Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies

Background: Bevacizumab is frequently combined with 5-fluorouracil-based chemotherapy for patients with metastatic colorectal cancer (mCRC). The relative benefit of bevacizumab in older patients has not been widely studied and is of interest. Patients and methods: This retrospective analysis used data from three first-line randomized controlled studies and one second-line randomized controlled study of bevacizumab plus chemotherapy in medically fit (Eastern Cooperative Oncology Group performance status 0 or 1) patients with mCRC. Overall survival (OS) and on-treatment progression-free survival (PFS) were assessed in patients aged greater than 65, greater than or equal to 65, and greater than or equal to 70 years. Results were compared using unstratified hazard ratios (HRs). Grade 3-5 adverse events were also assessed. Results: Bevacizumab statistically significantly improved PFS [HR 0.58; 95% confidence interval (CI) 0.49-0.68] and OS (HR 0.85; 95% CI 0.74-0.97) in patients aged greater than or equal to 65 years; patients aged greater than or equal to 70 years had similar improvements. Benefits were consistent across the studies, irrespective of setting, bevacizumab dose, or chemotherapy regimen. Increases in thromboembolic events were observed in patients aged greater than or equal to 65 and greater than or equal to 70 years in the bevacizumab group compared with the control group, mainly as a result of increases in arterial thromboembolic events. No other substantial age-related increases in grade 3-5 adverse events were observed. Conclusions: In medically fit older patients, bevacizumab provides similar PFS and OS benefits as in younger patients

Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance)

Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin-binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment-by-marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild-type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild-type (WT) patients (chemo HR = 0.98, 95% CI = 0.74-1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05-2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02-2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67-1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68-13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31-2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88-1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32-1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab

Blood�based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance)

Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin�binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment�by�marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild�type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild�type (WT) patients (chemo HR = 0.98, 95% CI = 0.74–1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05–2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02–2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67–1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68–13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31–2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88–1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32–1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab

Phase I Safety, Pharmacokinetics, and Clinical Activity Study of Lapatinib (GW572016), a Reversible Dual Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinases, in Heavily Pretreated Patients With Metastatic Carcinomas

PURPOSE: This study (EGF10004) assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib (GW572016) in patients with ErbB1-expressing and/or ErbB2-overexpressing advanced-stage refractory solid tumors. PATIENTS AND METHODS: Heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were randomly assigned to one of five dose cohorts of lapatinib administered once daily. Pharmacokinetic samples were obtained on days 1 and 20. Clinical response was assessed every 8 weeks. RESULTS: Sixty-seven patients with metastatic solid tumors were treated with lapatinib. The most frequently reported drug-related adverse events were diarrhea (42%) and rash (31%). No grade 4 drug-related adverse events were reported. Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. Drug-related interstitial pneumonitis or cardiac dysfunction associated with other ErbB-targeted therapies was not reported. Four patients with trastuzumab-resistant metastatic breast cancer-two of whom were classified as having inflammatory breast cancer-had partial responses (PRs). Twenty-four patients with various other carcinomas experienced stable disease, of whom 10 received lapatinib for > or = 6 months. The relationships between lapatinib dose or serum concentration and clinical response could not be adequately characterized due to the limited response data. The incidence of diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose. CONCLUSION: Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients

Partner-assisted emotional disclosure for patients with gastrointestinal cancer: Results from a randomized controlled trial

For patients with cancer who are married or in an intimate relationship, their relationships with their partners play a critical role in their adaptation to their illness. However, cancer patients and their partners often have difficulty in talking with each other about their cancer-related concerns. Difficulties in communication may ultimately compromise both the patient-partner relationship and the patient's psychological adjustment. The present study tested the efficacy of a novel partner-assisted emotional disclosure intervention in a sample of patients with gastrointestinal (GI) cancer

Efficacy of manipulation for non-specific neck pain of recent onset: design of a randomised controlled trial

BACKGROUND: Manipulation is a common treatment for non-specific neck pain. Neck manipulation, unlike gentler forms of manual therapy such as mobilisation, is associated with a small risk of serious neurovascular injury and can result in stroke or death. It is thought however, that neck manipulation provides better results than mobilisation where clinically indicated. There is long standing and vigorous debate both within and between the professions that use neck manipulation as well as the wider scientific community as to whether neck manipulation potentially does more harm than good. The primary aim of this study is to determine whether neck manipulation provides more rapid resolution of an episode of neck pain than mobilisation. METHODS/DESIGN: 182 participants with acute and sub-acute neck pain will be recruited from physiotherapy, chiropractic and osteopathy practices in Sydney, Australia. Participants will be randomly allocated to treatment with either manipulation or mobilisation. Randomisation will occur after the treating practitioner decides that manipulation is an appropriate treatment for the individual participant. Both groups will receive at least 4 treatments over 2 weeks. The primary outcome is number of days taken to recover from the episode of neck pain. Cox regression will be used to compare survival curves for time to recovery for the manipulation and mobilisation treatment groups. DISCUSSION: This paper presents the rationale and design of a randomised controlled trial to compare the effectiveness of neck manipulation and neck mobilisation for acute and subacute neck pain

Chronic non-specific low back pain - sub-groups or a single mechanism?

Copyright 2008 Wand and O'Connell; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain is a substantial health problem and has subsequently attracted a considerable amount of research. Clinical trials evaluating the efficacy of a variety of interventions for chronic non-specific low back pain indicate limited effectiveness for most commonly applied interventions and approaches. Discussion: Many clinicians challenge the results of clinical trials as they feel that this lack of effectiveness is at odds with their clinical experience of managing patients with back pain. A common explanation for this discrepancy is the perceived heterogeneity of patients with chronic non-specific low back pain. It is felt that the effects of treatment may be diluted by the application of a single intervention to a complex, heterogeneous group with diverse treatment needs. This argument presupposes that current treatment is effective when applied to the correct patient. An alternative perspective is that the clinical trials are correct and current treatments have limited efficacy. Preoccupation with sub-grouping may stifle engagement with this view and it is important that the sub-grouping paradigm is closely examined. This paper argues that there are numerous problems with the sub-grouping approach and that it may not be an important reason for the disappointing results of clinical trials. We propose instead that current treatment may be ineffective because it has been misdirected. Recent evidence that demonstrates changes within the brain in chronic low back pain sufferers raises the possibility that persistent back pain may be a problem of cortical reorganisation and degeneration. This perspective offers interesting insights into the chronic low back pain experience and suggests alternative models of intervention. Summary: The disappointing results of clinical research are commonly explained by the failure of researchers to adequately attend to sub-grouping of the chronic non-specific low back pain population. Alternatively, current approaches may be ineffective and clinicians and researchers may need to radically rethink the nature of the problem and how it should best be managed

Trajectories of body weight change and survival among patients with mCRC treated with systemic therapy: Pooled analysis from the ARCAD database

Background Higher body mass index is associated with a higher incidence of colorectal cancer (CRC) but also with improved survival in metastatic CRC (mCRC). Whether weight change after mCRC diagnosis is associated with survival remains largely unknown. Methods We analysed individual patient data for previously untreated patients enrolled in five phase 3 randomised trials conducted between 1998 and 2006. Weight measurements were prospectively collected at baseline and up to 59.4 months after diagnosis. We used stratified multivariable Cox models to assess the prognostic associations of weight loss with overall and progression-free survival, adjusting for other factors. The primary end-point was a difference in overall survival (OS) between populations with weight loss and stable or increasing weight. Findings Data were available for 3504 patients. The median weight change at 3 months was −0.54% (IQR −3.9 … +1.5%). We identified a linear trend of increasing risk of death associated with progressive weight loss. Unstratified median OS was 20.5, 18.0, and 11.9 months (p < 0.001) for stable weight or gain, <5% weight loss, and ≥5% weight loss at 3 months, respectively. Weight loss was associated with a higher risk of death (<5% loss: aHR 1.18 [1.06–1.30], p < 0.002; ≥5% loss: aHR 1.87 [1.67–2.1], p < 0.001) as compared to stable or increasing weight at 3 months post-baseline (reference), while adjusting for age, sex, performance, and a number of metastatic sites. Interpretation Patients losing weight during systemic therapy for metastatic colorectal cancer have significantly shorter OS. The degree of weight loss is proportional to the observed increased risk of death and remains evident among underweight, normal weight, and obese individuals. On-treatment weight change could be used as an intermediate end-point