Plasma Cetuximab Concentrations Correlate With Survival in Patients With Advanced KRAS Wild Type Colorectal Cancer.

BACKGROUND: Cetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. Limited data suggest a wide variation in cetuximab plasma concentrations after standard dosing regimens. We correlated cetuximab plasma concentrations with survival and toxicity. METHODS: The CO. 20 study randomized patients with RAS WT advanced colorectal cancer in a 1:1 ratio to cetuximab 400 mg/m2 intravenously followed by weekly maintenance of 250 mg/m2, plus brivanib 800 mg orally daily or placebo. Blood samples obtained at week 5 precetuximab treatment were analyzed by ELISA. Patients were grouped into tertiles based on plasma cetuximab concentrations. Cetuximab concentration tertiles were correlated with survival outcomes and toxicity. Patient demographic and biochemical parameters were evaluated as co-variables. RESULTS: Week 5 plasma cetuximab concentrations were available for 591 patients (78.8%). The median overall survival (OS) was 11.4 months and 7.8 months for patients in the highest (T3) and lowest tertiles (T1) respectively. On multivariable analysis, plasma cetuximab concentration was associated with OS (HR 0.66, 95% confidence interval [CI]: 0.53-0.83, P < .001, T3 vs. T1), and a trend towards progression-free survival (HR 0.82, 95% CI: 0.66-1.02, P = .07, T3 vs. T1). There was no association between cetuximab concentration and skin toxicity or diarrhea. CONCLUSION: The standard cetuximab dosing regimen may not be optimal for all patients. Further pharmacokinetic studies are needed to optimize cetuximab dosing given the potential improvement in OS.

Impact of burnout on empathy.

AIM: Burnout has a damaging effect on both the wellbeing of medical professionals and patients alike. Empathy is an important part of the therapeutic relationship and could be damaged by burnout. We aimed to describe the prevalence of burnout, assess levels of empathy and explore the relationship between burnout and empathy among senior medical officers (SMOs). We hypothesised that there would be a negative correlation between empathy and burnout. METHOD: This was a cross-sectional observational study involving SMOs from a variety of specialities. The focus is on SMOs with relatively prolonged contact times with patients. Email invitations were sent out requesting participation in an electronic survey on the QuestionPro platform. The survey comprised 42 questions enquiring about demographics, empathy (Jefferson Scale of Physician Empathy) and burnout (Copenhagen Burnout Inventory). Correlational analyses were performed. RESULTS: Three hundred and fourteen invitations were sent out and 178 responses were received (56.7% response rate). Forty-five percent of SMOs surveyed were experiencing high levels of personal burnout. There was a statistically significant negative correlation between empathy and patient-related burnout (p=0.018). CONCLUSIONS: The results show high levels of personal burnout among SMOs and suggest that empathy reduces as patient-related burnout increases. The nature of this relationship is a complex one, and other contributing variables should be considered.

Follow-up strategies for patients treated for non-metastatic colorectal cancer.

BACKGROUND: This is the fourth update of a Cochrane Review first published in 2002 and last updated in 2016.It is common clinical practice to follow patients with colorectal cancer for several years following their curative surgery or adjuvant therapy, or both. Despite this widespread practice, there is considerable controversy about how often patients should be seen, what tests should be performed, and whether these varying strategies have any significant impact on patient outcomes. OBJECTIVES: To assess the effect of follow-up programmes (follow-up versus no follow-up, follow-up strategies of varying intensity, and follow-up in different healthcare settings) on overall survival for patients with colorectal cancer treated with curative intent. Secondary objectives are to assess relapse-free survival, salvage surgery, interval recurrences, quality of life, and the harms and costs of surveillance and investigations. SEARCH METHODS: For this update, on 5 April 2109 we searched CENTRAL, MEDLINE, Embase, CINAHL, and Science Citation Index. We also searched reference lists of articles, and handsearched the Proceedings of the American Society for Radiation Oncology. In addition, we searched the following trials registries: ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We contacted study authors. We applied no language or publication restrictions to the search strategies. SELECTION CRITERIA: We included only randomised controlled trials comparing different follow-up strategies for participants with non-metastatic colorectal cancer treated with curative intent. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently determined study eligibility, performed data extraction, and assessed risk of bias and methodological quality. We used GRADE to assess evidence quality. MAIN RESULTS: We identified 19 studies, which enrolled 13,216 participants (we included four new studies in this second update). Sixteen out of the 19 studies were eligible for quantitative synthesis. Although the studies varied in setting (general practitioner (GP)-led, nurse-led, or surgeon-led) and 'intensity' of follow-up, there was very little inconsistency in the results.Overall survival: we found intensive follow-up made little or no difference (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.80 to 1.04: I² = 18%; high-quality evidence). There were 1453 deaths among 12,528 participants in 15 studies. In absolute terms, the average effect of intensive follow-up on overall survival was 24 fewer deaths per 1000 patients, but the true effect could lie between 60 fewer to 9 more per 1000 patients.Colorectal cancer-specific survival: we found intensive follow-up probably made little or no difference (HR 0.93, 95% CI 0.81 to 1.07: I² = 0%; moderate-quality evidence). There were 925 colorectal cancer deaths among 11,771 participants enrolled in 11 studies. In absolute terms, the average effect of intensive follow-up on colorectal cancer-specific survival was 15 fewer colorectal cancer-specific survival deaths per 1000 patients, but the true effect could lie between 47 fewer to 12 more per 1000 patients.Relapse-free survival: we found intensive follow-up made little or no difference (HR 1.05, 95% CI 0.92 to 1.21; I² = 41%; high-quality evidence). There were 2254 relapses among 8047 participants enrolled in 16 studies. The average effect of intensive follow-up on relapse-free survival was 17 more relapses per 1000 patients, but the true effect could lie between 30 fewer and 66 more per 1000 patients.Salvage surgery with curative intent: this was more frequent with intensive follow-up (risk ratio (RR) 1.98, 95% CI 1.53 to 2.56; I² = 31%; high-quality evidence). There were 457 episodes of salvage surgery in 5157 participants enrolled in 13 studies. In absolute terms, the effect of intensive follow-up on salvage surgery was 60 more episodes of salvage surgery per 1000 patients, but the true effect could lie between 33 to 96 more episodes per 1000 patients.Interval (symptomatic) recurrences: these were less frequent with intensive follow-up (RR 0.59, 95% CI 0.41 to 0.86; I² = 66%; moderate-quality evidence). There were 376 interval recurrences reported in 3933 participants enrolled in seven studies. Intensive follow-up was associated with fewer interval recurrences (52 fewer per 1000 patients); the true effect is between 18 and 75 fewer per 1000 patients.Intensive follow-up probably makes little or no difference to quality of life, anxiety, or depression (reported in 7 studies; moderate-quality evidence). The data were not available in a form that allowed analysis.Intensive follow-up may increase the complications (perforation or haemorrhage) from colonoscopies (OR 7.30, 95% CI 0.75 to 70.69; 1 study, 326 participants; very low-quality evidence). Two studies reported seven colonoscopic complications in 2292 colonoscopies, three perforations and four gastrointestinal haemorrhages requiring transfusion. We could not combine the data, as they were not reported by study arm in one study.The limited data on costs suggests that the cost of more intensive follow-up may be increased in comparison with less intense follow-up (low-quality evidence). The data were not available in a form that allowed analysis. AUTHORS' CONCLUSIONS: The results of our review suggest that there is no overall survival benefit for intensifying the follow-up of patients after curative surgery for colorectal cancer. Although more participants were treated with salvage surgery with curative intent in the intensive follow-up groups, this was not associated with improved survival. Harms related to intensive follow-up and salvage therapy were not well reported.

Hypofractionation for clinically localized prostate cancer.

BACKGROUND: Using hypofractionation (fewer, larger doses of daily radiation) to treat localized prostate cancer may improve convenience and resource use. For hypofractionation to be feasible, it must be at least as effective for cancer-related outcomes and have comparable toxicity and quality of life outcomes as conventionally fractionated radiation therapy. OBJECTIVES: To assess the effects of hypofractionated external beam radiation therapy compared to conventionally fractionated external beam radiation therapy for men with clinically localized prostate cancer. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid) and trials registries from 1946 to 15 March 2019 with reference checking, citation searching and contact with study authors. Searches were not limited by language or publication status. We reran all searches within three months (15th March 2019) prior to publication. SELECTION CRITERIA: Randomized controlled comparisons which included men with clinically localized prostate adenocarcinoma where hypofractionated radiation therapy (external beam radiation therapy) to the prostate using hypofractionation (greater than 2 Gy per fraction) compared with conventionally fractionated radiation therapy to the prostate delivered using standard fractionation (1.8 Gy to 2 Gy per fraction). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. Two authors independently assessed trial quality and extracted data. We used Review Manager 5 for data analysis and meta-analysis. We used the inverse variance method and random-effects model for data synthesis of time-to-event data with hazard ratios (HR) and 95% confidence intervals (CI) reported. For dichotomous data, we used the Mantel-Haenzel method and random-effects model to present risk ratios (RR) and 95% CI. We used GRADE to assess evidence quality for each outcome. MAIN RESULTS: We included 10 studies with 8278 men in our analysis comparing hypofractionation with conventional fractionation to treat prostate cancer.Primary outcomesHypofractionation may result in little or no difference in prostate cancer-specific survival [PC-SS] (HR 1.00, 95% CI 0.72 to 1.39; studies = 8, participants = 7946; median follow-up 72 months; low-certainty evidence). For men in the intermediate-risk group undergoing conventional fractionation this corresponds to 976 per 1000 men alive after 6 years and 0 more (44 fewer to 18 more) alive per 1000 men undergoing hypofractionation.We are uncertain about the effect of hypofractionation on late radiation therapy gastrointestinal (GI) toxicity (RR 1.10, 95% CI 0.68 to 1.78; studies = 4, participants = 3843; very low-certainty evidence).Hypofractionation probably results in little or no difference to late radiation therapy genitourinary (GU) toxicity (RR 1.05, 95% CI 0.93 to 1.18; studies = 4, participants = 3843; moderate-certainty evidence). This corresponds to 262 per 1000 late GU radiation therapy toxicity events with conventional fractionation and 13 more (18 fewer to 47 more) per 1000 men when undergoing hypofractionation.Secondary outcomesHypofractionation results in little or no difference in overall survival (HR 0.94, 95% CI 0.83 to 1.07; 10 studies, 8243 participants; high-certainty evidence). For men in the intermediate-risk group undergoing conventional fractionation this corresponds to 869 per 1000 men alive after 6 years and 17 fewer (54 fewer to 17 more) participants alive per 1000 men when undergoing hypofractionation.Hypofractionation may result in little to no difference in metastasis-free survival (HR 1.07, 95% CI 0.65 to 1.76; 5 studies, 4985 participants; low-certainty evidence). This corresponds to 981 men per 1000 men metastasis-free at 6 years when undergoing conventional fractionation and 5 more (58 fewer to 19 more) metastasis-free per 1000 when undergoing hypofractionation.Hypofractionation likely results in a small, possibly unimportant reduction in biochemical recurrence-free survival based on Phoenix criteria (HR 0.88, 95% CI 0.68 to 1.13; studies = 5, participants = 2889; median follow-up 90 months to 108 months; moderate-certainty evidence). In men of the intermediate-risk group, this corresponds to 804 biochemical-recurrence free men per 1000 participants at six years with conventional fractionation and 42 fewer (134 fewer to 37 more) recurrence-free men per 1000 participants with hypofractionationHypofractionation likely results in little to no difference to acute GU radiation therapy toxicity (RR 1.03, 95% CI 0.95 to 1.11; 4 studies, 4174 participants at 12 to 18 weeks' follow-up; moderate-certainty evidence). This corresponds to 360 episodes of toxicity per 1000 participants with conventional fractionation and 11 more (18 fewer to 40 more) per 1000 when undergoing hypofractionation. AUTHORS' CONCLUSIONS: These findings suggest that moderate hypofractionation (up to a fraction size of 3.4 Gy) results in similar oncologic outcomes in terms of disease-specific, metastasis-free and overall survival. There appears to be little to no increase in both acute and late toxicity.

Investigating strategies to improve clinical trial opportunities for patients with cancer in New Zealand-INSIGHT.

AIMS: Fewer than 5% of adult cancer patients participate in clinical trials, with multiple patient, clinician and institutional barriers identified. This study aimed to explore patient factors that impact access to cancer trials in New Zealand. METHODS: A questionnaire that included demographics and factors that might impact trial participation was circulated via nine district health boards (DHBs) and four cancer foundations to patients with a cancer diagnosis. RESULTS: Between July 2016 and August 2017, 691 patients responded, 62% female and 77% aged >50 years. Most patients (86%) would consider trial participation, which differed by income (p=0.0001) but not by age, tumour type or gender. Patients would consider attending another hospital (44%) or relocating (11%); 10% considered trials a last resort. Advantageous factors to participation included: benefiting others (92%), better treatment (82%), more scans and longer follow-up (47% and 51%). Disincentives included fear of randomisation (78%), treatment toxicities (71%), time and cost of more visits (40%) and unspecified future research (32%). CONCLUSION: Identified barriers to trial participation were similar in New Zealand to other developed countries. In this motivated cohort, patients are very interested in trial participation at any stage of their treatment and did not mind extra travel or tests.

The New Zealand PIPER Project: colorectal cancer survival according to rurality, ethnicity and socioeconomic deprivation-results from a retrospective cohort study.

AIM: To investigate differences in survival after diagnosis with colorectal cancer (CRC) by rurality, ethnicity and deprivation. METHODS: In this retrospective cohort study, clinical records and National Collections data were merged for all patients diagnosed with CRC in New Zealand in 2007-2008. Prioritised ethnicity was classified using New Zealand Cancer Registry data; meshblock of residence at diagnosis was used to determine rurality and socioeconomic deprivation. RESULTS: Of the 4,950 patients included, 1,938 had died of CRC by May 2014. The five-year risks of death from CRC were: Maori 47%; Pacific 59%; non-Maori-non-Pacific (nMnP) 38%. After adjustment for demographic characteristics, comorbidity and disease stage at diagnosis, compared to nMnP the relative risk (RR) for Maori was 1.1 (95%CI: 0.8-1.3) and for Pacific 1.8 (95% CI: 1.4-2.5). We found no differences in risk of death from CRC by rurality, but some differences by deprivation. CONCLUSIONS: Disparity in outcome following diagnosis with CRC exists in New Zealand. Much of this disparity can be explained by stage of disease at diagnosis for Maori, but for Pacific peoples and those in deprived areas other factors may influence outcome. Further analyses of the PIPER data will explore the impact of any differences in management.

Phase II Study of the Dual EGFR/HER3 Inhibitor Duligotuzumab (MEHD7945A) versus Cetuximab in Combination with FOLFIRI in Second-Line RAS Wild-Type Metastatic Colorectal Cancer.

Purpose: Duligotuzumab is a dual-action antibody directed against EGFR and HER3.Experimental Design: Metastatic colorectal cancer (mCRC) patients with KRAS ex2 wild-type received duligotuzumab or cetuximab and FOLFIRI until progression or intolerable toxicity. Mandatory tumor samples underwent mutation and biomarker analysis. Efficacy analysis was conducted in patients with RAS exon 2/3 wild-type tumors.Results: Of 134 randomly assigned patients, 98 had RAS ex2/3 wild-type. Duligotuzumab provided no progression-free survival (PFS) or overall survival (OS) benefit compared with cetuximab, although there was a trend for a lower objective response rate (ORR) in the duligotuzumab arm. No relationship was seen between PFS or ORR and ERBB3, NRG1, or AREG expression. There were fewer skin rash events for duligotuzumab but more diarrhea. Although the incidence of grade ≥3 AEs was similar, the frequency of serious AEs was higher for duligotuzumab.Conclusions: Duligotuzumab plus FOLFIRI did not appear to improve the outcomes in patients with RAS exon 2/3 wild-type mCRC compared with cetuximab + FOLFIRI. Clin Cancer Res; 24(10); 2276-84. ©2018 AACR.

Follow-up strategies for patients treated for non-metastatic colorectal cancer.

BACKGROUND: It is common clinical practice to follow patients with colorectal cancer (CRC) for several years following their curative surgery or adjuvant therapy, or both. Despite this widespread practice, there is considerable controversy about how often patients should be seen, what tests should be performed, and whether these varying strategies have any significant impact on patient outcomes. This is the second update of a Cochrane Review first published in 2002 and first updated in 2007. OBJECTIVES: To assess the effects of intensive follow-up for patients with non-metastatic colorectal cancer treated with curative intent. SEARCH METHODS: For this update, we searched CENTRAL (2016, Issue 3), MEDLINE (1950 to May 20th, 2016), Embase (1974 to May 20th, 2016), CINAHL (1981 to May 20th, 2016), and Science Citation Index (1900 to May 20th, 2016). We also searched reference lists of articles, and handsearched the Proceedings of the American Society for Radiation Oncology (2011 to 2014). In addition, we searched the following trials registries (May 20th, 2016): ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We further contacted study authors. No language or publication restrictions were applied to the search strategies. SELECTION CRITERIA: We included only randomised controlled trials comparing different follow-up strategies for participants with non-metastatic CRC treated with curative intent. DATA COLLECTION AND ANALYSIS: Two authors independently determined trial eligibility, performed data extraction, and assessed methodological quality. MAIN RESULTS: We studied 5403 participants enrolled in 15 studies. (We included two new studies in this second update.) Although the studies varied in setting (general practitioner (GP)-led, nurse-led, or surgeon-led) and "intensity" of follow-up, there was very little inconsistency in the results.Overall survival: we found no evidence of a statistical effect with intensive follow-up (hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.78 to 1.02; I² = 4%; P = 0.41; high-quality evidence). There were 1098 deaths among 4786 participants enrolled in 12 studies.Colorectal cancer-specific survival: this did not differ with intensive follow-up (HR 0.93, 95% CI 0.78 to 1.12; I² = 0%; P = 0.45; moderate-quality evidence). There were 432 colorectal cancer deaths among 3769 participants enrolled in seven studies.Relapse-free survival: we found no statistical evidence of effect with intensive follow-up (HR 1.03, 95% CI 0.90 to 1.18; I² = 5%; P = 0.39; moderate-quality evidence). There were 1416 relapses among 5253 participants enrolled in 14 studies.Salvage surgery with curative intent: this was more frequent with intensive follow-up (risk ratio (RR) 1.98, 95% CI 1.53 to 2.56; I² = 31%; P = 0.14; high-quality evidence). There were 457 episodes of salvage surgery in 5157 participants enrolled in 13 studies.Interval (symptomatic) recurrences: these were less frequent with intensive follow-up (RR 0.59, 95% CI 0.41 to 0.86; I² = 66%; P = 0.007; moderate-quality evidence). Three hundred and seventy-six interval recurrences were reported in 3933 participants enrolled in seven studies.Intensive follow-up did not appear to affect quality of life, anxiety, nor depression (reported in three studies).Harms from colonoscopies did not differ with intensive follow-up (RR 2.08, 95% CI 0.11 to 40.17; moderate-quality evidence). In two studies, there were seven colonoscopic complications in 2112 colonoscopies. AUTHORS' CONCLUSIONS: The results of our review suggest that there is no overall survival benefit for intensifying the follow-up of patients after curative surgery for colorectal cancer. Although more participants were treated with salvage surgery with curative intent in the intensive follow-up group, this was not associated with improved survival. Harms related to intensive follow-up and salvage therapy were not well reported.

Methods of a national colorectal cancer cohort study: the PIPER Project.

AIM: Colorectal cancer is one of the most common cancers, and second-leading cause of cancer-related death, in New Zealand. The PIPER (Presentations, Investigations, Pathways, Evaluation, Rx [treatment]) project was undertaken to compare presentation, investigations, management and outcomes by rurality, ethnicity and deprivation. This paper reports the methods of the project, a comparison of PIPER patient diagnoses to the New Zealand Cancer Registry (NZCR) data, and the characteristics of the PIPER cohort. METHOD: National, retrospective cohort review of secondary care medical records (public and private) of all cases of ICD-10-AM C18-C20 on the NZCR in the calendar years 2007 and 2008 (main cohort) and an extended sample of Maori and Pacific cases, and non-Maori non-Pacific controls in 2006 and 2009 (extended cohort). RESULTS: Of the 6,387 patients identified from the NZCR 5,610 (88%) were eligible for PIPER. Reasons for exclusion were non-adenocarcinoma histology (3%) and non-colorectal primary (2%). Data were collected on 3,695 patients with colon cancer, 1,385 with rectal cancer and 466 with cancer of the recto sigmoid junction. CONCLUSIONS: The PIPER Project has generated comprehensive population level data detailing the diagnosis and management of colorectal adenocarcinoma in New Zealand. This will be used to assess the care provided to patients, and the impact of variations in care occurring between patient groups.

Fraction size in radiation therapy for breast conservation in early breast cancer.

BACKGROUND: Shortening the duration of radiation therapy would benefit women with early breast cancer treated with breast conserving surgery. It may also improve access to radiation therapy by improving efficiency in radiation oncology departments globally. This can only happen if the shorter treatment is as effective and safe as conventional radiation therapy. This is an update of a Cochrane Review first published in 2008 and updated in 2009. OBJECTIVES: To assess the effect of altered radiation fraction size for women with early breast cancer who have had breast conserving surgery. SEARCH METHODS: We searched the Cochrane Breast Cancer Specialised Register (23 May 2015), CENTRAL (The Cochrane Library 2015, Issue 4), MEDLINE (Jan 1996 to May 2015), EMBASE (Jan 1980 to May 2015), the WHO International Clinical Trials Registry Platform (ICTRP) search portal (June 2010 to May 2015) and ClinicalTrials.gov (16 April 2015), reference lists of articles and relevant conference proceedings. No language or publication constraints were applied. SELECTION CRITERIA: Randomised controlled trials of altered fraction size versus conventional fractionation for radiation therapy in women with early breast cancer who had undergone breast conserving surgery. DATA COLLECTION AND ANALYSIS: Two authors performed data extraction independently, with disagreements resolved by discussion. We sought missing data from trial authors. MAIN RESULTS: We studied 8228 women in nine studies. Eight out of nine studies were at low or unclear risk of bias. Altered fraction size (delivering radiation therapy in larger amounts each day but over fewer days than with conventional fractionation) did not have a clinically meaningful effect on: local recurrence-free survival (Hazard Ratio (HR) 0.94, 95% CI 0.77 to 1.15, 7095 women, four studies, high-quality evidence), cosmetic outcome (Risk ratio (RR) 0.90, 95% CI 0.81 to 1.01, 2103 women, four studies, high-quality evidence) or overall survival (HR 0.91, 95% CI 0.80 to 1.03, 5685 women, three studies, high-quality evidence). Acute radiation skin toxicity (RR 0.32, 95% CI 0.22 to 0.45, 357 women, two studies) was reduced with altered fraction size. Late radiation subcutaneous toxicity did not differ with altered fraction size (RR 0.93, 95% CI 0.83 to 1.05, 5130 women, four studies, high-quality evidence). Breast cancer-specific survival (HR 0.91, 95% CI 0.78 to 1.06, 5685 women, three studies, high quality evidence) and relapse-free survival (HR 0.93, 95% CI 0.82 to 1.05, 5685 women, three studies, moderate-quality evidence) did not differ with altered fraction size. We found no data for mastectomy rate. Altered fraction size was associated with less patient-reported (P < 0.001) and physician-reported (P = 0.009) fatigue at six months (287 women, one study). We found no difference in the issue of altered fractionation for patient-reported outcomes of: physical well-being (P = 0.46), functional well-being (P = 0.38), emotional well-being (P = 0.58), social well-being (P = 0.32), breast cancer concerns (P = 0.94; 287 women, one study). We found no data with respect to costs. AUTHORS' CONCLUSIONS: We found that using altered fraction size regimens (greater than 2 Gy per fraction) does not have a clinically meaningful effect on local recurrence, is associated with decreased acute toxicity and does not seem to affect breast appearance, late toxicity or patient-reported quality-of-life measures for selected women treated with breast conserving therapy. These are mostly women with node negative tumours smaller than 3 cm and negative pathological margins.

Quality of life in patients with K-RAS wild-type colorectal cancer: the CO.20 phase 3 randomized trial.

BACKGROUND: The CO.20 trial randomized patients with K-RAS wild-type, chemotherapy-refractory, metastatic colorectal cancer to receive cetuximab (CET) plus brivanib alaninate (BRIV) or CET plus placebo (CET/placebo). METHODS: Quality of life (QoL) was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 at baseline and at 2, 4, 6, 8, 12, 16, and 24 weeks until disease progression. Predefined coprimary QoL endpoints were time to deterioration (first worsening from baseline of ≥ 10 points) on the Physical Function (PF) and Global (GHS) scales. RESULTS: Of 750 randomized patients, 721 (358 of whom received CET/BRIV) were assessable for QoL. QoL compliance and baseline PF and GHS scores did not differ by treatment arm. The median time to deterioration was 1.6 months versus 1.1 months for GHS (P =.02) and 5.6 months versus 1.7 months for PF (P <.0001) favoring CET/placebo. Secondary analysis favored CET/placebo for QOL response on the PF, Cognitive Function, Fatigue, Nausea, Appetite, and Diarrhea scales. A greater percentage of patients on the CET/BRIV arm had PF worsening at 6 weeks (31% vs 17%). Clinical adverse events of ≥ grade 3 were more common with CET/BRIV than with CET/placebo, including fatigue (25% vs 11%), hypertension, rash, diarrhea, abdominal pain, dehydration, and anorexia. CONCLUSIONS: Compared with CET/placebo, the combination of CET/BRIV worsened time to QoL deterioration for patients with K-RAS wild-type, chemotherapy-refractory, metastatic colorectal cancer on the PF and GHS scales of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. This result may be due to higher rates of fatigue and gastrointestinal adverse events.

Summary of guidance for the management of early bowel cancer.

Colorectal cancer is an important public health problem and one of the most common cancers registered in New Zealand. In 2009 the New Zealand Guidelines Group were commissioned to produce and evidence-based summary of current New Zealand and international data to inform best practice in the management of people with early bowel cancer. A guideline development team was convened, representing a range of stakeholder groups who met to discuss and agree on the recommendations for a clinical practice guideline. This article summarises the guideline methods and reports the recommendations from the Management of Early Bowel Cancer guideline, published in 2011.

Fraction size in radiation treatment for breast conservation in early breast cancer.

BACKGROUND: Shortening the duration of radiation therapy would benefit women with early breast cancer treated with breast conserving surgery. It may also improve access to radiation therapy by improving efficiency in radiation oncology departments globally. This can only happen if the shorter treatment is as effective and safe as conventional radiation therapy. This is an updated version of the original Cochrane Review published in Issue 3, 2008. OBJECTIVES: To determine the effect of altered radiation fraction size on outcomes for women with early breast cancer who have undergone breast conserving surgery. SEARCH STRATEGY: We searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE, EMBASE and the WHO ICTRP search portal to June 2009, reference lists of articles and relevant conference proceedings. We applied no language constraints. SELECTION CRITERIA: Randomised controlled trials of unconventional versus conventional fractionation in women with early breast cancer who had undergone breast conserving surgery. DATA COLLECTION AND ANALYSIS: The authors performed data extraction independently, with disagreements resolved by discussion. We sought missing data from trial authors. MAIN RESULTS: Four trials reported on 7095 women. The women were highly selected: tumours were node negative and 89.8% were smaller than 3 cm. Where the breast size was known, 87% had small or medium breasts. The studies were of low to medium quality. Unconventional fractionation (delivering radiation therapy in larger amounts each day but over fewer days than with conventional fractionation) did not affect: (1) local recurrence risk ratio (RR) 0.97 (95% CI 0.76 to 1.22, P = 0.78), (2) breast appearance RR 1.17 (95% CI 0.98 to 1.39, P = 0.09), (3) survival at five years RR 0.89 (95% CI 0.77 to 1.04, P = 0.16). Acute skin toxicity was decreased with unconventional fractionation: RR 0.21 (95% CI 0.07 to 0.64, P = 0.007). AUTHORS' CONCLUSIONS: Two new studies have been published since the last version of the review, altering our conclusions. We have evidence from four low to medium quality randomised trials that using unconventional fractionation regimens (greater than 2 Gy per fraction) does not affect local recurrence, is associated with decreased acute toxicity and does not seem to affect breast appearance or late toxicity for selected women treated with breast conserving therapy. These are mostly women with node negative tumours smaller than 3 cm and negative pathological margins. Long-term follow up (> 5 years) is available for a small proportion of the patients randomised. Longer follow up is required for a more complete assessment of the effect of altered fractionation.

Transient retinal effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA, ASA404), an antitumor vascular-disrupting agent in phase I clinical trials.

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an anticancer vascular-disrupting agent, has induced transient visual symptoms in some patients. Exploratory investigations were undertaken to characterize the visual disturbances in two consecutive phase I trials. METHODS: Assessments were made in 21 patients before and immediately after a 20-minute IV infusion of DMXAA, including visual acuity, funduscopy, color discrimination, pattern electroretinography (PERG), pattern visual-evoked potentials (VEP), and full-field electroretinography (ERG). Evaluation of late effects was undertaken subsequently in 12 patients before and after 6 weeks of IV DMXAA at one dose per week. RESULTS: Frequency and intensity of transient visual disturbance increased with DMXAA dose, occurring in two thirds of patients at 3000 mg x m(-2). Symptoms included blurring, flickering, fragmentation, alteration of colors, and contrast and mild photosensitivity, starting during the infusion and resolving completely, usually within 60 minutes. Visual acuity was unchanged but color discrimination was perturbed. Dose-dependent increases in PERG P50 implicit time by up to 23 ms returned toward baseline values within 90 minutes. Prominent transient changes on ERG included prolonged scotopic rod and 30-Hz flicker implicit times and reduced 30-Hz flicker amplitude. In the second trial, no clinically significant sustained effects were detected, although an increase in bright flash a-wave implicit time (P = 0.022) was seen on whole-group analysis. In vitro studies showed nonspecific phosphodiesterase inhibition by DMXAA. CONCLUSIONS: DMXAA induced acute, transient disturbance of retinal activity consistent with phosphodiesterase inhibition. No clinically significant cumulative effects were noted and most effects occurred at doses higher than those used in ongoing clinical trials (ClinicalTrials.gov numbers, NCT00856336, NCT00863733, and NCT00003697).

Fraction size in radiation treatment for breast conservation in early breast cancer.

BACKGROUND: Shortening the duration of radiation therapy would benefit women with early breast cancer treated with breast conservation. It may also improve access to radiation therapy by improving efficiency in radiation oncology departments globally. This can only happen if the shorter treatment is as effective and safe as conventional radiation therapy. OBJECTIVES: To assess the effects of altered fraction size on women with early breast cancer who have undergone breast conserving surgery. SEARCH STRATEGY: We searched the Cochrane Breast Cancer Group Specialised Register (June 2006), MEDLINE (November 2006), EMBASE (November 2006), reference lists for articles, and relevant conference proceedings. No language constraints were applied. SELECTION CRITERIA: Randomised controlled trials of unconventional versus conventional fractionation in women with early breast cancer who had undergone breast conserving surgery. DATA COLLECTION AND ANALYSIS: Data extraction was performed independently by the authors with disagreements resolved by discussion. Missing data was sought by contacting the authors concerned. MAIN RESULTS: Two trials were included and reported on 2644 women. The women were highly selected with node negative tumours smaller than 5 cm and negative pathological margins; 46% of the women had a cup separation size of less than 25 cm. The studies were of high quality. Data for local recurrence and breast appearance were not available in a form which could be combined. Unconventional fractionation (delivering radiation therapy in larger amounts each day but over fewer days than with conventional fractionation) did not appear to affect: (1) local-recurrence free survival (absolute difference 0.4%, 95% CI -1.5% to 2.4%), (2) breast appearance (risk ratio (RR) 1.01, 95% CI 0.88 to 1.17; P = 0.86), (3) survival at five years (RR 0.97, 95% CI 0.78 to 1.19; P = 0.75), (4) late skin toxicity at five years (RR 0.99, 95% CI 0.44 to 2.22; P = 0.98, or (5) late radiation toxicity in sub-cutaneous tissue (RR 1.0, 95% CI 0.78 to 1.28; P = 0.99). AUTHORS' CONCLUSIONS: We have evidence from two high quality randomised trials that the use of unconventional fractionation regimes (greater than 2 Gy per fraction) does not affect breast appearance or toxicity and does not seem to affect local recurrence for selected women treated with breast conserving therapy. These are women with node negative tumours smaller than 5 cm and negative pathological margins. Two new trials have been published in March 2008. Their results are consistent with our findings. The results of these trials will be incorporated in the next update of this review.

Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study.

PURPOSE: This phase III study compared the safety and efficacy of the following three different irinotecan-containing regimens in the first-line treatment of metastatic colorectal cancer: irinotecan plus infusional fluorouracil (FU)/leucovorin (LV) (FOLFIRI), irinotecan plus bolus FU/LV (mIFL), and irinotecan plus oral capecitabine (CapeIRI). PATIENTS AND METHODS: A total of 430 previously untreated metastatic colorectal cancer patients were randomly assigned to receive FOLFIRI (n = 144), mIFL (n = 141), or CapeIRI (n = 145). Patients were concurrently randomly assigned to a double-blind treatment with celecoxib or placebo. After a protocol amendment, an additional 117 patients were randomly assigned to either FOLFIRI plus bevacizumab (FOLFIRI+Bev; n = 57) or mILF plus bevacizumab (mIFL+Bev; n = 60), whereas the CapeIRI arm was discontinued. The primary study end point was progression-free survival (PFS), with secondary end points of overall survival (OS), response rate, and toxicity. RESULTS: Median PFS was 7.6 months for FOLFIRI, 5.9 months for mIFL (P = .004 for the comparison with FOLFIRI), and 5.8 months for CapeIRI (P = .015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (P = .09), and 18.9 months for CapeIRI (P = .27). CapeIRI was associated with higher rates of severe vomiting, diarrhea, and dehydration. After the amendment to add bevacizumab, the median survival time has not yet been reached for FOLFIRI+Bev and was 19.2 months for mIFL+Bev (P = .007). FOLFIRI+Bev was associated with a higher rate of > or = grade 3 hypertension than mIFL+Bev. CONCLUSION: FOLFIRI and FOLFIRI+Bev offered superior activity to their comparators and were comparably safe. An infusional schedule of FU should be the preferred irinotecan-based regimen in first-line metastatic colorectal cancer.

5,6-Dimethylxanthenone-4-acetic acid in the treatment of refractory tumors: a phase I safety study of a vascular disrupting agent.

This phase I safety study aimed to identify the optimal dose of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) for combination studies. Using a crossover design, 15 patients with refractory tumors were allocated randomly to receive six sequential doses of DMXAA (300, 600, 1,200, 1,800, 2,400, and 3,000 mg m(-2)), each given once-weekly as a 20-minute i.v. infusion. The drug was generally well tolerated. Transient, moderate increases in the heart rate-corrected cardiac QT interval occurred at the two highest doses. DMXAA produced transient dose-dependent increases in blood pressure. Transient, dose-related visual disturbances occurred at the two highest doses. No significant changes in K(trans) and k(ep) were observed but V(e), a secondary dynamic contrast-enhanced magnetic resonance imaging variable, increased significantly after giving DMXAA. At 1,200 mg m(-2), the Cmax and the area under the concentration-time curve over 24 hours for total and free DMXAA plasma concentrations were 315 +/- 25.8 microg/mL, 29 +/- 6.4 microg/mL x d, 8.0 +/- 1.77 microg/mL, and 0.43 +/- 0.07 microg/mL x d, respectively. Plasma levels of the vascular damage biomarker 5-hydroxyindoleacetic acid increased in the 4 hours after treatment in a dose-dependent fashion up to 1,200 mg m(-2), with a plateau thereafter. Doses in the range of 1,200 mg m(-2) have been selected for further studies (phase II combination studies with taxanes and platins are under way) because this dose produced no significant effect on heart rate-corrected cardiac QT interval, produced near maximum levels of 5-hydroxyindoleacetic acid, achieved DMXAA plasma concentrations within the preclinical therapeutic range, and was well tolerated.

Degradation kinetics of VX on concrete by secondary ion mass spectrometry.

At trace coverages on concrete surfaces, the nerve agent VX (O-ethyl S-2-diisopropylaminoethyl methyl phosphonothiolate) degrades by cleavage of the P-S and S-C bonds, as revealed by periodic secondary ion mass spectrometry (SIMS). The observed kinetics were (pseudo-) first-order, with a half-life of 2-3 h at room temperature. The rate increased with surface pH and temperature, with an apparent second-order constant of k(OH) = 0.64 M(-1) min(-1) at 25 degrees C and an activation energy of 50-60 kJ mol(-1). These values are consistent with a degradation mechanism of alkaline hydrolysis within the adventitious water film on the concrete surface. Degradation of bulk VX on concrete would proceed more slowly.

Postoperative follow-up strategies for patients after potentially curative surgery for colorectal cancer at Christchurch Hospital.

AIM: To describe the follow-up patterns of patients with colorectal cancer (CRC) having had surgery with curative intent. METHODS: A retrospective study was undertaken of follow-up patterns in patients who had undergone 'curative' surgery for colorectal cancer at Christchurch Hospital from 1 January 1996 to 31 December 2000. Patients were identified from three sources: the General Surgical Audit Database (Otago system), the hospital clinical Casemix DRG Database, and the Oncology Service database. Patients were included only if they had surgery with curative intent, within the stated period, and had follow-up at Christchurch Hospital. Data extracted included: patient demographics, details of initial surgery, adjuvant therapies, recurrences, and details of follow-up arrangements (including investigations). RESULTS: Of 893 patients coded as having CRC, 284 patients met the inclusion criteria. Patients were excluded for the following reasons: no operation (64), operation before 1996 (18), palliative surgery (345), previous cancer (55), no cancer (32), died within 30 days of surgery (26), follow-up outside of Christchurch region (39), and notes unavailable (30). The median age was 72 (range 28.6-99.9 years). Median follow-up time was 732 days. Most patients (91%) were followed-up by their surgeon. Patients had an average of 2.6 visits to their specialist in the first year of follow-up. Unplanned clinic visits accounted for 8.3% of all clinic visits--resulting in a number of unplanned investigations. During the follow-up period, patients had 112 colonoscopies, 68 CT scans, 8 abdominal ultrasounds, and 7 barium enemas. Recurrence was detected in 58 patients (20.4%); 23 (39.7%) recurrences were detected in the first year of follow-up. Of the 279 patients who had some form of follow-up, 9 asymptomatic patients had recurrent disease (detected as a result of a planned clinic visit) and had a potentially curative procedure for recurrence. CONCLUSIONS: The number of visits per year correlated closely with the earlier findings of Connor et al,4 however the number of investigations carried out was variable and substantially less than had been reported. Follow-up visits have limited value for the detection of asymptomatic potentially curable recurrent disease.