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Assessment of neurocognitive function (NCF) is important in brain tumor clinical trials, however there are varying methodologies available. We used the Cogstate computerized NCF testing battery and the mini-mental state examination (MMSE) to prospectively assess cognition in adult patients with recurrent glioblastoma (GBM) enrolled in the CABARET randomized phase II clinical trial of bevacizumab versus bevacizumab plus carboplatin chemotherapy. We determined completion rates; compared NCF results between trial arms; and assessed baseline NCF as a predictor of survival outcome. 93 of 103 eligible patients completed baseline Cogstate NCF testing. Completion rates were between 60 and 100% across each timepoint, and 38% at disease progression. There was no evidence of difference between arms in time to deterioration in NCF using either test. Prior to disease progression, deterioration on the Cogstate tests was substantially more common (90%) than deterioration on the MMSE (37%), and decline in the Cogstate composite score within the first 8 weeks was associated with shorter overall survival. This testing methodology may be useful when determining net clinical benefit for therapies in patients with recurrent GBM.

BACKGROUND: Metastatic colorectal cancer (mCRC) patients with a right-sided primary (RC) have an inferior survival to mCRC arising from a left-sided primary (LC). Previous analyses have suggested multiple factors contribute. METHODS: The Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Registry prospectively captured data on consecutive mCRC patients. RC were defined as tumors proximal to the splenic flexure; LC were those at and distal to the splenic flexure and included rectal cancers. Patient, tumor, treatment, and survival data were analyzed stratified by side. RESULTS: Of 2306 patients enrolled from July 2009-March 2018, 747 (32%) had an RC. Patients with RC were older, more likely to be female and have a Charlson score ≥3. RC were more frequently BRAF mutated, deficient in mismatch repair, associated with peritoneal metastases, and less likely to receive chemotherapy. Progression-free survival on first-line systemic therapy was inferior for RC patients (8.1 vs. 10.8 months, hazard ratio [HR] for progression in RC 1.38, P

BACKGROUND Bevacizumab has been associated with prolonged progression-free survival for patients with recurrent glioblastoma; however, not all derive a benefit. An early indicator of efficacy or futility may allow early discontinuation for nonresponders. This study prospectively assessed the role of early magnetic resonance imaging (eMRI) and its correlation with subsequent routine magnetic resonance imaging (MRI) results and survival. METHODS Patients were part of a randomized phase 2 clinical trial (CABARET) comparing bevacizumab with bevacizumab plus carboplatin for recurrent glioblastoma. eMRI was conducted after 4 weeks in the trial (after 2 treatments with bevacizumab [10 mg/kg every 2 weeks]). The results were compared with the results of the subsequent 8-week MRI standard. RESULTS For 119 of 122 patients, eMRI was available, and 111 had subsequent MRI for comparison. Thirty-six (30%) had an early radiological response, and 17 (14%) had progressive disease. The concordance between eMRI and 8-week MRI was moderate (κ = 0.56), with most providing the same result (n = 79 [71%]). There was strong evidence that progression-free survival and overall survival were predicted by the eMRI response (both P values < .001). The median survival was 8.6 months for an eMRI response, 6.6 months for stable disease, and 3.7 months for progressive disease; the hazard ratio (progressive disease vs stable disease) was 3.4 (95% confidence interval, 1.9-6.0). Landmark analyses showed that eMRI progression was a strong predictor of mortality independent of other potential baseline predictors. CONCLUSIONS In this study, early progression on MRI appears to be a robust marker of a poor prognosis for patients on bevacizumab. Cancer 2017. © 2017 American Cancer Society.

BackgroundIn patients with recurrent glioblastoma, the benefit of bevacizumab beyond progression remains uncertain. We prospectively evaluated continuing or ceasing bevacizumab in patients who progressed while on bevacizumab.MethodsCABARET, a phase II study, initially randomized patients to bevacizumab with or without carboplatin (Part 1). At progression, eligible patients underwent a second randomization to continue or cease bevacizumab (Part 2). They could also receive additional chemotherapy regimens (carboplatin, temozolomide, or etoposide) or supportive care.ResultsOf 120 patients treated in Part 1, 48 (80% of the anticipated 60-patient sample size) continued to Part 2. Despite randomization, there were some imbalances in patient characteristics. The best response was stable disease in 7 (30%) patients who continued bevacizumab and 2 (8%) patients who stopped receiving bevacizumab. There were no radiological responses. Median progression-free survival was 1.8 vs 2.0 months (bevacizumab vs no bevacizumab; hazard ratio [HR], 1.08; 95% CI, .59–1.96; P = .81). Median overall survival was 3.4 vs 3.0 months (HR, .84; 95% CI, .47–1.50; P = .56 and HR .70; 95% CI .38–1.29; P = .25 after adjustment for baseline factors). Quality-of-life scores did not significantly differ between arms. While the maximum daily steroid dose was lower in the continuation arm, the difference was not statistically significant.ConclusionsPatients who continued bevacizumab beyond disease progression did not have clear survival improvements, although the study was not powered to detect other than very large differences. While these data provide the only randomized evidence related to continuing bevacizumab beyond progression in recurrent glioblastoma, the small sample size precludes definitive conclusions and suggests this remains an open question.

The CABARET trial (ACTRN12610000915055) reported no difference in overall survival (OS) between patients with recurrent glioblastoma (GBM) randomized to either bevacizumab monotherapy or bevacizumab plus carboplatin. However, a subset of patients showed durable responses and prolonged survival, with recorded survival times of over 30 months in five of 122 patients (4%). Patient selection for bevacizumab therapy would be enhanced if a predictive biomarker of response or survival could be identified; this biomarker sub-study attempted to identify novel biomarkers. Patients who opted to participate in this sub-study and who had adequate biospecimens for analysis (n = 54) were retrospectively evaluated for the expression of a series of tumor proteins. Immunohistochemistry (IHC) was used to measure the expression of 19 proteins previously implicated in cancer treatment response to bevacizumab. MGMT promoter methylation was also assessed. Tumor DNA from five patients with outlying survival duration (‘poor’ and ‘exceptional’ survivors) was subjected to whole genome sequencing (WGS). No single protein expression level, including VEGF-A, predicted OS in the cohort. WGS of poor and exceptional survivors identified a gain in Chromosome 19 that was exclusive to the exceptional survivors. Validation of this finding requires examination of a larger independent cohort.

Background Emerging evidence on the optimal use of chemotherapy and biologics in patients with metastatic colorectal cancer should impact management in routine care. Recent studies have demonstrated benefits for initial triplet chemotherapy (5-fluorouracil, oxaliplatin and irinotecan, FOLFOXIRI) and for initial treatment with an epidermal growth factor receptor inhibitor (EGFRi) in patients with a RAS wild-type tumour and a left-sided primary tumour. Aim To explore evolving pattern of metastatic colorectal cancer care over time in Australia. Methods We analysed data from the Treatment of Recurrent and Advanced Colorectal Cancer registry. Results From July 2009 to December 2017, 2552 metastatic colorectal cancer patients were entered into the Treatment of Recurrent and Advanced Colorectal Cancer registry. Of 1585 patients who initially underwent chemotherapy, treatment was with a doublet in 76%. FOLFOXIRI was given to 22 patients (1.4%), mostly young patients and those with potentially resectable disease. Along with first-line chemotherapy, 61% received bevacizumab, while 3.3% received an EGFRi, predominantly over the last 2 years. Within the KRAS wild-type left-sided tumour cohort, EGFRi use increased from 9% in 2015 to 37% in 2017. Across treatment sites, there was a wide variation in the utilisation of FOLFOXIRI and EGFRi therapy; bevacizumab use was more consistent. A clear impact on survival outcomes from these regimens is not evident, potentially due to multiple confounders. Conclusion Doublet chemotherapy + bevacizumab remains the dominant initial strategy, with limited uptake of triplet chemotherapy and of EGFRi. Potential explanations include uncertainty about the significance of post hoc analyses for EGFRi and concerns regarding adverse events for both strategies.

Background The true survival benefit of noncurative primary tumor resection in patients with de novo metastatic colorectal cancer (mCRC) remains uncertain. The present study examined the effect of primary tumor resection on systemic inflammation and survival in patients with mCRC. Materials and Methods Consecutive patients with de novo mCRC who had undergone primary tumor resection were identified from a prospective database. Patients were excluded if they had undergone resection of metastases, had undergone delayed primary resection, or if blood samples were unavailable. The neutrophil/lymphocyte ratio (NLR) was used as a biomarker of systemic inflammation. Overall survival (OS) was compared between patient groups according to the pre- and postprimary resection NLR. The associations between the reversal of an elevated NLR and primary tumor bulk or performance status were explored. Results A total of 145 eligible patients were identified from the database, with a median age of 70 years. The baseline NLR was elevated (> 5) in 65 patients, 36 (55%) of whom had a low NLR after surgery. The reversal of an elevated NLR was associated with significantly improved OS (hazard ratio, 0.53; P = .017). A similar benefit was seen after excluding patients undergoing emergency primary resection. NLR reversal was more frequent in patients with larger primary tumors or good performance status. Conclusion The present study is the first to demonstrate a relationship between the reversal of a systemic inflammatory response and the improved survival after primary resection in those with mCRC. A greater effect was seen in patients with large primary tumors. If validated, these observations could guide clinical decision-making in patients with mCRC at presentation.

Objectives The elderly accounts for a large proportion of patients with metastatic colorectal cancer (mCRC). This study reviews patterns of care and outcomes for elderly patients with mCRC in the community setting. Materials and Methods Elderly patients (≥ 65 years) with mCRC on the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) registry were identified. Treatment, bevacizumab-related adverse events, and overall survival (OS) were analysed by age cohorts, comparing those aged 65–74 vs. 75–84 vs. ≥ 85 years and correlated with potential prognostic factors. Factors affecting chemotherapy and bevacizumab administration were analysed using logistic regression analysis. Results Of 1439 patients, 363, 352, and 106 were aged 65–74, 75–84, and ≥ 85 years, respectively. 584 (71%) patients received first-line chemotherapy, with chemotherapy use declining with advancing age (84%, 69%, and 34% in 65–74-, 75–84- and ≥ 85-year-olds, respectively). Seven (10%) patients aged ≥ 85 years were not treated with chemotherapy on the basis of age alone. Only 10 of 36 very elderly patients who received chemotherapy also received bevacizumab. Factors affecting bevacizumab administration included age, treatment location, and comorbidities. There was no impact of age on bevacizumab-related adverse events. Resection of metastatic disease occurred in 173 (21%) patients overall, with rates declining with age (26% vs. 21% vs. 6%). Conclusion Chemotherapy usage and resection of metastatic disease decline with advancing age. A minority of patients are not treated with systemic therapy due to advanced age alone. Our cohort suggests underutilisation of bevacizumab in older patients, but where given, toxicity rates did not increase with age.

Background. The optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy. Methods. This was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS). Results. One hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64-1.33, P =. 66). ORR was 14% (combination) versus 6% (monotherapy) (P =. 18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82-1.69, P =. 38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately. Conclusions. Adding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies.

Aims Considerable progress in cancer treatment is leading to better outcomes, but the cost of therapy is placing increasing pressure on the health system. Understanding the real-world cost of therapies for each stage will become increasingly important in informing treatment selection and health policy. Methods To explore the cost of treating colorectal cancer in the modern era, data were entered onto a prospective database at four hospitals. We estimated the impact of bevacizumab by using data from July 2009, and projected the likely impact of the recent listing of cetuximab. The utility of these data for estimating the cost-effectiveness of treatment was explored. Results Cancer stage and age at diagnosis were major determinants of treatment received and the associated cost. The cost of early stage disease has not substantially changed whereas therapies such as oxaliplatin and irinotecan were significant contributors to substantial increases in stage IV disease, now $71 156 per patient. Bevacizumab has added at least $10 247 per patient and we estimate that cetuximab will add a further $12 022. An exploratory analysis of the cost-effectiveness of oxaliplatin for adjuvant therapy of stage III colon cancer suggests that this is well within the accepted range. Conclusion These data suggest that recent progress in the treatment of later stages of colorectal cancer is being achieved at significant financial cost. The increased costs of managing later stages of disease make an investment in prevention and early detection ever more attractive.

Bevacizumab has been associated with prolonged progression-free survival for patients with recurrent glioblastoma; however, not all derive a benefit. An early indicator of efficacy or futility may allow early discontinuation for nonresponders. This study prospectively assessed the role of early magnetic resonance imaging (eMRI) and its correlation with subsequent routine magnetic resonance imaging (MRI) results and survival.Patients were part of a randomized phase 2 clinical trial (CABARET) comparing bevacizumab with bevacizumab plus carboplatin for recurrent glioblastoma. eMRI was conducted after 4 weeks in the trial (after 2 treatments with bevacizumab [10 mg/kg every 2 weeks]). The results were compared with the results of the subsequent 8-week MRI standard.For 119 of 122 patients, eMRI was available, and 111 had subsequent MRI for comparison. Thirty-six (30%) had an early radiological response, and 17 (14%) had progressive disease. The concordance between eMRI and 8-week MRI was moderate (κ = 0.56), with most providing the same result (n = 79 [71%]). There was strong evidence that progression-free survival and overall survival were predicted by the eMRI response (both P values.001). The median survival was 8.6 months for an eMRI response, 6.6 months for stable disease, and 3.7 months for progressive disease; the hazard ratio (progressive disease vs stable disease) was 3.4 (95% confidence interval, 1.9-6.0). Landmark analyses showed that eMRI progression was a strong predictor of mortality independent of other potential baseline predictors.In this study, early progression on MRI appears to be a robust marker of a poor prognosis for patients on bevacizumab. Cancer 2017;123:3576-82. © 2017 American Cancer Society.

Aim Assessment of magnetic resonance imaging (MRI) in glioblastoma can be challenging. For patients with recurrent glioblastoma managed on the CABARET trial, we compared disease status assessed at hospitals and subsequent blinded central expert radiological review. Methods MRI results and clinical status at specified time points were used for site and central assessment of disease status. Clinical status was determined by the site. Response Assessment in Neuro-Oncology (RANO) criteria were used for both assessments. Site and central assessments of progression-free survival (PFS) and response rates were compared. Inter-rater variability for central review progression dates was assessed. Results Central review resulted in shorter PFS in 45% of 89 evaluable patients (n = 40). Median PFS was 3.6 (central) versus 3.9 months (site) (hazard ratio 1.5, 95% confidence interval 1.3–1.8, P

Anti-angiogenic therapy for glioblastoma has been in the spotlight for several years, as researchers and clinicians strive to find agents with meaningful efficacy against glioblastoma. Bevacizumab in particular, in the second half of the last decade, became the most significant breakthrough in anti-glioblastoma therapy since temozolomide. Optimism for bevacizumab has been somewhat challenged given recent clinical trials that have raised questions regarding its clinical effectiveness, the optimal timing of its use and the validity of endpoints, among other issues. In addition, uncertainty has recently arisen regarding the effects of bevacizumab on quality of life and neurocognitive function, two key clinical endpoints of unquestionable significance among glioblastoma patients. In this review, we highlight these controversies and other recent work related to bevacizumab for glioblastoma.

Aim As multiple new agents have been added to the treatment options for patients with metastatic colorectal cancer, survival outcomes in clinical trials have continued to improve. Similarly, improved outcomes in routine clinical care would be anticipated, but have yet to be demonstrated. Here, we aim to explore whether survival gains demonstrated in clinical trials are reproducible in routine practice, and whether factors beyond new therapies may be contributing to improved outcomes. Methods Comparison of comprehensive treatment and outcome data for consecutive patients diagnosed in 2003–2006 versus 2007–2010 at four specialist hospitals in Australia. Results Data were available on 965 patients; median age 66.1 years (range 19–93), 572 (59%) were male. For the latter time period, there was an increase in patients receiving any treatment (74% vs 66%, P = 0.014), initial combination chemotherapy (57% vs 44%, P

Background: The changing treatment landscape for metastatic colorectal cancer creates multiple potential treatment strategies. An Australian-centric database capturing comprehensive information across a range of treatment locations would create a valuable resource enabling multiple important research questions to be addressed. Aims: To establish a collection of a consensus dataset capturing treatment and outcomes at multiple public and private hospitals across Australia. Methods: An electronic database was developed by a panel of clinicians, to capture an agreed dataset for patients with newly diagnosed metastatic colorectal cancer. Of particular interest were clinician decision-making, the impact of comorbidities and the frequency of major adverse events. Results: Since July 2009, data collection has been established at six public and eight private hospitals across three Australian states and territories. Successful linkage and analysis, with support from BioGrid Australia, of selected data on the initial 864 patients demonstrates that data can be captured from diverse sites, including public and private practice, that multiple factors impact on treatment delivered and outcomes achieved and that comprehensive data on rare but important adverse events can be captured. As a clinical research tool, the project has been highly successful, generating multiple presentations at national and international conferences related to a diverse range of research questions. Conclusions: Multistate, project-specific data collection involving large numbers of patients is achievable. Providing invaluable insight into the routine clinical management of metastatic colorectal cancer in the era of targeted therapies, this also creates a significant resource for research, including many questions not being addressed by clinical trials.

In recurrent glioblastoma, health-related quality of life (HRQL) is a crucial trial endpoint. We examined HRQL outcomes as a secondary endpoint for patients in the CABARET randomized phase 2 trial. 122 patients were randomly allocated to bevacizumab monotherapy or bevacizumab plus carboplatin. We calculated change scores from baseline for each HRQL measure on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Brain Cancer Module (QLQ-BN20), together with time to deterioration in HRQL, and the proportion of participants with clinically meaningful improvements in specific disease-related symptoms. At baseline, 117 of 122 randomized patients (96%) attempted questionnaires. Questionnaire participation rates were >90% for patients continuing on treatment, however at the end-of-treatment visit only 72 (64% of eligible participants) returned a form. There were no differences between arms in change scores over the treatment period. Time to ≥10 point deterioration in scores from baseline was also similar between arms. HRQL deterioration occurred largely before progression for the domains tested, but scores in HRQL domains specifically relevant to symptoms of recurrent glioblastoma also improved for about 50% of patients with symptoms at baseline. Neither detrimental nor beneficial effects on HRQL were seen with carboplatin added to bevacizumab, with a proportion of patients on both arms experiencing symptomatic benefit. Given the reduced questionnaire completion at end of treatment, time to HRQL deterioration is a feasible and robust clinical trial endpoint in this patient population. Clinical trials registration number: ACTRN12610000915055.

Bevacizumab, an anti-angiogenic agent, is FDA-approved for use in patients with recurrent glioblastoma multiforme (rGBM). The radiologic evaluation of tumor response to bevacizumab is complex and there is no validated method of monitoring tumor vascularity during therapy. We evaluated perfusion-weighted MR imaging (PWI) in our cohort of patients enrolled in the CABARET trial, which examined the effectiveness of bevacizumab with or without carboplatin in patients with rGBM. Pre-treatment and early follow-up (4- and 8-week) PWI were used to calculate relative cerebral blood volume (rCBV) histogram statistics of the contrast-enhancing and FLAIR hyperintense tumor volumes. A novel rCBV measurement (load) was developed to estimate the total volume of perfused tumor blood vessels. Changes in all rCBV measures were examined for correlations with progression-free (PFS) and overall survival (OS). All of our 15 patients enrolled in the CABARET trial were included. Median PFS and OS were 23 and 45 weeks respectively. Kaplan-Meier analysis of pre-treatment PWI revealed an 18 week reduction in median OS in patients with high tumor rCBV (p = 0.031). Changes in rCBV measures, especially load, correlated significantly with PFS and OS at both follow-up time-points. Patients with the greatest reduction in rCBVload by 8-weeks of therapy had a significantly increased median OS (30 weeks; p = 0.013). PWI may be of significant clinical utility in managing patients with rGBM, particularly those treated with anti-angiogenic agents such as bevacizumab. These findings need to be confirmed prospectively in larger studies.

With an ever-increasing focus on personalized medicine, all factors known to affect treatment response need to be considered when defining optimal therapy for individual patients. While the prognostic impact of primary tumor site on colorectal cancer (CRC) outcomes is established, emerging data suggest potential differences in response to biologic therapies. We studied the impact of tumor site on bevacizumab efficacy in patients with metastatic CRC.We analyzed data of patients in an Australian prospective multicenter metastatic CRC (mCRC) registry who received first-line chemotherapy. Tumor site was defined as right colon, cecum to transverse; left colon, splenic flexure to rectosigmoid; and rectum. Kaplan-Meier and Cox models were used for survival analyses.Of 926 patients, 297 had right colon, 354 left colon, and 275 rectum primary disease. Median age was 68.6, 65.9, and 63.3 years, respectively (P = .001). Right colon disease was significantly associated with intraperitoneal spread (P .0001), while left colon and rectum disease preferentially metastasized to the liver and lungs, respectively (P .0001 in both settings). A total of 636 patients (68.7%) received bevacizumab. Progression-free survival was superior for bevacizumab-treated patients in all groups but appeared greatest in right colon disease (hazard ratio, 0.46; 95% confidence interval, 0.36-0.60; P ≤ .001). Overall survival was longest in patients with disease of the rectum, followed by left colon and right colon (median, 26.2, 23.6, and 18.2 months, respectively; P = .0004).Tumor site appears to be prognostic in mCRC, with rectum and right colon disease associated with the best and worst outcomes, respectively. Patients who received bevacizumab in addition to chemotherapy had superior outcomes, with the effect appearing greatest in patients with right colon disease.

To investigate the safety and efficacy of adding bevacizumab to first-line chemotherapy in metastatic colorectal cancer patients with peritoneal disease.We compared rates of gastrointestinal perforation in patients with metastatic colorectal cancer and peritoneal disease receiving first-line chemotherapy with and without bevacizumab in three distinct cohorts: (1) the AGITG MAX trial (Phase III randomised clinical trial comparing capecitabine vs capecitabine and bevacizumab vs capecitabine, bevacizumab and mitomycinC); (2) the prospective Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry (any first-line regimen ± bevacizumab); and (3) two cancer centres in New South Wales, Australia [Macarthur Cancer Therapy Centre and Liverpool Cancer Therapy Centre (NSWCC) from January 2005 to Decenber 2012, (any first-line regimen ± bevacizumab). For the AGITG MAX trial capecitabine was compared to the other two arms (capecitabine/bevacizumab and capecitabine/bevacizumab/mitomycinC). In the AGITG MAX trial and the TRACC registry rates of gastrointestinal perforation were also collected in patients who did not have peritoneal metastases. Secondary endpoints included progression-free survival, chemotherapy duration, and overall survival. Time-to-event outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test.Eighty-four MAX, 179 TRACC and 69 NSWCC patients had peritoneal disease. There were no gastrointestinal perforations recorded in either the MAX subgroup or the NSWCC cohorts. Of the patients without peritoneal disease in the MAX trial, 4/300 (1.3%) in the bevacizumab arms had gastrointestinal perforations compared to 1/123 (0.8%) in the capecitabine alone arm. In the TRACC registry 3/126 (2.4%) patients who had received bevacizumab had a gastrointestinal perforation compared to 1/53 (1.9%) in the chemotherapy alone arm. In a further analysis of patients without peritoneal metastases in the TRACC registry, the rate of gastrointestinal perforations was 9/369 (2.4%) in the chemotherapy/bevacizumab group and 5/177 (2.8%) in the chemotherapy alone group. The addition of bevacizumab to chemotherapy was associated with improved progression-free survival in all three cohorts: MAX 6.9 m vs 4.9 m, HR = 0.64 (95%CI: 0.42-1.02); P = 0.063; TRACC 9.1 m vs 5.5 m, HR = 0.61 (95%CI: 0.37-0.86); P = 0.009; NSWCC 8.7 m vs 6.8 m, HR = 0.75 (95%CI: 0.43-1.32); P = 0.32. Chemotherapy duration was similar across the groups.Patients with peritoneal disease do not appear to have an increased risk of gastrointestinal perforations when receiving first-line therapy with bevacizumab compared to systemic therapy alone.

Anti-angiogenic therapy for glioblastoma has been in the spotlight for several years, as researchers and clinicians strive to find agents with meaningful efficacy against glioblastoma. Bevacizumab in particular, in the second half of the last decade, became the most significant breakthrough in anti-glioblastoma therapy since temozolomide. Optimism for bevacizumab has been somewhat challenged given recent clinical trials that have raised questions regarding its clinical effectiveness, the optimal timing of its use and the validity of endpoints, among other issues. In addition, uncertainty has recently arisen regarding the effects of bevacizumab on quality of life and neurocognitive function, two key clinical endpoints of unquestionable significance among glioblastoma patients. In this review, we highlight these controversies and other recent work related to bevacizumab for glioblastoma.

685 Background: The FIRE3 study reported that cetuximab added to first line combination chemotherapy versus the addition of bevacizumab to the same chemotherapy backbone, with a planned switch to the alternative biologic in second line therapy, resulted in improved overall survival. One possible explanation is that the sequence of biologic administration in mCRC impacts on treatment benefit. Examination of the efficacy of anti-EGFR therapy in cohorts where patients have and have not received prior bevacizumab will inform this. Methods: We interrogated our prospective database (ACCORD), which records comprehensive detail on demographics, treatments received and patient outcomes for consecutive mCRC patients in real world practice across multiple institutions in Australia. We included patients receiving 2nd and subsequent line anti-EGFR monotherapy. Disease control rate (DCR) (partial response plus stable disease), progression free survival (PFS) and overall survival (OS) from the start of anti-EGFR were determined as a function of prior bevacizumab use. Results: From a total of 1511 patients treated between 01/10/2002 and 31/12/2014,129 patients treated with single agent anti- EGFR were identified, 75 had received prior bevacizumab. Demographics, performance status and tumour characteristics were similar between the 2 groups. 84% were confirmed KRAS exon 2 wild type. Prior treatment with bevacizumab did not impact DCR (35% vs 40%, p = 0.5065), median PFS (3.0 vs 3.0 months, p = 0.9460) or OS (8.6 vs 8.4 months, HR 0.95, p = 0.8073). Similarly, for bevacizumab treated patients, the time since last dose of bevacizumab to start of anti-EGFR ( < 3 months (n = 26) vs 3-6 months (n = 17) vs > 6 months (n = 32)) did not impact PFS (2.3 vs 3.6 vs 3 months) or OS (8.9 vs 10.1 vs 7.1 months, HR: 0.88, p = 0.82). Conclusions: There was no evident impact of previous bevacizumab treatment, or time from previous bevacizumab treatment, on the efficacy of single agent anti-EGFR therapy in a routine clinical practice cohort. Our data do not support the notion that prior bevacizumab renders tumors more or less sensitive to subsequent anti EGFR therapy.

The management of gastric cancer remains a challenge. In recent years, the most important advances have been achieved in the adjuvant setting for patients with locally advanced disease, where significant survival benefits have been demonstrated for both perioperative chemotherapy and adjuvant chemoradiotherapy. These findings have changed the standard of care for patients with resectable disease. In the setting of metastatic gastric cancer, the development of new cytotoxic regimens must consider the balance between efficacy and toxicity in patients whose overall prognosis is poor. Major advances in recent years include the development of orally administered fluoropyrimidine analogues, which can be used in place of intravenous fluorouracil, and the addition of newer agents such as oxaliplatin and docetaxel, which have demonstrated efficacy in patients with advanced disease. Targeted therapies have had a major impact on the management of certain malignancies, and while their evaluation in the treatment of advanced gastric cancer remains early, it is likely that these agents will continue to be developed and studied in combination with chemotherapy. This article reviews recent advances in the use of chemotherapy for advanced gastric cancer. Targeted therapies, their mechanisms of action and emerging data supporting their use in gastric cancer are also discussed. The two randomized phase III trials supporting adjuvant therapy for locally advanced, resectable gastric cancer are discussed in detail, together with strategies for future trials in this area. Overall, there remains optimism that further incremental gains will be achieved with future studies combining chemotherapy, radiotherapy and targeted therapies, both in the adjuvant and metastatic disease settings.

2003 Background: In patients (pts) with recurrent glioblastoma (rGBM), the benefit of bevacizumab beyond progression (BBP) remains uncertain. Retrospective studies of pts with rGBM receiving BBP ha...

Aim: With an ever-increasing focus on personalised medicine, all factors known to affect treatment response need to be considered when defining optimal therapy for individual patients (pts). While the prognostic impact of primary tumour site on CRC outcomes is established, emerging data suggest potential differences in response to biologic therapies. Here we explore the impact of tumour site on bevacizumab (BEV) efficacy in pts with mCRC. Methods: Analysis of pts in an Australian prospective multicentre mCRC registry who received first-line palliative chemotherapy from July 2009 to March 2014. Tumour site was defined as: right colon (RCC)–caecum to transverse, left colon (LCC)–splenic flexure to rectosigmoid, and rectum (RC). Kaplan-Meier and Cox models were used for survival analyses. Results: Of 698 pts, 224 had RCC, 266 LCC and 208 RC primaries. Median age was 69, 66 and 63 years respectively (p Median PFS (months) Bevacizumab vs no bevacizumab Hazard ratio * 95% CI P value RCC 8.7 vs 5.6 0.60 0.42-0.85 0.004 LCC 11.8 vs 8.3 0.69 0.49-0.96 0.028 RC 13.5 vs 9.1 0.74 0.51-1.06 0.101 * Adjusted for age, sex, PS, comorbidity. Conclusions: Tumour site was prognostic in this cohort, with RC and RCC associated with best and worst outcomes respectively. Patients who received bevacizumab in addition to chemotherapy had superior PFS, with the effect appearing greatest in RCC patients. Although known prognostic factors were adjusted for, other clinicopathologic differences that may contribute to patient outcomes cannot be excluded. Patient accrual is ongoing and molecular analyses are planned. Disclosure: H. Wong, A.J. Lomax, M. Tacey, J. Shapiro, A. Zimet, D. Yip, R. Jennens, G. Richardson, J. Tie, S. Kosmider P. Parente, L. Lim, P. Cooray, B. Tran, J. Desai and B. Wong: Roche Products Pty Ltd (Australia) has provided financial assistance for the development, installation and maintenance of this clinical database. K. Field and L. Nott declare: Roche Products Pty Ltd (Australia) has provided financial assistance for the development, installation and maintenance of this clinical database. I have also received honoraria and other renumeration from Roche. J. McKendrick: Roche Products Pty Ltd (Australia) has provided financial assistance for the development, installation and maintenance of this clinical database. I also have an advisory relationship with Roche. P. Gibbs: Roche Products Pty Ltd (Australia) has provided financial assistance for the development, installation and maintenance of this clinical database. I have also received honoraria from Roche.

e14558 Background: With an ever-increasing focus on personalized medicine, all factors known to affect treatment response need to be considered when defining optimal therapy for an individual patient (pt). While the prognostic impact of primary tumor site on CRC outcomes is established, emerging data suggest potential differences in response to biologic therapies. Here we explore the impact of tumor site on BEV efficacy in pts with mCRC. Methods: Analysis of pts enrolled in an Australian prospective multicenter mCRC registry. Pts diagnosed from July 2009 to December 2013 and treated with first line chemotherapy were included. Tumor site was defined as: right colon (RCC) – cecum to transverse, left colon (LCC) – splenic flexure to rectosigmoid, and rectum (RC). Kaplan Meier and Cox models were used for survival analyses. Results: Of 541 pts, 160 (29.6%) had RCC, 201 (37.2%) LCC and 180 (33.3%) RC primaries. Median age was 69, 66 and 63 years respectively (p=0.002). There was no significant difference in pe...

2017 Background: The optimal use of bevacizumab (bev) in recurrent glioblastoma (GBM) remains uncertain including the choice between monotherapy or combination therapy as well as the role of continuing bev beyond disease progression. Methods: This was a sequential stratified two part randomized phase II study. Eligibility criteria included: recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, ECOG PS 0-2. The primary objective (Part 1) was to determine the effect of bev plus carboplatin versus bev alone on 6 month progression-free survival (6PFS) using modified RANO criteria. Bev was given 2-weekly 10mg/kg, carboplatin 4-weekly AUC5. On progression, patients (pts) able to continue treatment were randomized to continue or cease bev (Part 2). Secondary endpoints included response rate (RR); cognitive function; quality of life; toxicity and overall survival (OS). Results: 122 pts (median age 55) were enrolled from 18 Australian sites. 87 (71.3%) were PS 0-1. The current median follow up is 14.7 months with median on-treatment time 3.7 months. 6PFS was 26% (combination) versus 24% (monotherapy) (HR 0.96, 95%CI (0.66, 1.39), p = 0.82). RR (CR+PR) was 15% versus 13%. Median OS was 6.9 versus 6.4 months (HR 1.08, 95%CI (0.74, 1.59), p = 0.68). There were 2 treatment (bev) related deaths in the combination arm (one GI perforation, one CNS hemorrhage). To date, overall incidence of bev-related AEs is similar to prior literature with 10 (8.3%) venous thromboembolic events and 5 (4.2%) hemorrhages (all grades) reported. There were 3 episodes of G3-4 neutropenia, all in the combination arm (5%) and 9 episodes of G3-4 thrombocytopenia. As of January 14, 2013, 47 pts have continued on to Part 2. Data for bev beyond progression is not yet available. Conclusions: In this study of patients with recurrent GBM, the addition of carboplatin to bev did not result in additional clinical benefit compared to bev monotherapy. This large multicentre population-based study demonstrated that clinical outcomes in patients with recurrent GBM treated with bev were inferior to previously reported studies. Ongoing follow-up of patients on bev beyond progression, and novel secondary and exploratory endpoints continues. Clinical trial information: ACTRN12610000915055.

Background Glioblastoma (GBM) is the most aggressive malignant glial tumor. There is no accepted standard management after disease progression. Much remains unknown about the optimal use of bevacizumab (bev), including the role of continuing beyond progression, and patterns of radiological progression during and after use. In addition, the new Response Assessment in Neuro-Oncology (RANO) criteria have yet to be validated prospectively. Methods This study is a multi-centre, stratified randomised phase II trial. Patients have recurrent GBM after radiotherapy and temozolomide, have had no other chemotherapy for GBM, and have ECOG performance status 0–2. At least three months have elapsed since radiotherapy. In Part 1, patients are randomised 1:1 to intravenous bev 10 mg/kg 2-weekly and carboplatin AUC5 4-weekly or bev monotherapy. On progression, eligible patients are randomised to continue or cease bev (Part 2). The primary objective is to determine the effect of bev plus carboplatin versus bev alone on progression-free survival according to modified RANO criteria. Secondary endpoints are response rates, cognitive function, quality of life, steroid dose, toxicity, and overall survival. CogState, a validated neurocognitive testing system, is being used prospectively for the first time in this population and compared with mini-mental state examination. Exploratory endpoints include biomarker analyses, comparison of modified RANO and modified MacDonald criteria, predictive value of early MRI after 2 doses of bev, steroid dosing, and location and type of radiological progression during and after therapy. Results Enrolment commenced in Nov 2010, completing Part 1 accrual in Mar 2012 with 122 patients randomised from 17 Australian sites. Randomisation to Part 2 continues. Feasibility and safety data will be presented; efficacy outcome results are not expected until 2013. Conclusions The study results will significantly improve knowledge regarding the use of bevacizumab in the setting of recurrent GBM, as well as providing for the first time a prospective analysis of CogState neurocognitive testing for patients with brain tumours. Disclosure M.A. Rosenthal: Roche Advisory Board member. H. Wheeler: Roche Advisory Board member. E. Hovey: Roche Advisory Board member. A.K. Nowak: Roche Advisory Board member and has received research funding through Roche Australia. R.J. Simes: Roche Advisory Board Member. All other authors have declared no conflicts of interest.

665 Background: Clinical trials support the addition of bevacizumab (Bev) to first line chemotherapy for metastatic colorectal cancer (mCRC). However, given that there are alternate biological agents that can be used with chemotherapy; and rare but potentially serious toxicities with Bev, there has been variable use of the drug in routine care. The purpose of this study was to prospectively explore 1st line use of Bev in routine clinical care. Methods: A multi-site data collection was initiated in July 2009 when Bev became publicly available in Australia. A particular focus was capturing information regarding clinician decision-making that is not routinely recorded or is often poorly documented. Comprehensive comorbidity data was collected, along with specific factors, both patient (pt) and disease-related, that may impact on treatment decisions. Major adverse events that may be related to Bev were also recorded. Results: For the 2-year period from July 2009-June 2011, a database search identified 278 pts diagnosed with mCRC at five participating hospitals. 240 pts (86%) had received 1st line chemotherapy. 102 (43%) also received Bev, the majority in combination with oxaliplatin based chemotherapy (n = 81, 79%). Bev use increased significantly from 40.4% (34/84) of all pts receiving chemotherapy in July-December 2009, to 65.8% (25/38) in January-June 2011 (p=0.0114). Overall the most frequent reasons for clinicians advising against the use of Bev were a bleeding or asymptomatic primary in situ (n=28, 23%), known hypertension (n=14, 11%), clinical trial participation (n=14, 11%), poor performance status (n=9, 7%), and perceived risk of arterial ischemic event (n=8, 6.5%). There have been four episodes of gastro-intestinal perforation, 3 in pts receiving Bev (2.9% of Bev treated patients). Conclusions: Bev use in first line mCRC has significantly increased over time, presumably as further positive safety data emerges regarding safety in older and frailer pts, and clinician prescribing experience increases. The major grounds for not using Bev in the 1st line mCRC setting were specific clinical contexts where the risk of adverse events may be increased.