicities.

Background: Colorectal cancer (CRC) and its treatments can cause distressing short and long-term side effects as well as significant functional consequences. Current models of follow-up do not adequately address these issues. We conducted a multi-center RCT of an innovative program (Survivor-Care (SC)); designed to have a beneficial effect on psychological distress, supportive care needs (SCN) and quality of life (QOL). Method(s): At the end of active treatment for stage IIII CRC, eligible patients (>=18 years, adequate English) were randomized 1:1 to usual care (UC) or to UC+SC. SC comprised educational materials, needs assessment, an individualized survivorship care plan, nurseled endoftreatment session and three follow up (FU) phone calls. Distress (BSI-18), SCN (CaSUN) and QOL (EORTC QLQ-C30, CR29) were assessed at baseline, 2 (FU1) and 6 (FU2) months. Primary hypothesis: SC would have a beneficial effect on distress at FU1. Secondary hypotheses: SC would have a beneficial effect on (1) SCN and QOL at FU1; and (2) distress, SCN and QOL at FU2. 15 items assessed satisfaction with survivorship care. Sample size of 180 (90/arm) was based on 80% power, 2sided alpha of 0.05, to detect a between groups difference of 3.6 on BSI-18 at FU1. Outcome analysis was ITT. Result(s): Of 221 patients randomized (111 UC, 110 SC), 4 were ineligible and 1 lost to FU, leaving 110 UC, 106 SC. Groups appeared well balanced. Median age was 64, 52% male, 56% colon, 35% rectal cancer, 10% overlap. Stage I 7%, II 22%, III 71%. Intervention fidelity was acceptable. Baseline distress and QOL were similar to population norms. Between groups differences in distress at FU1 (primary outcome), distress at FU2 and SCN and QOL at FU1 and FU2 were small and non-significant. SC patients were more satisfied with survivorship care than UC patients (significant differences on 10 of 15 items). Conclusion(s): The addition of SC to UC did not have a beneficial effect on distress, SCN or QOL outcomes but S

Introduction: Although neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can improve operability and local disease control, there is a lack of reliable biomarkers that predict response to chemotherapy or long-term survival. Since expression of aldehyde dehydrogenase-1 (ALDH1) is associated with the stem-like properties of self-renewal and innate chemoresistance in breast cancer, we asked whether expression in serial tumor samples treated with NAC could identify women more likely to benefit from this therapy. Method(s): Women with locally advanced breast cancer were randomly assigned to receive four cycles of anthracycline-based chemotherapy, followed by four cycles of taxane therapy (Arm A), or the same regimen in reverse order (Arm B). Tumor specimens were collected at baseline, after four cycles, and then at surgical resection. ALDH1 expression was determined by immunohistochemistry and correlated with tumor response using Fisher's exact test while Kaplan-Meier method was used to calculate survival. Result(s): A hundred and nineteen women were enrolled into the study. Fifty seven (48%) were randomized to Arm A and 62 (52%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these, 26 (22%) achieved a pathological complete response (pCR) after NAC. There was no correlation between baseline ALDH1 expression and tumor grade, stage, hormone receptor, human epidermal growth factor receptor 2 (HER2) status and Ki67 index. ALDH1 negativity at baseline was significantly associated with pCR (P = 0.004). The presence of ALDH1(+) cells in the residual tumor cells in non-responding women was strongly predictive of worse overall survival (P = 0.024). Moreover, serial analysis of specimens from non-responders showed a marked increase in tumor-specific ALDH1 expression (P = 0.028). Overall, there was no survival difference according to the chemotherapy sequence. However, poorly responding tumours from women receiving docetaxel

Background: The SIRFLOX study assessed the efficacy and safety of combining FOLFOX chemotherapy (+/- bev) with SIRT as first-line treatment of patients with CRC liver metastases. Planned sub-analyses analyses included +/- extra-hepatic metastases, +/- bev and site of first progression. Method(s): SIRFLOX was an international, multi-centre, open-label, RCT in chemotherapy-naive patients with non-resectable, liver-only or liverdominant mCRC. Arm A: mFOLFOX6 +/- bev vs. arm B: mFOLFOX6 +/- bev +SIRT using yttrium-90 resin microspheres (SIR-Spheres; Sirtex) administered once with cycle 1. The primary endpoint was overall PFS using RECIST v1.0. Stratification variables included +/- extra-hepatic metastases, and +/- bev. Liver PFS was assessed by Competing Risk analysis. First progression was judged by independent reader blinded to study arm. Result(s): 530 patients were randomised (A, n = 263; B, n = 267), 212 (40%) had EHD; 292 (55%) received bev. Median follow-up was 36.1 months. Median overall PFS was 10.2 vs. 10.7 months in A vs. B, respectively (p = 0.428). Median liver PFS was 12.6 vs. 20.5 months in A vs. B (p = 0.002). Median Liver PFS was 12.4 vs. 21.1 months in A vs. B (p = 0.003) for patients with liver-only metastases, and 12.6 vs. 16.7 months (p = 0.147) for those with liver and extra-hepatic metastases. Median Liver PFS was 10.6 vs. 18.9 months in A vs. B (p = 0.028) for patients with ITT -bev, and 12.7 vs. 21.0 months (p = 0.018) for those with ITT +bev. The site of first progression was more frequently the liver (+/- other sites) in A [164/ 178, 92.1%] vs. B [120/166, 72.3%] (p < 0.001). All-causality grade >=3 adverse events occurred in 73.3% vs. 85.4% (NS) of patients in A vs. B. Conclusion(s): In first-line treatment of patients with non-resectable CRC liver metastases, adding SIRT to FOLFOX-based chemotherapy failed to improve overall PFS. The addition of SIRT significantly extended median liver PFS and reduced the frequency that first disease progres

The landscape of advanced non-small lung cancer (NSCLC) therapies has rapidly been evolving beyond chemotherapy over the last few years. The discovery of oncogenic driver mutations has led to new ways in classifying NSCLC as well as offered novel therapeutic targets for anticancer therapy. Targets such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with appropriate tyrosine kinase inhibitors (TKIs). Other driver mutations such as ROS, MET, RET, BRAF have also been investigated with targeted agents with some success in the early phase clinical setting. Novel strategies in the field of immune-oncology have also led to the development of inhibitors of cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 receptor (PD-1), which are important pathways in allowing cancer cells to escape detection by the immune system. These inhibitors have been successfully tried in NSCLC and also now bring the exciting possibility of long term responses in advanced NSCLC. In this review recent data on novel targets and therapeutic strategies and their future prospects are discussed.Copyright © 2015 by the authors; licensee MDPI, Basel, Switzerland.

Background: Preclinical studies in small cell lung cancer cell lines and xenograft models have shown that Hyaluronic acid (HA) can be effectively used to deliver Irinotecan (IR) and selectively decrease CD44 expressing (stem cell-like) tumour cells and prolong duration of response. This "proof of principle" study aims to replicate these findings in the clinical setting and obtain data on safety and response rates. Method(s): Extensive Small Cell Lung Cancer (ESCLC) patients with measurable disease (suitable for biopsy), PS 0-2, medically fit and able to give informed consent were screened for this study. A safety cohort (n=5) were treated with HA-IR (150mg/m2) and Carboplatin(C) at 5 AUC, q3 weekly with subsequent patients stratified as 1st or 2nd line. All 2nd line patients received open label HA-IR+C while 1st line patients were randomized to receive either HA-IR+C or equivalent dosing regimen of IR+C. Sequential tumour biopsies were obtained at baseline and after 1 or 2 cycles. Tumour response was measured by CT/PET scan at baseline, after 1 cycle and every 2 cycles subsequently. A final biopsy at disease progression was planned. Blood samples for circulating tumour cells (CTCs) were obtained at baseline, and at every cycle. Result(s): Patients N=16, Age: median= 60; Range 39-78. Three 2nd line patients were not evaluated due to rapid early disease progression after Cycle 1. Overall toxicity profile of HA-IR+C was similar to IR+C with grade III/IV diarrhoea and neutropenia seen in 15% and 20% respectively. One patient (7%) had grade III anaemia, while no grade III/IV nausea or vomiting was observed. No biopsy related complications were observed. Of 13 patients evaluated for tumour response, the overall response rate was 60% with 1 (7%) complete and 7 (53%) partial responses. Three patients (24%) achieved stable disease while 2 patients (16%) progressed during the treatment. To date median progression-free survival is 5.9 months (7.6 months in first line and 3.1 m

Patient-derived xenograft (PDX) models generated from surgical specimens are gaining popularity as preclinical models of cancer. However, establishment of PDX lines from small cell lung cancer (SCLC) patients is difficult due to very limited amount of available biopsy material. We asked whether SCLC cells obtained from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) could generate PDX lines that maintained the phenotypic and genetic characteristics of the primary tumor. Following successful EBUS-TBNA sampling for diagnostic purposes, we obtained an extra sample for cytologic analysis and implantation into the flanks of immunodeficient mice. Animals were monitored for engraftment for up to 6 months. Histopathologic and immunohistochemical analysis, and targeted next-generation resequencing, were then performed in both the primary sample and the derivative PDX line. A total of 12 patients were enrolled in the study. EBUS-TBNA aspirates yielded large numbers of viable tumor cells sufficient to inject between 18,750 and 1,487,000 cells per flank, and to yield microgram quantities of high-quality DNA. Of these, samples from 10 patients generated xenografts (engraftment rate 83%) with a mean latency of 104 days (range 63-188). All but one maintained a typical SCLC phenotype that closely matched the original sample. Identical mutations that are characteristic of SCLC were identified in both the primary sample and xenograft line. EBUS-TBNA has the potential to be a powerful tool in the development of new targeting strategies for SCLC patients by providing large numbers of viable tumor cells suitable for both xenografting and complex genomic analysis.Copyright © 2014 Leong et al.

Patient-derived xenograft (PDX) models generated from surgical specimens are gaining popularity as preclinical models of cancer. However, establishment of PDX lines from small cell lung cancer (SCLC) patients is difficult due to very limited amount of available biopsy material. We asked whether SCLC cells obtained from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) could generate PDX lines that maintained the phenotypic and genetic characteristics of the primary tumor. Following successful EBUS-TBNA sampling for diagnostic purposes, we obtained an extra sample for cytologic analysis and implantation into the flanks of immunodeficient mice. Animals were monitored for engraftment for up to 6 months. Histopathologic and immunohistochemical analysis, and targeted next-generation re-sequencing, were then performed in both the primary sample and the derivative PDX line. A total of 12 patients were enrolled in the study. EBUS-TBNA aspirates yielded large numbers of viable tumor cells sufficient to inject between 18,750 and 1,487,000 cells per flank, and to yield microgram quantities of high-quality DNA. Of these, samples from 10 patients generated xenografts (engraftment rate 83%) with a mean latency of 104 days (range 63-188). All but one maintained a typical SCLC phenotype that closely matched the original sample. Identical mutations that are characteristic of SCLC were identified in both the primary sample and xenograft line. EBUS-TBNA has the potential to be a powerful tool in the development of new targeting strategies for SCLC patients by providing large numbers of viable tumor cells suitable for both xenografting and complex genomic analysis.

Background: Current cancer treatment failure is due to a small population of slow-growing and drug resistant cells known as cancer stem cells (CSCs). Unlimited self-renewal and exclusive tumerogenicity are hypothesized to be the properties of stem cells responsible for relapse. In Vitro studies have proved that NSCLC cells expressing certain markers (CD44, CD 133 and ALDH 1) have stem cell properties. We aimed to investigate the expression of three cancer stem cell markers (CD44, CD133, ALDH 1) in NSCLC and evaluated their prognostic values for postoperative relapse and correlation with histological subtypes. Method(s): Tumours were obtained from 102 patients with stage 1 NSCLC (both Adenocarcinoma and SCC) who underwent surgical resection (1999-2008). Sequentially sampled paraffin sections were immunoprobed with antibodies for CD44standard, CD133 and ALDH 1 followed by reaction with DAB-conjugated secondary antibodies. All slides were scored by an independent pathologist in a blinded manner. Statistical analysis was conducted where correlations between CSC biomarker expression, histological subtypes and cancer recurrence rates was performed. Cumulative risks for developing recurrence of lung cancer after curative treatment of primary tumours was calculated using the Kaplan-Meier method and was compared between the groups using the log-rank test. Result(s): 102 pts with age range of 42-84 (median 68) underwent radical surgery and were pathologically staged as WHO stage1A (64) or 1B (38). Median follow up was 60 months (10-108) where follow up data was unavailable for 2 patients. Within the patient population 39% had relapsed; 31% had distant and 8% locoregional relapses where within these relaspses, 17/63 (23%) were Stage 1A and 22/37(59%) stage 1B. Analysis demonstrated a higher expression of CD44 in Squamous Cell Carcinoma (SCC) than Adenocarcinoma (ACA). Within the 102 stained sections, 53% in SCC vs. 24% in ACA were positive for CD44 (p=0.005) with 61% of positi

Background:Cetuximab can reverse chemotherapy resistance in colorectal cancer. This study evaluated the efficacy and safety of the combination of docetaxel and cetuximab as a second-line treatment in docetaxel-refractory oesophagogastric cancer. Method(s):Patients received docetaxel 30 mg m-2 on days 1 and 8, every 3 weeks and cetuximab 400 mg m-2 on day 1, then 250 mg m-2 weekly. Biomarker mutation analysis was performed. Result(s):A total of 38 patients were enrolled. Response rates were PR 6% (95% CI 2-19%), s.d. 43% (95% CI 28-59%). Main grade 3/4 toxicities were febrile neutropenia, anorexia, nausea, diarrhoea, stomatitis, and acneiform rash. Median progression-free and overall survival were 2.1 and 5.4 months, respectively. A landmark analysis showed a trend to improved survival times with increased grade of acneiform rash. No KRAS, BRAF or PIK3CA mutations were observed. Conclusion(s):Cetuximab and docetaxel achieve modest responses rates, but maintain comparable survival times to other salvage regimens with low rates of toxicity. © 2013 Cancer Research UK.

The cancer stem cell (CSC) model is based on a myriad of experimental and clinical observations suggesting that the malignant phenotype is sustained by a subset of cells characterized by the capacity for self-renewal, differentiation and innate resistance to chemotherapy and radiation. CSC may be responsible for disease recurrence after definitive therapy and may therefore be functionally synonymous with minimal residual disease. Similar to other solid tumours, several putative surface markers for lung CSC have been identified, including CD133 and CD44. In addition, expression and/or activity of the cytoplasmic enzyme aldehyde dehydrogenase ALDH and capacity of cells to exclude membrane permeable dyes (known as the 'side population') correlate with stem-like function in vitro and in vivo. Embryonic stem cell pathways such as Hedgehog, Notch and WNT may also be active in lung cancers stem cells and therefore may be therapeutically targetable for maintenance therapy in patients achieving a complete response to surgery, radiotherapy or chemotherapy. This paper will review the evidence regarding the existence and function of lung CSC in the context of the experimental and clinical evidence and discuss some ongoing controversies regarding this model. © 2013 Asian Pacific Society of Respirology.

Background Expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and CD133 has been functionally associated with a stem cell phenotype in normal and malignant cells. The prevalence of such cells in solid tumours should therefore correlate with recurrence and/ or metastasis following definitive surgical resection. The aim of this study was to evaluate the prognostic significance of ALDH1A1 and CD133 in surgically resected, early stage non-small cell lung cancer (NSCLC). Methods A retrospective analysis of ALDH1A1 and CD133 expression in 205 patients with pathologic stage I NSCLC was performed using immunohistochemistry. The association between the expression of both markers and survival was determined. Results We identified 62 relapses and 58 cancer-related deaths in 144 stage 1A and 61 stage 1B patients, analysed at a median of 5-years follow-up. Overexpression of ALDH1A1 and CD133, detected in 68.7% and 50.7% of primary tumours, respectively, was an independent prognostic indicator for overall survival by multivariable Cox proportional hazard model (p=0.017 and 0.039, respectively). Overexpression of ALDH1A1, but not of CD133, predicted poor recurrence-free survival (p=0.025). When categorised into three groups according to expression of ALDH1A1/CD133, patients with overexpression of both ALDH1A1 and CD133 belonged to the group with the shortest recurrence-free and overall survival (p=0.015 and 0.017, respectively). Conclusions Expression of ALDH1A1 and CD133, and coexpression of ALDH1A1 and CD133, is strongly associated with poor survival in early-stage NSCLC following surgical resection. These data are consistent with the hypothesis that expression of stem cell markers correlates with recurrence as an indirect measure of selfrenewal capacity.

Background: This randomized phase II study evaluated the efficacy and safety of P, a fully human mAb against the epidermal growth factor receptor combined with T-based chemotherapy in advanced OG cancer. Method(s): Eligible pts had histologically confirmed metastatic OG cancer (adeno-carcinoma and squamous cell carcinoma) were 18 years of age, PS 0-2, with adequate renal, haematologic and liver function with measurable disease. All pts provided informed consent. Selection was not based on kras determination. Pts received T 30mg/m2 d1,8, C 60mg/m2 d1 and F; investigator choice of 5FU infusion 160mg/m2/d or capecitabine 500mg/m2bd continuous +/-P 9 mg/kg d1 q3w. Treatment was administered for 8 cycles or until PD. The primary endpoint was response rate according to RECIST (1.1) assessed q6w. Planned enrolment target was 100 pts. Stratification variables included histology, PS and choice of F. Result(s): From April 2010 to November 2011, 77 pts were enrolled from 15 institutions. A safety alert from the REAL3 study (also involving P in OG cancer) prompted an unplanned review of data from ATTAX3 by the IDMC. The IDMC found no evidence of adverse outcomes associated with P, but as it did not appear that P would significantly improve efficacy, they recommended cessation of the study to new enrolment. Previously enrolled pts were treated and followed according to protocol. Median follow up is 24m. Treatment arms were well balanced; median age 59, 64y, male 77%, 87%, PS0-1 95%,90%, adenocarcinoma 90%,90%, capecitabine 67%, 66% for TCF/TCF-P, respectively. Common grade 3/4 toxicities include infection 18%,24%, febrile neutropenia 10%, 5%, anorexia 10%, 24%, nausea 18%,30%, stomatitis 3%,5%, diarrhoea 15%,24% , acneiform rash 0%, 8%, fatigue 18%, 30%, hypomagnesemia 10%, 16% for TCF/TCF-P. Efficacy outcomes are summarized in Table. Conclusion(s): The addition of P to T-based chemotherapy in advanced OG cancer did not improve efficacy and was associated with an increase in som

Oncogenic driver mutations frequently occur in lung cancer and play role in carcinogenesis. These mutations are usually associated with distinct clinical and histological features and are attractive targets for anticancer therapy. Recently, several molecularly distinct phenotypes of NSCLC based on specific and mutually exclusive genetic derangements have been described. Few targets like epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with EGFR tyrosine kinase inhibitors (TKIs) and crizotinib, respectively. Many more inhibitors of specific driver mutations involving genes like ROS, c-MET, FGFR, mTOR, IGFR and RET are currently under development. However, efforts to target some mutated genes like K-RAS have been unsuccessful. Moreover, the emerging challenge of acquired resistance to initially effective therapy is becoming another major concern. In this review recent data on novel molecular targets and their future prospects are discussed. © 2013 Elsevier Ltd. All rights reserved.

BACKGROUND: Expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and CD133 has been functionally associated with a stem cell phenotype in normal and malignant cells. The prevalence of such cells in solid tumours should therefore correlate with recurrence and/or metastasis following definitive surgical resection. The aim of this study was to evaluate the prognostic significance of ALDH1A1 and CD133 in surgically resected, early stage non-small cell lung cancer (NSCLC). METHODS: A retrospective analysis of ALDH1A1 and CD133 expression in 205 patients with pathologic stage I NSCLC was performed using immunohistochemistry. The association between the expression of both markers and survival was determined. RESULTS: We identified 62 relapses and 58 cancer-related deaths in 144 stage 1A and 61 stage 1B patients, analysed at a median of 5-years follow-up. Overexpression of ALDH1A1 and CD133, detected in 68.7% and 50.7% of primary tumours, respectively, was an independent prognostic indicator for overall survival by multivariable Cox proportional hazard model (p=0.017 and 0.039, respectively). Overexpression of ALDH1A1, but not of CD133, predicted poor recurrence-free survival (p=0.025). When categorised into three groups according to expression of ALDH1A1/CD133, patients with overexpression of both ALDH1A1 and CD133 belonged to the group with the shortest recurrence-free and overall survival (p=0.015 and 0.017, respectively). CONCLUSIONS: Expression of ALDH1A1 and CD133, and coexpression of ALDH1A1 and CD133, is strongly associated with poor survival in early-stage NSCLC following surgical resection. These data are consistent with the hypothesis that expression of stem cell markers correlates with recurrence as an indirect measure of self-renewal capacity.

BACKGROUND: Cetuximab can reverse chemotherapy resistance in colorectal cancer. This study evaluated the efficacy and safety of the combination of docetaxel and cetuximab as a second-line treatment in docetaxel-refractory oesophagogastric cancer. METHODS: Patients received docetaxel 30 mg m(-2) on days 1 and 8, every 3 weeks and cetuximab 400 mg m(-2) on day 1, then 250 mg m(-2) weekly. Biomarker mutation analysis was performed. RESULTS: A total of 38 patients were enrolled. Response rates were PR 6% (95% CI 2-19%), s.d. 43% (95% CI 28-59%). Main grade 3/4 toxicities were febrile neutropenia, anorexia, nausea, diarrhoea, stomatitis, and acneiform rash. Median progression-free and overall survival were 2.1 and 5.4 months, respectively. A landmark analysis showed a trend to improved survival times with increased grade of acneiform rash. No KRAS, BRAF or PIK3CA mutations were observed. CONCLUSION: Cetuximab and docetaxel achieve modest responses rates, but maintain comparable survival times to other salvage regimens with low rates of toxicity.

Chemotherapy plus trastuzumab is the standard first-line treatment for Human Epidermal Receptor 2-positive (HER2-positive) metastatic breast cancer. The aim of this international phase II trial was to determine the efficacy and safety profile of an oral chemotherapy doublet, oral vinorelbine plus capecitabine, and trastuzumab in this setting. Patients and Methods: In this single-Arm, multicenter, openlabel phase II study, in the first-line metastatic setting, patients received 3-weekly cycles of oral vinorelbine at 80 mg/m2 (first cycle dose 60 mg/m2) day 1 and day 8, plus capecitabine at 1000 (750 if =65 years) mg/m2 twice daily on days 1-14, plus trastuzumab at 4 mg/kg intravenously (i.v.) on day 1 (loading dose) then 2 mg/kg i.v. weekly thereafter. Treatment was continued until progression or unacceptable toxicity. Results: Fifty patients with a median age of 53.5 years were enrolled. Most (82%) had visceral involvement and 34% had more than two metastatic sites. The objective response rate (RECIST 1.0) in 44 evaluable patients was 77% [95% Confidence Interval (CI)=62-89%], including complete response in 21%. The clinical benefit rate (response or stable disease for =6 months) was 93% [95% CI=81-99%]. Median duration of response was 13.3 [95% CI=9.8-15.7] months, median progression-free survival was 12.8 [95% CI=10.8- 16.9] months and median overall survival was 47.0 [95% CI=30.5-64.3] months. Median number of cycles was 10 (range 1-81). The majority of patients (72%) received more than 18 weeks and 32% more than 48 weeks of treatment. The most frequent treatment-related grade 3/4 adverse events were neutropenia (71%), hand-foot syndrome (20%) and diarrhea (16%). A low-rate of grade 2 alopecia was observed (14%). Conclusion: The triple combination of oral vinorelbine, capecitabine and trastuzumab is highly active in terms of response rate, progression-free survival and overall survival, with a manageable toxicity profile.

Aim: Gemcitabine (G) and docetaxel (D) have both shown activity in the treatment of anthracycline-pretreated patients with metastatic breast cancer. This phase II study was designed to evaluate the safety and efficacy of the GD combination. Method(s): Patients with measurable locally advanced or metastatic breast cancer who had previously received anthracycline-based therapy were eligible. The patients received D 40mg/m 2 followed by G 800 mg/m2 IV on s 1 and 8 every 3 weeks for a maximum of eight cycles. Result(s): Thirty patients were enrolled and received a median offive cycles (range 0-8). Of these, 24 were evaluable for efficacy, with an overall response rate of 29.2% (95% CI, 12.6-51.1%). An additional 36.7% had a stable disease for an overall clinical benefit of 65.9%. The median duration of response was 2.1 months (95% CI, 2.0-3.6 months) and the median time to disease progression was 5.5 months (95% CI, 2.0-8.9 months). The median survival time was 16.7 months (95% CI, 7.3-32.0 months). Myelosuppression was the major toxicity, with grade 3/4 neutropenia in 73.3% of patients and febrile neutropenia in 6.7%. Conclusion(s): Weekly G and D is an active and safe regimen in treating metastatic breast cancer. The response rate was lower than that previously reported for this combination, which may relate to the lower doses used and the weekly D schedule. It may be worthwhile to further explore this combination to determine the optimal dosing schedule. © 2009 The Authors Journal compilation © 2009 Blackwell Publishing Asia Pty Ltd.

Standard chemoradiotherapy with infusional 5FU for locally advanced pancreatic cancer (LAPC) has limited efficacy in this disease. The combination of Capecitabine (Cap) and Gemcitabine (Gem) are synergistic and are potent radiosensitisers. The aim of this phase I trial was thus to determine the highest administered dose of the Cap plus Gem combination with radical radiotherapy (RT) for LAPC. Patients had LAPC, adequate organ function, ECOG PS 0-1. During RT, Gem was escalated from 20-50 mg m-2 day-1 (twice per week), and Cap 800-2000 mg m-2 day-1 (b.i.d, days 1-5 of each week). Radiotherapy 50.4 Gy/28 fractions/5.5 weeks, using 3D-conformal techniques. Three patients were entered to each dose level (DL). Dose-limiting toxicity(s) (DLTs) were based on treatment-related toxicities. Twenty patients were accrued. Dose level (DL) 1: Cap/Gem; 800/20 mg m -2 day-1 (3 patients), DL2: 1000/20 (12 patients), DL3: 1300/30 (5 patients). Dose-limiting toxicities were observed in DL3; grade 3 dehydration (1 patient) and grade 3 diarrhoea and dehydration (1 patient). Dose level 2 was the recommend phase 2 dose. Disease control rate was 75%: PR=15%, SD=60%. Median overall survival was 11.2 months. The addition of Cap and Gem to radical RT was feasible and active and achieved at relatively low doses. © 2009 Cancer Research UK.

Purpose: The objective of this study was to conduct a randomised phase II study in second-line metastatic colorectal cancer with the purpose of confirming preliminary clinical data indicating that the formulation of irinotecan with the drug carrier, hyaluronan (HA) reduced toxicity of the drug. Method(s): Irinotecan-naive patients were randomized to receive either irinotecan (350 mg/m2) or HA-Irinotecan (HA 1,000 mg/m2 and irinotecan at 350 mg/m2) every 3 weeks for a maximum of eight cycles. Result(s): Seventy-six patients (41 HA-Irinotecan and 35 irinotecan-alone) were enrolled. There was no significant difference in any individual, or overall, grade 3 or 4 toxicity. There was a trend for increased diarrhea in the HA-Irinotecan-treated patients (20 versus 9%; P = 21), potentially explained by a disproportionate number of baseline toxicity-associated risk factors in this treatment group. The median number of cycles completed was six for HA-Irinotecan patients and two for irinotecan-alone patients (P = 0.005). When compared to the control arm, HA-Irinotecan patients had a significantly longer median progression-free survival of 5.2 versus 2.4 months (P = 0.017) and time to treatment failure (4 vs. 1.8 months; P = 0.007). Median overall survival was 10.1 months for HA-Irinotecan compared to 8.0 months for irinotecan patients (P = 0.196). Conclusion(s): Further studies are required to define the safety of the formulation of irinotecan with HA. While this study was not adequately powered to demonstrate survival differences, these phase II data indicated HA-Irinotecan to be a promising therapy demonstrating improved efficacy compared to irinotecan-alone. © 2010 Springer-Verlag.

Objective: To evaluate the frequency and management of anaemia in Australian adults with solid and haematological malignancies. Design(s): 6-month observational, prospective, multicentre study. Participant(s): 694 patients recruited from outpatient oncology clinics in 24 hospitals in five Australian states between 9 April 2001 and 31 July 2001. Main Outcome Measure(s): Frequency of anaemia (haemoglobin [Hb] level < 120 g/L) at enrolment and over ensuing 6 months, by tumour type, disease status and cancer treatment; anaemia treatment and "trigger" Hb level for this treatment. Result(s): Participants had median age 60 years, and 61% were women. Prevalence of anaemia at enrolment was 35% (199/562), with 78% of these 199 having mild anaemia (Hb, 100-119 g/L). Frequency of anaemia (either present at enrolment or developing during the study) was 57% overall (323/566), and varied with tumour type, from 49% (lymphoma/myeloma) to 85% (urogenital cancer). Patients who received radiotherapy either in combination or concomitant with chemotherapy were more likely to have anaemia (73%) than those receiving chemotherapy alone (58%) (P=0.004). Of all chemotherapy patients not anaemic at enrolment, 23% developed anaemia by the second monthly follow-up. Independent predictors for anaemia in chemotherapy patients were low baseline Hb level (odds ratio [OR], 5.4; 95% CI, 2.7-10.9) and use of platinum chemotherapeutic agents (OR, 4.8; 95% CI, 2.1-11.4) (P<0.001). Anaemia was treated in 41% of patients with anaemia at enrolment - by transfusion (36%), iron (5%) and erythropoietic agents (2%). Frequency of anaemia treatment varied between tumour types, from 19% (breast cancer) to 60% (leukaemia). The mean "trigger Hb" for initiating transfusion was 95 g/L. Conclusion(s): Anaemia is prevalent among Australian patients with cancer managed in hospital oncology units. Its management varies between tumour types. Many patients do not receive treatment for their anaemia.

Preclinical data indicates that cyclooxygenase-2 (COX-2) inhibition impairs plasma cell growth and potentially synergizes with thalidomide. We performed a trial in previously treated patients with myeloma using thalidomide up to a maximum dose of 800 mg/d with celecoxib (400 mg bid). Outcomes were compared with a prior trial of thalidomide. Sixty-six patients with median age of 67 (range, 43-85) received a median dose of thalidomide and celecoxib of 400 and 800 mg/d, respectively, with median durations of treatment of 27 and 13 weeks, respectively. The most common toxicities associated with premature discontinuation of celecoxib (n = 30 of 53, 57%) were fluid retention and deterioration of renal function. Overall response rate (RR) was 42% and with 20 months median follow-up; the actuarial median progression-free survival and overall survival were 6.8 and 21.4 months, respectively. Unlike our prior study, age >65 years was not predictive of inferior RR due to improvement in RR in older patients with the combination (37% versus 15%, P = 0.08). The RR was superior in patients who received a total dose of celecoxib exceeding 40 g in the first 8 weeks of therapy (62% versus 30%, P = 0.021). Progression-free survival and overall survival were also improved. Other predictors for inferior progression-free survival were age >65 years (P = 0.016) and elevated beta2-microglobulin (P = 0.017). This study provides evidence that the addition of high-dose celecoxib adds to the antimyeloma activity of thalidomide but this comes with unacceptable toxicity. Future studies should use newer COX-2 inhibitors with thalidomide, or their respective derivatives. © 2005 American Association for Cancer Research.

Background:Docetaxel administered 3-weekly with cisplatin and 5-fluorouracil leads to better survival than does standard therapy in patients with oesophagogastric cancer, but leads to high rates of haematological toxicity. Weekly docetaxel is associated with less haematological toxicity. This randomised phase II study tested weekly docetaxel-based combination chemotherapy regimens, with the aim of maintaining their activity while reducing toxicity. Method(s):Patients with histologically confirmed metastatic oesophageal or gastric carcinoma were randomised to receive weekly docetaxel (30 mg m 2) on days 1 and 8, cisplatin (60 mg m 2) on day 1, and 5-fluorouracil (200 mg m 2 per day) continuously, every 3 weeks (weekly TCF, wTCF); or docetaxel (30 mg m 2) on days 1 and 8 and capecitabine (1600 mg m 2 per day) on days 1-14, every 3 weeks (weekly TX, wTX). Result(s):A total of 106 patients were enrolled (wTCF, n50; wTX, n56). Response rates, the primary end point, were 47% with wTCF and 26% with wTX. Rates of febrile neutropenia were low in each arm. Median progression-free and overall survival times were 5.9 and 11.2 months for wTCF and 4.6 and 10.1 months for wTX, respectively. Conclusion(s):Weekly TCF and TX have encouraging activity and less haematological toxicity than TCF administered 3-weekly. Weekly docetaxel-based combination regimens warrant further evaluation in this disease. © 2010 Cancer Research UK.

Background: X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects. Method(s): We assessed the pattern of X chromosome inactivation using methylation-specific polymerase chain reaction amplification of the exon 1 microsatellite region of the X-linked androgen receptor (AR) gene in DNA from blood samples obtained from control subjects without a personal history of breast or ovarian cancer (n = 735), ovarian cancer patients (n = 313), familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2 (n = 235), and affected and unaffected carriers of mutations in BRCA1 (n = 260) or BRCA2 (n = 63). We defined the pattern of X chromosome inactivation as skewed when the same X chromosome was active in at least 90% of cells. The association between skewed X inactivation and disease and/or BRCA mutation status was assessed by logistic regression analysis. The association between skewed X inactivation and age at cancer diagnosis was assessed by Cox proportional hazards regression analysis. All statistical tests were two-sided. Result(s): The age-adjusted frequency of skewed X inactivation was not statistically significantly higher in ovarian cancer or familial breast cancer case subjects compared with control subjects. Skewed X inactivation was higher in BRCA1 mutation carriers than in control subjects (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.1 to 6.2; P =. 02), particularly among unaffected women (OR = 6.1, 95% CI = 1.5 to 31.8; P =. 005). Among BRCA1 mutation carriers, those with skewed X inactivation were older at diagnosis of breast or ovarian cancer than those without skewed X inactivation (hazard ratio [HR] o

Mental, neurological, and substance use (MNS) disorders are leading causes of the global burden of disease and profoundly impact the social and economic well-being of individuals and communities. The majority of people affected by MNS disorders globally do not have access to evidence-based interventions and many experience discrimination and abuses of their human rights. A United Nations General Assembly Special Session (UNGASS) is needed to focus global attention on MNS disorders as a core development issue requiring commitments to improve access to care, promote human rights, and strengthen the evidence on effective prevention and treatment.

Background: The aim of this pilot study was to evaluate the correlation between response to neoadjuvant chemotherapy (NCT) in patients with locally advanced breast cancer and plasma levels of carboxy-terminal cross-linked telopeptide of type 1 collagen (ICTP). ICTP is a degradation product of Type 1 collagen which is one of the major component of extracellular matrix (stroma) of tumours. Degradation of this collagenous matrix by tumour or stromal cell-derived proteolytic activity may facilitate tumour cells or some degraded component into systemic circulation. Alterations in these products may be useful monitoring tumour behaviour and treatment reponse in cancer patients. Material(s) and Method(s): Following informed consent, 21 patients with locally advanced breast cancer suitable for NCT were recruited. Participants were randomly assigned to receive either sequential FEC100(x4) and Docetaxel 100/m2(x4), or the reverse sequence. Serial assessment of response was performed with physical examination, mammography, ultrasound, tumour biopsy and PET scans. Blood samples were collected at baseline, after 4 cycles of chemotherapy and lastly at the time of surgery. Plasma ICTP levels were determined in a blinded way using the UNIQ ICTP RIA assay(Orion Diagnostics, Finland) and compared with final pathological response (complete/partial vs no response). Result(s): Increase in ICTP level was seen in 12/13 patients responding to NCT. Eight patients with poor pathological response had mixed levels with no overall increase in ICTP level. The trend seen did not reach statistical significance. Discussion(s): It is speculated that the rise in ICTP level is in response to ongoing stromal resonse in these patients' tumours and hence increase in matrix metalloproteinase (MMP) activity. This study is limited by small numbers of patients enrolled. Further investigation by gene expression studies is required to confirm these observations and the usefulness of ICTP in monitoring treatmen

Purpose: To determine whether adding bevacizumab, with or without mitomycin, to capecitabine monotherapy improves progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) in an open-label, three-arm randomized trial. Patients and Methods: Overall, 471 patients in Australia, New Zealand, and the United Kingdom with previously untreated, unresectable mCRC were randomly assigned to the following: capecitabine; capecitabine plus bevacizumab (CB); or capecitabine, bevacizumab, and mitomycin (CBM). We compared CB with capecitabine and CBM with capecitabine for progression-free survival (PFS). Secondary end points included overall survival (OS), toxicity, response rate (RR), and quality of life (QOL). Result(s): Median PFS was 5.7 months for capecitabine, 8.5 months for CB, and 8.4 months for CBM (capecitabine v CB: hazard ratio [HR], 0.63; 95% CI, 0.50 to 0.79; P < .001; C v CBM: HR, 0.59; 95% CI, 0.47 to 0.75; P < .001). After a median follow-up of 31 months, median OS was 18.9 months for capecitabine and was 16.4 months for CBM; these data were not significantly different. Toxicity rates were acceptable, and all treatment regimens well tolerated. Bevacizumab toxicities were similar to those in previous studies. Measures of overall QOL were similar in all groups. Conclusion(s): Adding bevacizumab to capecitabine, with or without mitomycin, significantly improves PFS without major additional toxicity or impairment of QOL. Copyright © 2010 by American Society of Clinical Oncology.

Introduction: The aims of this study were to investigate whether drug sequence (docetaxel followed by anthracyclines or the drugs in reverse order) affects changes in the maximal standard uptake volume (SUVmax) on [18F]flourodeoxyglucose positron emission tomography (FDG-PET) during neoadjuvant chemotherapy in women with locally advanced breast cancer. Method(s): Women were randomly assigned to receive either drug sequence, and FDG-PET scans were taken at baseline, after four cycles and after eight cycles of chemotherapy. Tumour response to chemotherapy was evaluated based on histology from a surgical specimen collected upon completion of chemotherapy. Result(s): Sixty women were enrolled into the study. Thirty-one received docetaxel followed by anthracyclines (Arm A) and 29 received drugs in the reverse order (Arm B). Most women (83%) had ductal carcinoma and 10 women (17%) had lobular or lobular/ductal carcinoma. All but one tumour were downstaged during therapy. Overall, there was no significant difference in response between the two drug regimens. However, women in Arm B who achieved complete pathological response had mean FDG-PET SUVmax reduction of 87.7% after four cycles, in contrast to those who had no or minor pathological response. These women recorded mean SUVmax reductions of only 27% (P < 0.01). Women in Arm A showed no significant difference in SUVmax response according to pathological response. Sensitivity, specificity, accuracy and positive and negative predictive values were highest in women in Arm B. Conclusion(s): Our results show that SUVmax uptake by breast tumours during chemotherapy can be dependent on the drugs used. Care must be taken when interpreting FDG-PET in settings where patients receive varied drug protocols. © 2010 Schneider-Kolsky et al.; licensee BioMed Central Ltd.

Background: The aim of this study was to evaluate the correlation between serum VEGF level and response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Method(s): Following informed consent, 63 patients with locally advanced breast cancer suitable for NCT were recruited. Participants were randomly assigned to receive either sequential FEC100 (x4) and Docetaxel 100/m2 (x4), or the reverse sequence. Serial assessment of response was performed with physical examination, mammography, ultrasound, tumor biopsy and PET scans. Blood samples were collected at baseline and after 4 cycles of chemotherapy. Serum VEGF levels were determined by using enzyme-linked immunosorbent assay (ELISA) and correlated with final pathological response (complete, partial or no response). Result(s): Data from fifty-seven patients were evaluable. Of those, thirteen patients (22.8%) achieved complete pathological response (pCR), 18 (31.5%) had residual node negative disease (pPR) and 26 (45.5%) had less significant response (NR) to NCT. There was no correlation between baseline serum VEGF levels and other base line tumour characteristics of grade, size, cell type, hormone receptor, Her2 status, or tumor PET SUV. There was a weak correlation of tumor micro-vessel density as assessed by CD31 stain and serum VEGF (r=0.3). There was a statistically significant association between lower baseline serum VEGF (<200pg/ml) and better final pathological response (pCR or pPR) (p= 0.030). Serial measurements looking at increase or decrease of serum VEGF during treatment showed no useful predictive trends (p=0.979). Conclusion(s): Our study showed a statistically significant correlation between baseline serum VEGF and final pathological response to NCT in patients with locally advanced breast cancer. Serum VEGF may be potentially used as one of the markers in predicting response to NCT and thereby useful in selecting patients for appropriate treatment. However, this study is limite

The aims of this study were to (i) compare the effect of drug sequence on tumour glucose uptake volumes (SUV) using PET; and (ii) correlate SUV uptake changes with pathological response to chemotherapy in women with locally advanced breast cancer undergoing sequential chemotherapy with Taxotere and Anthracyclines. Women with biopsy confirmed breast cancer were randomised to receive either Taxotere (4 cycles) followed by Anthracyclines (4 cycles) or drugs in reverse order. All underwent FDG- PET before chemotherapy, after 4 cycles and after completion of chemotherapy. Changes in SUV after 4 cycles were compared to baseline and correlated to pathological response after surgery. At that stage, patients were classified into either complete elimination of tumour (cPR), small residual tumour (pPR) or no response (nPR).The two groups were compared using Mann Whitney U test, Kruskal Wallis and Chi Square test. Sixty patients were recruited, 31 receiving Taxotere followed by Anthracyclines and 29 receiving drugs in reverse order. Most patients presented with ductal carcinoma. Overall, 23% of tumours achieved cPR, 30% a pPR and 47% a nPR. There was no significant difference in the pathological response rates between the two drug regimens. Women receiving Anthracyclines followed by Taxotere who achieved cPR had a median SUV reduction of 83% after 4 cycles, while those who had nPR had a median SUV reduction of only 27% (P < 0.01). In contrast, SUV reductions in the other group of women were not statistically different between the 3 pathological response rates. FDG-PET appears to be a useful predictor of tumour response to Anthracycline-based chemotherapy in women with breast cancer.

BACKGROUND: Docetaxel administered 3-weekly with cisplatin and 5-fluorouracil leads to better survival than does standard therapy in patients with oesophagogastric cancer, but leads to high rates of haematological toxicity. Weekly docetaxel is associated with less haematological toxicity. This randomised phase II study tested weekly docetaxel-based combination chemotherapy regimens, with the aim of maintaining their activity while reducing toxicity. METHODS: Patients with histologically confirmed metastatic oesophageal or gastric carcinoma were randomised to receive weekly docetaxel (30 mg m(-2)) on days 1 and 8, cisplatin (60 mg m(-2)) on day 1, and 5-fluorouracil (200 mg m(-2) per day) continuously, every 3 weeks (weekly TCF, wTCF); or docetaxel (30 mg m(-2)) on days 1 and 8 and capecitabine (1600 mg m(-2) per day) on days 1-14, every 3 weeks (weekly TX, wTX). RESULTS: A total of 106 patients were enrolled (wTCF, n=50; wTX, n=56). Response rates, the primary end point, were 47% with wTCF and 26% with wTX. Rates of febrile neutropenia were low in each arm. Median progression-free and overall survival times were 5.9 and 11.2 months for wTCF and 4.6 and 10.1 months for wTX, respectively. CONCLUSION: Weekly TCF and TX have encouraging activity and less haematological toxicity than TCF administered 3-weekly. Weekly docetaxel-based combination regimens warrant further evaluation in this disease.

INTRODUCTION: The aims of this study were to investigate whether drug sequence (docetaxel followed by anthracyclines or the drugs in reverse order) affects changes in the maximal standard uptake volume (SUVmax) on [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) during neoadjuvant chemotherapy in women with locally advanced breast cancer. METHODS: Women were randomly assigned to receive either drug sequence, and FDG-PET scans were taken at baseline, after four cycles and after eight cycles of chemotherapy. Tumour response to chemotherapy was evaluated based on histology from a surgical specimen collected upon completion of chemotherapy. RESULTS: Sixty women were enrolled into the study. Thirty-one received docetaxel followed by anthracyclines (Arm A) and 29 received drugs in the reverse order (Arm B). Most women (83%) had ductal carcinoma and 10 women (17%) had lobular or lobular/ductal carcinoma. All but one tumour were downstaged during therapy. Overall, there was no significant difference in response between the two drug regimens. However, women in Arm B who achieved complete pathological response had mean FDG-PET SUVmax reduction of 87.7% after four cycles, in contrast to those who had no or minor pathological response. These women recorded mean SUVmax reductions of only 27% (P < 0.01). Women in Arm A showed no significant difference in SUVmax response according to pathological response. Sensitivity, specificity, accuracy and positive and negative predictive values were highest in women in Arm B. CONCLUSIONS: Our results show that SUVmax uptake by breast tumours during chemotherapy can be dependent on the drugs used. Care must be taken when interpreting FDG-PET in settings where patients receive varied drug protocols.

BACKGROUND: Androgen ablation is the standard treatment for advanced prostate cancer. However, most patients will eventually develop progressive hormone-refractory prostate cancer (HRPC). The aim of the Pacl-Vin study was to determine the efficacy and safety of paclitaxel in combination with vinorelbine in patients with HRPC, following from a phase I trial. METHODS: Thirty castrate patients with progressive, metastatic prostate cancer were enrolled. Patients were treated with paclitaxel 40 mg/m2, vinorelbine 20 mg/m2 intravenously on day 1 and day 8 of a 21-day cycle. RESULTS: Two patients demonstrated a partial response and seven patients had stable disease from a cohort of 10 patients with measurable disease. Of 30 patients assessable for prostate-specific antigen (PSA) response, 19 showed stable disease, which was maintained for at least 4 weeks, while six (20%) experienced>or=50% decline in PSA levels. Median overall survival was 7.3 months (interquartile range (IQR): 4.7-9.9 months). Median progression-free survival was 3.3 months (IQR: 2.5-7.0 months). Improvement in quality of life measures was noted after three cycles of therapy. Grade 3 and 4 toxicities were: neutropenia 8%, febrile neutropenia 4%, infection 2%, anaemia 3%, lethargy 1% and somnolescence 1%. One patient died as a result of neutropenic sepsis. CONCLUSION: In a poor prognostic cohort of patients paclitaxel and vinorelbine is a tolerable regimen, with a 20% PSA and objective response rate. The majority of patients achieved PSA stability. Furthermore, quality of life parameters, such as pain, were improved. However, the low level of activity of this regimen precludes its further testing.

Standard chemoradiotherapy with infusional 5FU for locally advanced pancreatic cancer (LAPC) has limited efficacy in this disease. The combination of Capecitabine (Cap) and Gemcitabine (Gem) are synergistic and are potent radiosensitisers. The aim of this phase I trial was thus to determine the highest administered dose of the Cap plus Gem combination with radical radiotherapy (RT) for LAPC. Patients had LAPC, adequate organ function, ECOG PS 0-1. During RT, Gem was escalated from 20-50 mg m(-2) day(-1) (twice per week), and Cap 800-2000 mg m(-2) day(-1) (b.i.d, days 1-5 of each week). Radiotherapy 50.4 Gy/28 fractions/5.5 weeks, using 3D-conformal techniques. Three patients were entered to each dose level (DL). Dose-limiting toxicity(s) (DLTs) were based on treatment-related toxicities. Twenty patients were accrued. Dose level (DL) 1: Cap/Gem; 800/20 mg m(-2) day(-1) (3 patients), DL2: 1000/20 (12 patients), DL3: 1300/30 (5 patients). Dose-limiting toxicities were observed in DL3; grade 3 dehydration (1 patient) and grade 3 diarrhoea and dehydration (1 patient). Dose level 2 was the recommend phase 2 dose. Disease control rate was 75%: PR=15%, SD=60%. Median overall survival was 11.2 months. The addition of Cap and Gem to radical RT was feasible and active and achieved at relatively low doses.