Anil A. Joy

Gastric Adenocarcinoma: Review and Considerations for Future Directions

Objective:This update reviews the epidemiology and surgical management, and the controversies of gastric adenocarcinoma. We provide the relevance of outcome data to surgical decision-making and discuss the application of gene-expression analysis to clinical practice. Summary Background Data:Gastric cancer mortality rates have remained relatively unchanged over the past 30 years, and gastric cancer continues to be one of the leading causes of cancer-related death. Well-conducted studies have stimulated changes to surgical decision-making and technique. Microarray studies linked to predictive outcome models are poised to advance our understanding of the biologic behavior of gastric cancer and improve surgical management and outcome. Methods:We performed a review of the English gastric adenocarcinoma medical literature (1980–2003). This review included epidemiology, pathology and staging, surgical management, issues and controversies in management, prognostic variables, and the application of outcome models to gastric cancer. The results of DNA microarray analysis in various cancers and its predictive abilities in gastric cancer are considered. Results:Prognostic studies have provided valuable data to better the understanding of gastric cancer. These studies have contributed to improved surgical technique, more accurate pathologic characterization, and the identification of clinically useful prognostic markers. The application of microarray analysis linked to predictive models will provide a molecular understanding of the biology driving gastric cancer. Conclusions:Predictive models generate important information allowing a logical evolution in the surgical and pathologic understanding and therapy for gastric cancer. However, a greater understanding of the molecular changes associated with gastric cancer is needed to guide surgical and medical therapy.

Effects of presurgical exercise training on cardiorespiratory fitness among patients undergoing thoracic surgery for malignant lung lesions

To determine the effects of preoperative exercise training on cardiorespiratory fitness in patients undergoing thoracic surgery for malignant lung lesions.

Evaluating Survivorship Care Plans: Results of a Randomized, Clinical Trial of Patients With Breast Cancer

PURPOSE An Institute of Medicine report recommends that patients with cancer receive a survivorship care plan (SCP). The trial objective was to determine if an SCP for breast cancer survivors improves patient-reported outcomes. PATIENTS AND METHODS Women with early-stage breast cancer who completed primary treatment at least 3 months previously were eligible. Consenting patients were allocated within two strata: less than 24 months and ≥ 24 months since diagnosis. All patients were transferred to their own primary care physician (PCP) for follow-up. In addition to a discharge visit, the intervention group received an SCP, which was reviewed during a 30-minute educational session with a nurse, and their PCP received the SCP and guideline on follow-up. The primary outcome was cancer-related distress at 12 months, assessed by the Impact of Event Scale (IES). Secondary outcomes included quality of life, patient satisfaction, continuity/coordination of care, and health service measures. RESULTS Overall, 408 survivors were enrolled through nine tertiary cancer centers. There were no differences between groups on cancer-related distress or on any of the patient-reported secondary outcomes, and there were no differences when the two strata were analyzed separately. More patients in the intervention than control group correctly identify their PCP as primarily responsible for follow-up (98.7% v 89.1%; difference, 9.6%; 95% CI, 3.9 to 15.9; P = .005). CONCLUSION The results do not support the hypothesis that SCPs are beneficial for improving patient-reported outcomes. Transferring follow-up to PCPs is considered an important strategy to meet the demand for scarce oncology resources. SCPs were no better than a standard discharge visit with the oncologist to facilitate transfer.

Cardiorespiratory exercise testing in clinical oncology research: systematic review and practice recommendations

The use of exercise testing as an objective assessment of cardiorespiratory fitness in clinical oncology research has increased substantially over the past decade. However, its quality has not been assessed. We did a systematic review of studies of formal exercise testing for adults with cancer. Studies were assessed according to the American Thoracic Society/American College of Chest Physicians (ATS/ACCP) recommendations for exercise testing. Overall, the reporting of exercise-testing methods and data for adults with cancer suggests that the conduct of these tests does not comply with national and international quality guidelines. We give recommendations for exercise testing in clinical oncology research. The adoption of consistent, formal standards for methods and data reporting in exercise testing is needed to ensure high-quality research in clinical oncology. Overall, we present information for clinicians and exercise-oncology researchers who assess and care for patients with cancer.

Cardiovascular risk profile of patients with HER2/neu-positive breast cancer treated with anthracycline-taxane-containing adjuvant chemotherapy and/or trastuzumab

Purpose: To evaluate the cardiovascular risk profile of a subset of patients with early-stage breast cancer treated with adjuvant taxane-anthracycline–containing chemotherapy and/or trastuzumab (Herceptin). Experimental Design: Twenty-six patients with breast cancer (mean, 20 months postchemotherapy) and 10 healthy age-matched women were studied. We measured 14 metabolic and vascular established cardiovascular disease (CVD) risk factors, body mass index, cardiorespiratory fitness, and left ventricular systolic function. All assessments were done within a 14-day period. Results: Cardiac abnormalities were suggested by left ventricular ejection fraction (LVEF) <50% in 8% of patients, LVEF remained >10% below pretreatment values in 38%, whereas 50% presented with resting sinus tachycardia. Brain natriuretic peptide was significantly elevated in 40% of patients and was correlated with LVEF (r = −0.72, P = < 0.001). For the majority of CVD risk factors, similar proportions of patients and controls (35-60%) were classified as “undesirable.” A significantly higher proportion of patients were classified with low cardiorespiratory fitness (46% versus 0%, P < 0.01), being overweight/obese (72% versus 50%, P < 0.05), and having resting sinus tachycardia (50% versus 0%, P < 0.01) compared with controls. Cardiorespiratory fitness and body mass index were correlated with CVD risk factors (r = −0.64 to 0.63, P < 0.05; r = −0.63 to 0.67, P < 0.05, respectively). Exploratory analyses revealed several differences between CVD risk factors based on chemotherapy regimen. Conclusion: Breast cancer survivors treated with adjuvant chemotherapy are at a higher risk of developing late-occurring CVD than age-matched controls due to direct and indirect treatment-related toxicity. (Cancer Epidemiol Biomarkers Prev 2007;16(5):1026–31)

A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer

BACKGROUND This phase III randomized trial compared pemetrexed 500 mg/m(2) (P500) with pemetrexed 900 mg/m(2) (P900) to determine whether higher dosing benefits non-small-cell lung cancer (NSCLC) patients as second-line therapy. PATIENTS AND METHODS Patients with locally advanced or metastatic NSCLC, previously treated with platinum-based chemotherapy, were randomly assigned to receive i.v. P500 or P900 every 3 week. RESULTS Accrual was terminated with 588/600 patients enrolled because an interim analysis indicated a low probability of improved survival and numerically greater toxicity on the P900 arm. P900 patients were permitted to continue treatment at P500. No statistical difference was observed between the treatment arms (P500 versus P900) for median survival {6.7 versus 6.9 months, hazard ratio [HR] = 1.0132 [95% confidence interval (CI) 0.837-1.226]}, progression-free survival [2.6 versus 2.8 months, HR = 0.9681 (95% CI 0.817-1.147)], or best overall tumor response [7.1% versus 4.3% (P = 0.1616)]. The incidence of drug-related grade 3/4 toxicity was typically <5% on both treatment arms, but was numerically higher on the P900 arm for most toxicity categories. CONCLUSIONS P900 did not improve any efficacy measure over P500. P500 i.v. every 3 week remains the standard pemetrexed dose for second-line treatment of platinum-pretreated advanced NSCLC.

Cognitive effects of Tamoxifen in pre-menopausal women with breast cancer compared to healthy controls

IntroductionThe selective estrogen receptor modulator, Tamoxifen (TAM), is one of the most frequently prescribed drugs for the treatment of breast cancer; however, its effects on the cognition of users have not been adequately studied. Although TAM is an effective anti-estrogen that blocks tumour growth in the breast, it could also influence the activity of other target estrogen sites, including the brain. The exact nature of this interaction is unknown.MethodsA cross-sectional design was used to compare cognitive task performance of two treatment groups: 1) women using TAM for the treatment of early breast cancer (n = 23); and 2) age-matched, healthy women not using TAM (n = 23). All participants were pre-menopausal, and recipients of chemotherapy were excluded from the study.ResultsIt was found that TAM users scored significantly worse than controls on tasks of immediate and delayed visual memory, verbal fluency, immediate verbal memory, visuo-spatial ability, and processing speed.Discussions/ConclusionsAlthough limited by the lack of baseline data and pre-morbid intelligence measures, the results of this exploratory study suggest that at least in pre-menopausal women, TAM may exert a widespread negative influence on cognitive abilities.Implications for Cancer SurvivorsLarger, randomized, prospective trials are required to confirm these results; however, TAM use in pre-menopausal breast cancer may be associated with cognitive difficulties. Knowledge and understanding of these complications will be important for professionals in communicating both the benefits and risks of TAM use in breast cancer survivors.

Effects of Aerobic Exercise Training in Anemic Cancer Patients Receiving Darbepoetin Alfa: A Randomized Controlled Trial

BACKGROUND Anemia in patients with solid tumors is a common problem that is associated with impaired exercise capacity, increased fatigue, and lower quality of life (QoL). Erythropoiesis-stimulating agents (ESAs) have been shown to improve these outcomes; however, it is unknown if additional benefits can be achieved with aerobic exercise training. METHODS We conducted a single-center, prospective, randomized, controlled trial in 55 mild-to-moderately anemic patients with solid tumors. Patients were randomized to either darbepoetin alfa alone (DAL, n = 29) or darbepoetin alfa plus aerobic exercise training (DEX; n = 26). The DEX group performed aerobic exercise training three times per week at 60%-100% of baseline exercise capacity for 12 weeks. The primary endpoint was QoL assessed by the Functional Assessment of Cancer Therapy-Anemia scale. Secondary endpoints were fatigue, cardiorespiratory fitness (VO(2peak)), hemoglobin (Hb) response, and darbepoetin alfa dosing. RESULTS Intention-to-treat analyses indicated significant improvements in QoL and fatigue in both groups over time but there were no between-group differences. The DEX group had a significantly greater VO(2peak) than the DAL group (mean group difference, +3.0 ml/kg per minute; 95% confidence interval, 1.2-4.7; p = .001) and there were borderline significant differences in favor of the DEX group for Hb response and darbepoetin alfa dosing. CONCLUSIONS Aerobic exercise training did not improve QoL or fatigue beyond the established benefits of DAL but it did result in favorable improvements in exercise capacity and a more rapid Hb response with lower dosing requirements. Our results may be useful to clinicians despite the more recent restrictions on the indications for ESAs.

Novel agents and associated toxicities of inhibitors of the pi3k/Akt/mtor pathway for the treatment of breast cancer

UNLABELLED The pi3k/Akt/mtor (phosphatidylinositol 3 kinase/ Akt/mammalian target of rapamycin) signalling pathway is an established driver of oncogenic activity in human malignancies. Therapeutic targeting of this pathway holds significant promise as a treatment strategy. Everolimus, an mtor inhibitor, is the first of this class of agents approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Everolimus has been associated with significant improvements in progression-free survival; however, it is also associated with increased toxicity related to its specific mechanism of action. METHODS A comprehensive review of the literature conducted using a focused medline search was combined with a search of current trials at http://ClinicalTrials.gov/. Summary tables of the toxicities of the various classes of pi3k/Akt/mtor inhibitors were created. A broad group of Canadian health care professionals was assembled to review the data and to produce expert opinion and summary recommendations for possible best practices in managing the adverse events associated with these pathway inhibitors. RESULTS Differing toxicities are associated with the various classes of pi3k/Akt/mtor pathway inhibitors. The most common unique adverse events observed in everolimus clinical trials in breast cancer include stomatitis (all grades: approximately 60%), noninfectious pneumonitis (15%), rash (40%), hyperglycemia (15%), and immunosuppression (40%). To minimize grades 3 and 4 toxicities and to attempt to attain optimal outcomes, effective management of those adverse events is critical. Management should be interdisciplinary and should use approaches that include education, early recognition, active intervention, and potentially prophylactic strategies. DISCUSSION Everolimus likely represents the first of many complex oral targeted therapies for the treatment of breast cancer. Using this agent as a template, it is essential to establish best practices involving and integrating multiple disciplines for the management of future pi3k/Akt/mtor signalling pathway inhibitors.

Canadian Cardiovascular Society Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy

Modern treatment strategies have led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Cardiotoxicity is now recognized as a leading cause of long-term morbidity and mortality among cancer survivors. This guideline, authored by a pan-Canadian expert group of health care providers and commissioned by the Canadian Cardiovascular Society, is intended to guide the care of cancer patients with established cardiovascular disease or those at risk of experiencing toxicities related to cancer treatment. It includes recommendations and important management considerations with a focus on 4 main areas: identification of the high-risk population for cardiotoxicity, detection and prevention of cardiotoxicity, treatment of cardiotoxicity, and a multidisciplinary approach to cardio-oncology. All recommendations align with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Key recommendations for which the panel provides a strong level of evidence include: (1) that routine evaluation of traditional cardiovascular risk factors and optimal treatment of preexisting cardiovascular disease be performed in all patients before, during, and after receiving cancer therapy; (2) that initiation, maintenance, and/or augmentation of antihypertensive therapy be instituted per the Canadian Hypertension Educational Program guidelines for patients with preexisting hypertension or for those who experience hypertension related to cancer therapy; and (3) that investigation and management follow current Canadian Cardiovascular Society heart failure guidelines for cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction during or after cancer treatment. This guideline provides guidance to clinicians on contemporary best practices for the cardiovascular care of cancer patients.