National Cancer Institute Of Canada Research Articles

Regulation of the PI3K pathway by the eIF2α kinase PKR

Objective Study the role of PKR in PI3K signaling pathway. Two important steps of translation initiation include the recognition of the mRNA cap structure by eIF4E and the recycling of eIF2. Each step is thought to be regulated independently through the interaction of eIF4E with 4E binding proteins (4E-BPs) and the phosphorylation of the α subunit of eIF2 at serine 51. Results we demonstrate that the eIF2α kinase PKR provides a link between the two steps. PKR induces phosphoinositide-3 kinase (PI3K) activity leading to activation of Akt and the mammalian target of Rapamycin (mTOR) and phosphorylation of 4E-BP1. Despite 4E-BP1 phosphorylation, its interaction with eIF4E is enhanced in cells with activated PKR and occurs in distinct cytoplasmic granules containing phosphorylated eIF2α. Induction of the PI3K pathway antagonizes the apoptotic effects of PKR caused by eIF2α phosphorylation. PKR is also involved in the activation of PI3K and 4E-BP1 phosphorylation by serum or interferon (IFN)- 1 _. Conclusion Our data demonstrate a novel signaling property of PKR through the regulation of the PI3K pathway. Source of Funding This work has been supported by a grant from the Canadian Institutes of Health Research (CIHR) to Dr. A. Koromilas. S. Kazemi and D. Baltzis are both Research Students of the Terry Fox Foundation through awards from the National Cancer Institute of Canada (NCIC).

Advances in our understanding of postoperative adjuvant chemotherapy in resectable non-small-cell lung cancer

After publication in 1995 of a meta-analysis of adjuvant chemotherapy in the treatment of NSCLC, a number of randomized trials investigated adjuvant chemotherapy using more active chemotherapeutic regimens and larger numbers of accrued patients per trial. This review will focus on recent clinical trials for adjuvant chemotherapy, and will help to interpret the applicability of these results to daily clinical practice. Four large-scale randomized trials that used platinum-based chemotherapy have reported positive results during the last 3 years. These trials included cisplatin-based chemotherapy [the International Adjuvant Lung Cancer (IALT) trial], cisplatin plus vinorelbine [the National Cancer Institute of Canada (NCIC) BR10 trial], and carboplatin plus paclitaxel [the Cancer and Leukemia Group B (CALGB) 9633 trial]. More recently, another adjuvant trial [Adjuvant Navelbine International Trialist Association (ANITA)] was reported, which has added greatly to our understanding of the potential role of adjuvant treatment. Regarding adjuvant UFT (tegafur and uracil) chemotherapy, an individual patient data-based meta-analysis demonstrated its significant effect on survival in selected patients with completely resected non-small-cell lung cancer. Recent trials indicate a survival benefit of postoperative adjuvant chemotherapy. These findings are anticipated to change the clinical management of patients with completely resectable non-small-cell lung cancer.

Clinical experience with erlotinib in non-small-cell lung cancer (NSCLC)

Lung cancer is the leading cause of cancer death worldwide. Despite the introduction of more- effective chemotherapeutic agents, it appears that a survival plateau has been reached, so new treatment strategies are clearly needed. One innovative therapeutic cancer strategy is the introduction of biological agents that target specific intracellular pathways related to the distinctive properties of cancer cells. Among these agents, epidermal growth factor receptor (EGFR)-targeting agents have received particular attention in lung cancer. Numerous EGFR blockers have been evaluated, including monoclonal antibodies to the receptor and small-molecule tyrosine kinase inhibitors. The present review focuses on the tyrosine kinase inhibitor erlotinib. Preclinical studies have shown that erlotinib blocks the growth of human non-small-cell lung cancer (NSCLC) cell lines in vitro by inhibiting the receptor and the downstream protein phosphorylation. In a randomized study conducted by the National Cancer Institute of Canada (BR.21) in second- and third-line NSCLC treatment, erlotinib significantly prolonged overall survival and decreased symptoms compared with placebo. A crucial aspect of the clinical development of molecular-targeted therapies is to understand which patients will obtain clinical benefit from their use. Sensitivity to erlotinib has been associated with EGFR mutations, most commonly deletions of four to six amino acids in exon 19 or a point mutation (L858R) in exon 21. Increased EGFR gene copy number has also been pointed out as a good predictive marker for erlotinib response. Intense research activity is ongoing to validate known predictive markers and to discover new tools which maximize clinical benefit using erlotinib. However, there is no conclusive evidence, as yet, linking response to survival.

Erlotinib in the treatment of non-small cell lung cancer

Inhibition of the epidermal growth factor receptor is one of the most promising novel therapeutic strategies to be used in the treatment of patients with non-small cell lung cancer. A number of compounds that target the epidermal growth factor receptor are in an advanced stage of clinical development including both antibodies directed against the receptor and small molecule inhibitors of epidermal growth factor receptor tyrosine kinase activity. This drug profile focuses on the development of erlotinib, an orally available inhibitor of epidermal growth factor receptor tyrosine kinase. Results of clinical trials are reviewed, two trials of erlotinib in combination, one with paclitaxel and carboplatin, the other with gemcitabine and cisplatin, and the National Cancer Institute of Canada – Clinical Trials Group BR21, the first study to demonstrate a survival benefit for this class of compound in non-small cell lung cancer. The future role of erlotinib in the management of patients with non-small cell lung cancer is also discussed.

TU‐D‐J‐6B‐03: Physics and Applications of Preclinical Micro‐Ultrasound Imaging

Bioresearch in functional genomics is poised to make major contributions to our understanding of normal development and human disease. This promise will, in part, rely on the development of new micro‐imaging technologies to provide quantitative longitudinal assessment of morphological and functional development of normal and abnormal tissues. In addition, imaging tools will need to be further refined to enable high throughput phenotypic assessment of the rapidly escalating numbers of targeted and random mouse mutations. This presentation will focus on the development of high frequency (20 to 70 MHz) ultrasound biomicroscopy (UBM) for mouse imaging. While UBM does not provide molecular specificity, it has the advantage of low cost, rapid imaging speed, portability and high resolution (30–100 microns). The physics of high frequency ultrasound will be reviewed and the latest developments in instrumentation will be presented. Applications of 2 and 3D imaging to mouse cardiovascular assessment, cancer and ocular diseases will be described. Recent advances in 3D UBM imaging now permit the volumes of growing experimental tumors to be assessed with relative ease. Examples of tumor growth studies will be presented. In particular, a human melanoma (MeWo) and a model of retinoblastoma will be examined. Further analysis of Doppler and other flow related data offers insight to microvascular development and its alteration during treatment. This is particularly relevant to angiogenesis and antiangiogenic treatments. As an example of antiangiogenic therapy, a study of DC101 (ImClone Systems), a monoclonal anti‐VEGFR2 antibody will be presented. The authors wish to acknowledge the financial support of the Canadian Institutes for Health Research, the National Cancer Institute of Canada with funds from the Terry Fox Foundation, the Ontario Research and Development Challenge Fund, and VisualSonics Inc. FSF also discloses a financial interest in VisualSonics Inc.

Association Between Aerobic Fitness And Adiponectin In Premenopausal Women

Systemic inflammation and the action of the adipocyte have been linked to cardiovascular disease and other chronic conditions, including cancer. Associated markers of inflammation and adiposite activity may be altered by lifestyle factors such as physical activity. PURPOSE To examine the association between aerobic fitness, adiponectin and c-reactive protein. METHODS An extreme-groups split design was used to compare adiponectin and c-reactive protein in premenopausal women with high aerobic fitness (n=16; VO2max ≥ 48 ml·kg·min−1) compared to average aerobic fitness (n=13; VO2max ≥ 40 ml·kg·min−1). Participants were healthy, regularly menstruating, Caucasian women, aged 20 to 42 years, with a normal body mass index (BMI) of 18–24.9, who were not using pharmacologic contraceptives, or tobacco products. Height, weight, and sum of four skinfolds (SSF) were obtained prior to completing an incremental exercise test to exhaustion on a cycle ergometer to determine maximal aerobic fitness (VO2max). A single blood sample was collected during the follicular phase of the following menstrual cycle. RESULTS No significant differences were seen in age, height, weight or BMI between groups, however, the average fitness group had a higher SSF (P=.001). The high fitness group (VO2max 53.0±0.9) had significantly higher adiponectin levels (15.4±1.6 μg/mL) than the average fitness group (VO2max 35.3±1.0) (10.3±1.1 μg/mL) (P=.017). No significant difference between groups was seen in c-reactive protein. Overall, a higher VO2max was associated with higher adiponectin (r=.44, P=0.012), while a higher SSF was associated with lower adiponectin (r=−.53, P=.002). A multivariate regression analysis showed that SSF(U = −.42, P=.051) but not VO2max (β =.16, P=.431), had an independent association with adiponectin levels. CONCLUSIONS This exploratory study found that higher aerobic fitness and lower SSF were associated with higher adiponectin levels. No difference in c-reactive protein was found. Supported by EFF Support for the Advancement of Scholarship from the University of Alberta and a Research Team Grant from the National Cancer Institute of Canada (NCIC) with funds from the Canadian Cancer Society(CCS) and the CCS/ NCIC Sociobehavioural Cancer Research Network.

Association Between Aerobic Fitness And Adiponectin In Premenopausal Women

Systemic inflammation and the action of the adipocyte have been linked to cardiovascular disease and other chronic conditions, including cancer. Associated markers of inflammation and adiposite activity may be altered by lifestyle factors such as physical activity. PURPOSE To examine the association between aerobic fitness, adiponectin and c-reactive protein. METHODS An extreme-groups split design was used to compare adiponectin and c-reactive protein in premenopausal women with high aerobic fitness (n=16; VO2max ≥ 48 ml·kg·min−1) compared to average aerobic fitness (n=13; VO2max ≥ 40 ml·kg·min−1). Participants were healthy, regularly menstruating, Caucasian women, aged 20 to 42 years, with a normal body mass index (BMI) of 18–24.9, who were not using pharmacologic contraceptives, or tobacco products. Height, weight, and sum of four skinfolds (SSF) were obtained prior to completing an incremental exercise test to exhaustion on a cycle ergometer to determine maximal aerobic fitness (VO2max). A single blood sample was collected during the follicular phase of the following menstrual cycle. RESULTS No significant differences were seen in age, height, weight or BMI between groups, however, the average fitness group had a higher SSF (P=.001). The high fitness group (VO2max 53.0±0.9) had significantly higher adiponectin levels (15.4±1.6 μg/mL) than the average fitness group (VO2max 35.3±1.0) (10.3±1.1 μg/mL) (P=.017). No significant difference between groups was seen in c-reactive protein. Overall, a higher VO2max was associated with higher adiponectin (r=.44, P=0.012), while a higher SSF was associated with lower adiponectin (r=−.53, P=.002). A multivariate regression analysis showed that SSF(U = −.42, P=.051) but not VO2max (β =.16, P=.431), had an independent association with adiponectin levels. CONCLUSIONS This exploratory study found that higher aerobic fitness and lower SSF were associated with higher adiponectin levels. No difference in c-reactive protein was found. Supported by EFF Support for the Advancement of Scholarship from the University of Alberta and a Research Team Grant from the National Cancer Institute of Canada (NCIC) with funds from the Canadian Cancer Society(CCS) and the CCS/ NCIC Sociobehavioural Cancer Research Network.

Quality Of Life Differences Among Non Hodgkinʼs Lymphoma Survivors Meeting And Not Meeting National Exercise Prescription Guidelines

Exercise has received increased attention as a supportive therapy for cancer survivors in which quality of life (QoL) benefits may accrue. However, the majority of cancer survivors do not achieve the minimal amounts of exercise required for health benefits. Non Hodgkin's lymphoma (NHL) is a unique cancer in which survivors may benefit from exercise rehabilitation. However, no studies to date have focused on exercise in this population. PURPOSE The purpose of this study was to examine QoL differences between NHL survivors meeting and not meeting national exercise prescription guidelines proposed by the American College of Sports Medicine and Centers for Disease Control and Prevention (i.e., at least 150 minutes of moderate-to-vigorous exercise/week). A secondary purpose was to examine exercise behavior changes across three distinct cancer-related time periods (i.e., pre-diagnosis, active treatment and off-treatment). METHODS 438 NHL survivors residing in Alberta, Canada completed a mailed questionnaire that retrospectively assessed self-reported exercise pre-diagnosis, during and off-treatment (Godin Leisure Time Exercise Questionnaire), and current QoL (Functional Assessment of Cancer Therapy). RESULT S: Analyses indicated that 33.8%, 6.5% and 23.7% of NHL survivors met national exercise prescription guidelines during pre-diagnosis, active and off-treatment periods, respectively. MANOVA indicated that NHL survivors meeting national exercise prescription guidelines both during and off-treatment had higher QoL scores than NHL survivors not meeting national guidelines. QoL difference scores between the two groups yielded small to medium effect sizes (d) ranging from .20 to .48 and met proposed standards for clinically important differences. MANOVA also indicated significant differences in exercise behavior across the three cancer-related time periods (all p <.05). CONCLUSION These results provide evidence that NHL survivors meeting national exercise prescription guidelines both during and off-treatment reported higher QoL than those survivors not meeting national exercise prescription guidelines. These findings corroborate research examining exercise behavior in other cancer populations and provide preliminary data to support a randomized controlled trial on exercise and QoL in this population. Supported by a Research Team Grant from the National Cancer Institute of Canada (NCIC) with funds from the Canadian Cancer Society (CCS) and the CCS/NCIC Sociobehavioural Cancer Research Network.

Chemotherapy Alone for Early Hodgkin's Lymphoma: An Emerging Option

Early stage Hodgkin’s lymphoma is a highly curable disease. Combined chemotherapy and radiation has resulted in high freedom-from-progression rates at 5 to 12 years in the range of 93% for stages I and II patients with asymptomatic presentations and approximately 85% for those with unfavorable disease characteristics. 1-3 The revelation of serious cardiac and second malignancy issues in long-term survivors treated with radiotherapy has prompted a reconsideration of its role when used alone or combined with chemotherapy. Thus, there is a serious need to assess the benefits of chemotherapy alone in patients with early stage disease, especially in those without bulky presentations. In this issue of the Journal of Clinical Oncology is the publication of a trial conducted by the National Cancer Institute of Canada (NCI-C) in collaboration with the Eastern Cooperative Oncology Group (ECOG) addressing the role of chemotherapy alone for early-stage Hodgkin’s lymphoma. 4 The trial was conceived in the early 1990s, when subtotal nodal radiation therapy with splenic irradiation was the standard treatment in Canada for clinically staged patients with early nonbulky stage I to IIA disease. The experimental arm was the chemotherapy regimen of doxorubicin, bleomycin, vincristine and dacarbazine (ABVD) alone for four cycles if a complete response (CR) was achieved after two cycles. Otherwise, patients received six cycles. The standard arm was radiation therapy alone, unless one of the following was present: erythocyte sedimentation rate (ESR) 50 mm/h, or four or more nodal sites, in which case patients received two cycles of ABVD before protocol irradiation. Approximately 70% of 399 total patients had one or two of these unfavorable features. Thus, for a considerable fraction of the patient population, the study was a comparison of combined-modality therapy with chemotherapy alone. At a median follow-up of 4.3 years, freedom from progression (FFP) was the only parameter that reached statistical significance, in which the standard arm had a FFP of 94% compared with 88% for chemotherapy alone (P .04). This difference was confined to the unfavorable group. Further, there were no differences in the event-free and overall survivals. Although the standard arm of this trial is no longer used, subsequent trials have confirmed that combined-modality therapy is superior in FFP compared to radiation alone and that chemotherapy with involved-field radiation therapy is comparable in benefit to more extensive-field radiation plus the same chemotherapy. 5

Clinical trial update: National Cancer Institute of Canada

The Breast Cancer Site Group (BCSG) of the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) has conducted a wide variety of clinical trials focussing on large phase III trials of adjuvant chemotherapy, adjuvant hormonal therapy, and optimal delivery of adjuvant radiation therapy. The Group has also fostered, together with the NCIC CTG Investigational New Drug (IND) Program, a series of phase II and phase I/II studies which will be carried through if possible, into the phase III setting.

A randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma: results of the 40955 EORTC trial

Previous small phase II trials have demonstrated that the combination of 5-fluorouracil (5FU) and cisplatin(CDDP) could have clinical activity in metastatic biliary tract cancer. This randomised phase II trial was designed to assess the activity and safety of a high-dose infusional weekly 5FU alone (HDFU) and the combination of 5FU, folinic acid (FA) and CDDP. Patients were included if they had histologically proven locally advanced or metastatic biliary tract carcinoma, World Health Organisation (WHO) performance status ⩽2, bilirubin <2 × upper normal limit, adequate haematological and renal functions and had not received prior chemotherapy, even in the adjuvant setting. Treatments: Arm A (HDFU) consisted of cycles of 5FU 3 g/m 2 intravenously (i.v.), 24 h infusion, weekly, for 6 weeks, followed by 1 week rest, every 7 weeks; Arm B (5FU + FA + CDDP) consisted of cycles of 5FU 2.0 g/m 2 i.v. with folinic acid 500 mg/m 2, 2 h-infusion, weekly, for 6 weeks, followed by 1 week rest plus cisplatin 50 mg/m 2, once every two weeks, for 6 weeks, followed by 1 week rest, every 7 weeks. From February 1997 to June 1999, 58 patients were randomised (29 in each arm). Patients had a median age of 58 years in Arm A and 62 years in Arm B, locally advanced disease was present in 21% of the patients in Arm A and 11% in Arm B. WHO performance status of 0/1/2 was noted in 48%/45%/7% of the patients in Arm A and 54%/43%/4% in Arm B. In both arms, the most common metastatic sites were the liver and peritoneum. Twenty-eight patients were eligible in each arm and one patient did not start the allocated therapy in Arm B. The median number of cycles was 2 [range 1–12] in Arm A and 2 [range 1–6] in Arm B. Responses for the eligible patients who started their allocated therapy were as follows: Complete Response (CR) 0% in Arm A, 4% in Arm B, Partial Response (PR) 7% in Arm A, 15% in Arm B resulting in an overall response rate [95% CI] of 7.1% in Arm A [0.9–23.5%] and 19% [6.3–38.1%] in Arm B. Disease stabilisation was observed in 46% in Arm A and 44% in Arm B. National Cancer Institute of Canada (NCIC) grade 3–4 adverse events (% of patients in Arm A/Arm B) were neutropenia 4%/26%, thrombopenia 0%/7%, stomatitis 0%/4%, vomiting 7%/14%, diarrhoea 0%/11% and neurotoxicity 4%/0%. There was one early toxic death in Arm B. The median overall survival (OS) [95% CI] was in Arm A/Arm B: 5.0 [4.0–7.4] months/8.0 [5.8–11.8] months and the median progression-free survival (PFS) was 3.3 [1.7–4.7] months/3.3 [2.3–6.7] months. Cisplatin in combination with 5FU + FA showed a higher activity than HDFU, but was more toxic. These results are not sufficient to start a phase III trial. However, our group is planning a phase III trial comparing 5FU + folinic acid versus the same schedule + oxaliplatin a platinum analogue.

Does Sex Influence the Impact That Smoking, Treatment Interruption and Impaired Pulmonary Function Have on Outcomes in Limited Stage Small Cell Lung Cancer Treatment?

To look for survival differences between men and women with limited stage small cell lung cancer (LS-SCLC) by examining stratified variables that impair treatment efficacy. A retrospective review of 215 LS-SCLC patients treated from 1989 to 1999 with concurrent chemotherapy-radiotherapy modelled on the 'early-start' thoracic radiotherapy arm of a National Cancer Institute of Canada randomized trial. Of 215 LS-SCLC patients, 126 (58.6%) were men and 89 (41.4%) were women. Smoking status during treatment for 186 patients (86.5%) was: 107 (58%) nonsmoking (NS) (76 [71%] male [M]; 31 [29%] female [F]) and 79 (42%) smoking (S) (36 M [46%]; 43 F [54%]) (continuing-to-smoke F versus M, P=0.001). Fifty-six patients (26%) had radiotherapy interruptions (RTI) during chemotherapy-radiotherapy because of toxicity. Radiotherapy breaks were not associated with sex (P=0.95). Survival by sex and smoking status at two years was: F + NS = 38.7%; F + S = 21.6%; M + NS = 22.9%; and M + S = 9.1% (P=0.0046). Survival by sex and RTI status at two years was: F + no RTI = 32.4%; F + RTI = 23.6%; M + no RTI = 23.0%; and M + RTI = 3.8% (P=0.0025). Diffusion capacity for carbon monoxide (DLCO) was recorded for 86 patients (40%) and median survival by sex and DLCO was F = 16.7 months and M = 12.1 months for a DLCO less than 60%; and for a DLCO 60% or more, F = 15.1 months and M = 15.3 months. First relapses were recorded in 132 cases (61%), with chest failure in men (45%) greater than for women (35%) and cranial failure rates similar between sexes (48%). Upon multivariable analysis, continued smoking was the strongest negative factor affecting survival. In LS-SCLC, women overall do better than men, with or without a negative variable. The largest quantifiable improvement in survival for women came from smoking cessation, and for men from avoidance of breaks during treatment.

Analysis and interpretation of health-related quality-of-life data from clinical trials: basic approach of The National Cancer Institute of Canada Clinical Trials Group

Clinicians are being confronted with increasing amounts of health-related quality of life (HRQOL) data. Thus, there is a need for a greater understanding of the analysis and interpretation of HRQOL so that the data can be reported in an appropriate manner. The approach of the Clinical Trials Group of the National Cancer Institute of Canada emphasises the clinical meaning of the results, while avoiding complex statistical modelling. It consists of four steps: calculating the questionnaire completion rates, calculating the baseline scores, determining the individual change in scores over time for the domains specified in the trial hypothesis, and culminates in determining the proportions of patients who have reported clinically meaningful changes in scores since baseline. A rationale supporting each step is given. This approach is presented as a simple and practical aid to the analysis, interpretation and reporting of HRQOL results.

Compliance with post-operative adjuvant chemotherapy in non-small cell lung cancer: An analysis of National Cancer Institute of Canada and intergroup trial JBR.10 and a review of the literature

Resected non-small cell lung cancer (NSCLC) has 5-years survival rates of 30-70%. The role of adjuvant chemotherapy remains unclear with poor compliance reported in most trials. The compliance with adjuvant chemotherapy (ACT) for stage IB and II NSCLC was analyzed using data from a North American multi-centre phase III study (accrual 1994-2001) that compared adjuvant chemotherapy to observation. Planned chemotherapy consisted of cisplatin (CIS) 50 mg/m2 days 1, 8 and vinorelbine (VIN) 25 mg/m2 days 1, 8, 15, 22 for four cycles; the VIN dose had been reduced from 30 mg/m2 after an initial cohort of patients experienced unacceptable toxicity. Four hundred and twenty-four patients were randomized after the amendment, 215 to the chemotherapy arm. Median age was 60 years, 64% were male and 84% had stage II disease. Thirty-seven patients completed one cycle, 14 completed two, 20 completed three and 108 patients completed all four cycles. Ten patients received no therapy. Multivariate analysis demonstrated statistically significant differences in compliance with extent of surgery, gender and age. Patients randomized in Canada were more likely to fail to complete chemotherapy due to refusal of therapy than their American counterparts. Patients who had pneumonectomies were more likely to discontinue therapy due to toxicity than those who had lesser resections. Extent of surgery may play a role in both the compliance and toxicity of ACT. Differences between nations in the perception of the risks and benefits of adjuvant chemotherapy regimens, both between physicians and patients, should be investigated further.

Estrogen Metabolites in Premenopausal Women with High versus Average Aerobic Fitness

1990 Physical activity is suggested to alter estrogen metabolism, a proposed biomarker of breast cancer risk, by causing a shift towards higher 2-OHE1 and lower 16a-OHE1 levels. PURPOSE: To investigate the association between aerobic fitness and estrogen metabolites, 2-OHE1 and 16a-OHE1. METHODS: An extreme-groups split design was used to compare 2-OHE1 and 16a-OHE1 profiles in women with high aerobic fitness (n = 17; VO2max = 48 ml × kg × min−1) to women with average aerobic fitness (n = 13; VO2max = 40 ml × kg × min−1). Participants were healthy, regularly menstruating Caucasian women, aged 20 to 42 years, with a normal body mass index (BMI) of 18–24, who were not using pharmacologic contraceptives, or tobacco products, and were not vegetarian. Height, weight, and sum of four skinfolds, were obtained prior to completing an incremental exercise test to exhaustion on a cycle ergometer to determine maximal aerobic fitness (VO2max). A single blood and urine sample was collected during the follicular and luteal phase of the following menstrual cycle for estradiol and estrogen metabolite determination, respectively. Saliva samples were collected daily during the luteal phase for progesterone determination. RESULTS: No significant differences were found between average and high fit women for 2- OHE1, 16a-OHE1, or the 2:16a-OHE1 ratio in either the follicular or luteal phase. In ancillary analyses, a higher sum of skinfolds was associated with significantly higher luteal 16-OHE1 levels (r = .39, P = 0.03) and lower luteal phase 2:16 OHE ratio (r = −.41, P = 0.02). Higher BMI was associated with lower follicular phase 2-OHE1 (r = −.37, p = 0.038) and lower follicular 2:16 OHE1 ratio (r = −40, P = 0.03). Estradiol levels were not different between groups. CONCLUSIONS: This is the first study to investigate the relationship between estrogen metabolites and aerobic fitness using metabolic parameters. This exploratory study failed to find an association between aerobic fitness and 2-OHE1 and 16a-OHE1 but found that body composition was positively associated with 2-OHE1 and 16a-OHE1 levels. Supported by EFF Support for the Advancement of Scholarship from the University of Alberta, and a Grant from the National Cancer Institute of Canada (NCIC) with funds from the Canadian Cancer Society (CCS) and the CCS/NCIC Sociobehavioural Cancer Research Network.

Predictors of Adherence in a Randomized Controlled Trial of Exercise in Prostate Cancer Survivors

1580 We conducted a randomized controlled trial designed to determine the effects of a 12 wk supervised resistance exercise training (RET) program on muscular strength, fatigue, and quality of life (QOL) in prostate cancer survivors receiving androgen deprivation therapy. We previously reported statistically significant and clinically meaningful changes in trial end points in favor of the exercise group. We also reported a 78.3% adherence rate to the intervention. PURPOSE: To examine predictors of exercise adherence in the trial. METHODS: Prostate cancer survivors (N = 155) completed measures of demographic, social cognitive, QOL, behavioral, and fitness variables before being randomized to either an exercise (n = 82) or control (n = 73) group. The exercise group was asked to perform supervised RET 3/wk for 12 wks. The control group was asked not to initiate RET. RESULTS: The exercise group attended 28.2 (78.3%) of the 36 sessions. Univariate analyses revealed eight statistically significant (ps <.05) predictors of exercise adherence during the trial including exercise stage of change, intention, age, QOL, fatigue, subjective norm, leg press test, and perceived behavioral control. A multivariate analysis indicated that there were three independent predictors of trial adherence that explained 20.4% of the variance: exercise stage of change (β = .26; p = .013), age (β = −.22; p = .037), and intention (β = .19; p = .073). Ancillary analyses indicated that the control group performed significantly more aerobic exercise outside of the trial than the exercise group (p = .020). This difference resulted from a significant decline in nonprogram-related aerobic exercise in the exercise group (p = .001) rather than an increase in the control group (p = .945). CONCLUSION: Exercise adherence in the trial was very good but not optimal. Moreover, the exercise group partly compensated for their RET program by reducing their nonprogram-related aerobic exercise. Adherence was predicted by variables from many different categories including social cognitive, QOL, behavioral, fitness, and demographic. These findings may have important implications for maximizing adherence during clinical trials of exercise in prostate cancer survivors. Supported by the National Cancer Institute of Canada

The Efficacy of Calcium Carbonate in the Treatment of Protease Inhibitor-Induced Persistent Diarrhea in HIV-Infected Patients

Background: Although some evidence exists to support the practice of using calcium carbonate to treat nelfinavir-induced diarrhea, there is a lack of data supporting the role of calcium in diarrhea induced by other protease inhibitors (PIs). Purpose: The objective of this prospective open-label study is to evaluate the efficacy of calcium carbonate in the treatment of PI-induced persistent diarrhea in HIV-infected patients. Method: Along with dietary advice, patients were asked to take oral calcium carbonate 500 mg twice daily for 2 weeks. Visual Analog Scale (VAS) and the National Cancer Institute of Canada (NCIC) scale were used to assess the severity of diarrhea. Data were analyzed using paired t tests to test for differences in VAS and NCIC scores between baseline and 14 days. Pearson correlation was used to explore the relationships between change in diarrhea and patient baseline factors. Results: At day 0, the mean VAS ± standard deviation was 6.6 ± 2.1 and decreased to 5.3 ± 1.9 (p = .01) after 14 days. At day 0, the mean NCIC score was 1.9 ± 0.8 and decreased to 1.2 ± 0.9 (p = .005) after 14 days. No baseline patient factors predicted change in NCIC or VAS grade. Conclusion: Calcium carbonate is associated with a reduction of diarrhea in individuals with diarrhea induced by PI.

Prevention strategies with aromatase inhibitors.

Aromatase (estrogen synthetase) inhibitors are superior to tamoxifen in terms of both efficacy and toxicity in the treatment of advanced breast cancer and also in the neoadjuvant setting. Recent results from the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial showed a marked reduction in contralateral primary breast cancer with anastrozole, an apparent prevention effect. A similar effect was seen in the MA.17 adjuvant trial comparing letrozole with placebo after 5 years of adjuvant tamoxifen. This has accelerated interest in aromatase inhibitors as primary preventive therapy. Two studies being conducted by the National Cancer Institute of Canada's Clinical Trials Group select women by virtue of mammographic breast density. The International Breast Cancer Intervention Study 2 trial randomizes women at elevated risk to anastrozole or placebo. Because of its steroidal structure, exemestane may be more effective than the nonsteroidal aromatase inhibitors and may protect bone and lipid metabolism from the effects of estrogen ablation. Elevated prostaglandin E2 levels from cyclooxygenase-2 induction by preinvasive and invasive breast lesions increase a number of tumor-promoting pathways, including aromatase, as well as angiogenetic, antiapoptotic, and others. Additive or synergistic effects between celecoxib, a cyclooxygenase-2 inhibitor, and exemestane have been demonstrated and have led to the National Cancer Institute of Canada's Clinical Trials Group MAP.3 trial, which will randomize women at elevated risk to placebo or to exemestane with or without celecoxib. The efficacy and long-term toxicity data from the aromatase inhibitor prevention trials, and the identification of risk profiles from trial results, are awaited with interest.

How Should We Treat Patients with Locally Advanced Prostate Cancer?

Men with locally advanced prostate cancer are generally offered active treatment (radiotherapy or hormone therapy alone or in combination) with the aim of extending progression-free and overall survival. There is now good evidence from recent studies to suggest that patients who are treated with radiotherapy benefit from the addition of neoadjuvant or adjuvant hormone therapy. However, the extent of the contribution of radiotherapy in patients receiving hormone therapy is unclear, as the trials evaluating this combination approach did not include a hormone therapy only arm. Two ongoing trials, an International Intergroup study involving the National Cancer Institute of Canada (NCIC), the Medical Research Council (MRC), and the National Cancer Institute (NCI) in the United States, and a Scandinavian Prostate Cancer Group (SPCG) trial, are addressing this issue. Results should be available in the latter part of the decade. The optimum nature and schedule of hormone therapy are also unresolved. When hormone therapy is used to treat locally advanced disease, either as adjuvant therapy or immediate monotherapy, patients have traditionally undergone medical (e.g. goserelin [‘Zoladex’ 1 ‘Zoladex’ and ‘Casodex’ are trademarks of the AstraZeneca group of companies. 1 ]) or surgical castration. However, bicalutamide (‘Casodex’ 1) 150 mg monotherapy may offer important benefits over castration with respect to quality of life, particularly the maintenance of physical capacity and sexual interest, as well as preservation of bone mineral density and muscle mass, while achieving a similar survival outcome. Nonetheless, the benefits of bicalutamide 150 mg monotherapy must be balanced against the risk of developing gynecomastia and/or breast pain. Patients presenting with locally advanced prostate cancer should be given a clear explanation on all available treatment options and allowed to make an informed choice.

Radiation induced mucositis: co-ordinating a research agenda.

A one-day workshop was hosted by the Symptom Control Committee of the National Cancer Institute of Canada, Clinical Trials Group (NCIC-CTG), in conjunction with the October 2002 annual meeting of the Canadian Association of Radiation Oncologists in Toronto, Ontario. The primary intention of the workshop was to direct the future research agenda of the Symptom Control Committee. Large group presentations were held initially to review the contemporary research issues of four selected areas of interest: fatigue, brain metastasis, bone metastasis and radiation-induced mucositis. Panel members were then charged with the identification of specific research proposals that could be considered for further development. Research questions were to be clinically relevant and currently appropriate. Any additional information needed before the launch of any potential trial was also requested. In this paper, we will review and summarise the outcomes from the radiation-induced mucositis sessions. Thirty-four participants participated in the large group sessions and contributed to one of four panel discussions on selected supportive care issues relevant to radiation oncologists. Three potential and non-overlapping research questions were identified; two involving mucositis management in patients receiving radical radiation for head and neck cancer, and a third for patients with advanced lung cancer undergoing combined radiation and chemotherapy and at risk for the development of symptomatic oesophagitis. The workshop successfully identified three potential research questions. The large group and the smaller panel discussions successfully established consensus on important aspects of future study designs. The current 'standard of care', appropriate experimental treatments, primary outcomes of interest and study population parameters were each important issues that were discussed. The importance of developing meaningful biological assays was reviewed, as was the need to ensure the appropriate storage of biological samples from patients for future study.