The economic impact of the transition from branded to generic oncology drugs.

Background: Economic evaluations are an integral component of many clinical trials. Costs used in those analyses are based on the prices of branded drugs when they first enter the market. The effect of genericization on the cost-effectiveness (ce) or cost-utility (cu) of an intervention is unknown because economic analyses are rarely updated using the costs of generic drugs. Methods: We re-examined the ce or cu of regimens previously evaluated in Canadian Cancer Trials Group (cctg) studies that included prospective economic evaluations and where genericization has occurred or is anticipated in Canada. We incorporated the new costs of generic drugs to characterize changes in ce or cu. We also determined acceptable cost levels of generic drugs that would make regimens reimbursable in a publicly funded health care system. Results: The four randomized controlled trials included (representing 1979 patients) were cctg br.10 (early lung cancer, adjuvant vinorelbine-cisplatin vs. observation, n = 172), cctg br.21 (metastatic lung cancer, erlotinib vs. placebo, n = 731), cctg co.17 (metastatic colon cancer, cetuximab vs. best supportive care, n = 557), and cctg ly.12 (relapsed or refractory lymphoma, gemcitabine-dexamethasone-cisplatin vs. cytarabine-dexamethasone-cisplatin, n = 619). Since the initial publication of those trials, the genericization of vinorelbine, erlotinib, cetuximab, and cisplatin has taken place or is expected in Canada. Costs of generics improved the ces and cus of treatment significantly. For example, genericization of erlotinib ($1460.25 per 30 days) resulted in an incremental cost-effectiveness ratio (icer) of $45,746 per life-year gained compared with $94,638 for branded erlotinib. Likewise, genericization of cetuximab ($275.80 per 100 mg) produced an icer of $261,126 per quality-adjusted life-year (qaly) gained compared with $299,613 for branded cetuximab. Decreases in the cost of generic cetuximab to $129.39 and $63.51 would further improve the icer to $150,000 and $100,000 per QALY respectively. Conclusions: Genericization of a costly oncology drug can modify the ce and cu of a regimen significantly. Failure to revisit economic analyses with the costs of generics could be a missed opportunity for funding bodies to optimize value-based allocation of health care resources. At current levels, the costs of generics might not be sufficiently low to sustain publicly funded health care systems.

Linkage of clinical trial and administrative data: a survey of cancer patient preferences.

BACKGROUND: Personal health information, including diagnoses and hospital admissions, is routinely collected in administrative databases. Patients enrolling on clinical trials consent to separate collection and storage of their personal health information. We evaluated patient preferences for linking long-term data from administrative databases with clinical trials. METHODS: Adults with cancer attending outpatient clinics at 3 Ontario hospitals were surveyed about their willingness, when faced with the hypothetical scenario of participating in a clinical trial, to provide potentially identifying information such as initials and date of birth to facilitate long-term research access to normally deidentified publicly collected databases. RESULTS: Of 569 patients surveyed, 335 (59%) were women, 452 (79%) were white, 385 (68%) had a post-secondary education, and 386 (68%) had never participated in a clinical trial. Median age in the group was 59 years. Most participants (93%, cohort 1) would allow long-term access to their information and allow personal information to be used to match clinical trial with administrative data. At the time of clinical trial closure, two thirds of participants (68%, cohort 2) preferred to make additional clinical information available through linkage with administrative databases, and 8 (9%) preferred to have no further information made available to researchers. No significant differences were found in the subset of patients who were part of a clinical trial and those who had never participated (p = 0.65). INTERPRETATION: Almost all patients would allow a clinical trial research team to access their confidential information, providing a more comprehensive assessment of an intervention's long-term risks and benefits.

Estimation of drug cost avoidance and pathology cost avoidance through participation in NCIC Clinical Trials Group phase III clinical trials in Canada.

BACKGROUND: Cost avoidance occurs when, because of provision of a drug therapy [drug cost avoidance (dca)] or a pathology test [pathology cost avoidance (pca)] during trial participation, health care payers need not pay for standard treatments or testing. The aim of our study was to estimate the total dca and pca for Canadian patients enrolled in relevant phase iii trials conducted by the ncic Clinical Trials Group. METHODS: Phase iii trials that had completed accrual and resulted in dca or pca were identified. The pca was calculated based on the number of patients screened and the test cost. The dca was estimated based on patients randomized, the protocol dosing regimen, drug cost, median dose intensity, and median duration of therapy. Costs are presented in Canadian dollars. No adjustment was made for inflation. RESULTS: From 1999 to 2011, 4 trials (1479 patients) resulted in pca and 17 trials (3195 patients) resulted in dca. The total pca was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). The total dca was estimated at $27,952,512, of which targeted therapy constituted 43% (five trials). The combined pca and dca was $32,147,361. CONCLUSIONS: Over the study period, trials conducted by the ncic Clinical Trials Group resulted in total cost avoidance (pca and dca) of approximately $7,518 per patient. Although not all trials lead to cost avoidance, such savings should be taken account when the financial impact of conducting clinical research is being considered.

A randomized, placebo-controlled trial (NCIC CTG MAP.2) examining the effects of exemestane on mammographic breast density, bone density, markers of bone metabolism and serum lipid levels in postmenopausal women.

We hypothesized that exemestane (EXE) would reduce mammographic breast density and have unique effects on biomarkers of bone and lipid metabolism. Healthy postmenopausal women were randomized to EXE (25 mg daily) or placebo (PLAC) for 12 months and followed for a total of 24 months. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms and secondary endpoints were changes in serum lipid levels, bone biomarkers, and bone mineral density (BMD). Ninety-eight women were randomized (49 to EXE; 49 to PLAC) and 65 had PD data at baseline and 12 months. Among women treated with EXE, PD was not significantly changed from baseline at 6, 12, or 24 months and was not different from PLAC. EXE was associated with significant percentage increase from baseline in N-telopeptide at 12 months compared with PLAC. No differences in percent change from baseline in BMD (lumbar spine and femoral neck) were observed between EXE and PLAC at either 12 or 24 months. Patients on EXE had a significantly larger percent decrease in total cholesterol than in the PLAC arm at 6 months and in HDL cholesterol at 3, 6, and 12 months. No significant differences in percent change in LDL or triglycerides were noted at any time point between the two treatment arms. EXE administered for 1 year to healthy postmenopausal women did not result in significant changes in mammographic density. A reversible increase in the bone resorption marker N-telopeptide without significant change in bone specific alkaline phosphatase or BMD during the 12 months treatment period and 1 year later was noted. Changes in lipid parameters on this trial were modest and reversible.

Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17.

BACKGROUND: MA.17 evaluated letrozole or placebo after 5 years of tamoxifen and showed significant improvement in disease-free survival (DFS) for letrozole [hazard ratio (HR) 0.57, P = 0.00008]. The trial was unblinded and placebo patients were offered letrozole. PATIENTS AND METHODS: An intent-to-treat analysis of all outcomes, before and after unblinding, on the basis of the original randomization was carried out. RESULTS: In all, 5187 patients were randomly allocated to the study at baseline and, at unblinding, 1579 (66%) of 2383 placebo patients accepted letrozole. At median follow-up of 64 months (range 16-95), 399 recurrences or contralateral breast cancers (CLBCs) (164 letrozole and 235 placebo) occurred. Four-year DFS was 94.3% (letrozole) and 91.4% (placebo) [HR 0.68, 95% confidence interval (CI) 0.55-0.83, P = 0.0001] and showed superiority for letrozole in both node-positive and -negative patients. Corresponding 4-year distant DFS was 96.3% and 94.9% (HR 0.80, 95% CI 0.62-1.03, P = 0.082). Four-year overall survival was 95.1% for both groups. The annual rate of CLBC was 0.28% for letrozole and 0.46% for placebo patients (HR 0.61, 95% CI 0.39-0.97, P = 0.033). CONCLUSIONS: Patients originally randomly assigned to receive letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS and CLBC, despite 66% of placebo patients taking letrozole after unblinding.

Clinical outcomes of ethnic minority women in MA.17: a trial of letrozole after 5 years of tamoxifen in postmenopausal women with early stage breast cancer.

BACKGROUND: Aromatase inhibitors are widely employed in the adjuvant treatment of early stage breast cancer. The impact of aromatase inhibitors has not been established in ethnic minority women. PATIENTS AND METHODS: The purpose of this study was to evaluate the impact of letrozole on minority women in MA.17, a placebo-controlled trial of letrozole following 5 years of tamoxifen in postmenopausal women with early stage breast cancer. Retrospective comparison of disease-free survival (DFS), side effects, and mean changes in quality of life (QOL) scores from baseline between Caucasian and minority women was performed. RESULTS: Minority (n = 352) and Caucasian (n = 4708) women were analyzed. There was no difference between these groups in DFS (91.6% versus 92.4% respectively for 4 year DFS). Letrozole, compared with placebo, significantly improved DFS for Caucasians (HR = 0.55; P < 0.0001) but not for minorities (HR = 1.39; P = 0.53). Among women who received letrozole, minorities had a significantly lower incidence of hot flashes (49% versus 58%; P = 0.02), fatigue (29% versus 39%; P = 0.005), and arthritis (2% versus 7%; P = 0.006) compared with Caucasians. Mean change in QOL scores for minority women who received letrozole demonstrated improved mental health at the 6-month assessment (P = 0.02) and less bodily pain at the 12-month assessment (P = 0.046). CONCLUSION: Letrozole improved DFS in Caucasians but a definite benefit in minority women has not yet been demonstrated. Minority women tolerated letrozole better than Caucasians in terms of toxicity. These results need confirmation in other trials of aromatase inhibitors.

Comparing the predictive value of neural network models to logistic regression models on the risk of death for small-cell lung cancer patients.

Cancer is one of the leading causes of mortality in the developed world, and prognostic assessment of cancer patients is indispensable in medical care. Medical researchers are accustomed to using regression models to predict patient outcomes. Neural networks have been proposed as an alternative with great potential. Nonetheless, empirical evidence remains lacking to support the application of this technique as the appropriate method to investigate cancer prognosis. Utilizing data on patients from two National Cancer Institute of Canada clinical trials, we compared predictive accuracy of neural network models and logistic regression models on risk of death of limited-stage small-cell lung cancer patients. Our results suggest that neural network and logistic regression models have similar predictive accuracy. The distributions of individual predicted probabilities are very similar. On occasion, however, the prediction pairs are quite different, suggesting that they do not always give the same interpretations of the same variables.

Priority-setting decisions for new cancer drugs: a qualitative case study.

BACKGROUND: Frameworks for legitimate and fair priority setting emphasise the importance of the rationales for priority setting decisions. However, priority setting rationales, in particular for new cancer drugs, are not well described. We describe the rationales used by a committee making funding decisions for new cancer drugs. METHODS: We did a qualitative case study of a priority setting committee (Cancer Care Ontario Policy Advisory Committee for the New Drug Funding Program) by analysing documents, interviewing committee members, and observing committee meetings. FINDINGS: We identified and described decisions and rationales related to 14 drugs in eight disease conditions over 3 years. Our main findings were that: priority setting existed in relation to resource mobilisation; clinical benefit was the primary factor in decisions; in the context of an expanding budget, rationales changed; rationales could change as costs for individual treatments increased; when all options were reasonable, groups funded a range of options and let patients decide; and priority setting rationales involve clusters of factors, not simple trade-offs. INTERPRETATION: Observing priority-setting decisions and their rationales in actual practice reveals lessons not contained in theoretical accounts.

Funding new cancer drugs in Ontario: closing the loop in the practice guidelines development cycle.

PURPOSE: The previously described practice guidelines development cycle follows an iterative model in which recommendations are reached by a process that incorporates practitioners at all phases. A key feature is the separation of the evidence-based systematic review and the generation of recommendations from policy decisions surrounding implementation. This article describes how this implementation phase has evolved in Ontario and how implementation has affected the guidelines process. METHODS: The development of the New Drug Funding Program in Ontario and the appointment of a policy advisory committee (PAC) to make funding recommendations were reviewed. The decision-making framework of the PAC is described in this article. RESULTS: The PAC has had to address a number of issues in making funding recommendations. These issues have included dealing with evidence arising solely from phase II versus phase III trials, using economic information, and involving community representatives in its deliberations. Its activities have had a substantial impact on the practice guidelines initiative. CONCLUSION: It is possible to integrate an evidence-based, practitioner-driven approach to clinical guideline development with a funding program that takes policy considerations into account. However, even though these two roles are conceptually separate, the needs of the funding program have inevitably had an impact on the guidelines process.

Bilateral massive adrenal hemorrhage. Assessment of putative risk factors by the case-control method.

Case reports and case series have identified putative risk factors for the development of bilateral massive adrenal hemorrhage (BMAH) in humans. The anatomy and physiology of the adrenal gland allow development of a model to fit the pathophysiology behind these risk factors. Until now, these risk factors were not systematically tested using analytical epidemiologic studies. A case-control study was undertaken using sources of cases and controls from multiple teaching hospitals in Ontario, Canada. The results of multivariate logistic regression indicated that thrombocytopenia (odds ratio [OR] = 14.6, 95% confidence intervals [CI] = 3.0-70.1, p < 0.001), heparin exposure of any route or type beyond 3 days (4-6 days: OR = 17.0, CI = 1.9-154.6; > 6 days: OR = 33.5, CI = 4.3-262.6; p < 0.001), and sepsis (OR = 6.3, CI = 1.2-32.2, p = 0.019) were most strongly and independently associated with development of BMAH. Another weaker positive association included invasive radiologic procedure (OR = 4.4, CI = 0.9-22.1, p = 0.055). Neither major surgery or duration of hospitalization were independent risk factors. Although coronary artery disease and possibly diabetes and hypertension appeared to be markers for lower risk of BMAH, this may be a result of bias introduced by using hospital controls ("Berkson bias"), as the effect was not explained by a protective effect of vasoactive medications. Thus, a picture of the high-risk patient should include a patient who has been treated with heparin (any route or type) beyond 3 days and has had thrombocytopenia (not necessarily induced by heparin) during the course of an illness. If the setting includes unexplained abdominal, chest, or back pain; fever; confusion; hypotension or shock; abrupt anemia; or electrolyte disorders, clinicians should not hesitate to cover empirically with lifesaving glucocorticoids while awaiting results of confirmatory tests.

Second primary malignancies following the treatment of early stage ovarian cancer: update of a study by the National Cancer Institute of Canada--Clinical Trials Group (NCIC-CTG).

BACKGROUND: Ovarian cancer is the leading cause of death from gynecological malignancies and the fourth most frequent fatal malignancy in women. Despite improved surgical techniques as many as 20% of women with early stage disease will eventually relapse and die from their disease. The post-operative management of these women remains controversial. Here we present the long term follow-up data of our previously published study, as well as the incidence of second primary malignancies in these women. PATIENTS AND METHODS: Two hundred fifty-seven eligible patients with stage I, IIA 'high risk' ovarian carcinoma and IIB, IIIO (disease confined to pelvis) were randomized to either whole abdominal radiotherapy 2.250 rads in ten fractions (107 patients), melphalan 8 mg/m2/d x 4 weeks x 18 courses (106 patients) or intraperitoneal chromic phosphate 10-20 mCi (44 patients). All patients were initially treated with pelvic radiotherapy. RESULTS: Overall survival estimates at 10 years were: 45% in the whole abdominal radiotherapy arm; 49% in the melphalan arm and 50% in the intraperitoneal chromic phosphate arm (P = 0.30). Relapse-free survival estimates at 10 years were: 50% in the whole abdominal radiotherapy arm, 62% in the melphalan arm and 51% in the chromic phosphate arm (P = 0.147). Long term follow-up has not demonstrated a significant difference between treatment arms. Second primary malignancies developed in 29 women (11%) after 2,229 person years of follow-up. This compares to 18.7 second primary malignancies which would have been expected in this group of age-matched controls and was statistically significant (P = 0.018). There was no significant difference in the total number of second primary malignancies between treatment arms. Melphalan appeared to be associated with an increased risk of developing leukemia/myelodysplastic syndrome compared to the whole abdominal radiotherapy arm (P = 0.06). CONCLUSIONS: Long-term follow-up has not demonstrated a significant difference in overall or disease free survival between treatment arms. An excess of second primary malignancies (35%) was observed suggesting that lifelong surveillance is required in this population. Further research with newer treatment programs are needed to improve the cure rates in this population.

Does a visible retinal embolus increase the likelihood of hemodynamically significant carotid artery stenosis in patients with acute retinal arterial occlusion?

OBJECTIVE: To determine the value of visible retinal emboli as a diagnostic "test" for the detection of hemodynamically significant carotid artery stenosis in the setting of acute retinal artery occlusion. METHODS: A cross-sectional diagnostic accuracy study was performed in a tertiary North American center, with the results of the dichotomous diagnostic test (the presence or absence of visible retinal emboli) being placed against the dichotomous outcome of the presence or absence of hemodynamically significant carotid artery stenosis (defined as > or = 60%, or < 60%, carotid artery stenosis on either side). RESULTS: Forty-eight (18.7%) of our 256 patients had hemodynamically significant carotid artery stenosis. The sensitivity and specificity of retinal emboli for the detection of hemodynamically significant carotid artery stenosis were 39% and 68%, respectively. The presence of a visible retinal embolus generated a likelihood ratio of 1.24 (95% confidence interval, 0.84-1.86). This value corresponds to a patient with a pretest probability of 50% having a posttest probability of 55.3%. The absence of a visible retinal embolus generated a likelihood ratio of 0.88 (95% confidence interval, 0.68-1.15). CONCLUSIONS: The presence of a visible retinal embolus is a poor diagnostic test for the detection of hemodynamically significant carotid artery stenosis in the setting of acute retinal artery occlusion. Accordingly, the presence of an embolus should not influence the decision to perform carotid Doppler ultrasonography in patients with acute retinal arterial occlusion.

Can different types of retinal emboli be reliably differentiated from one another? An inter- and intraobserver agreement study.

OBJECTIVE: To determine whether ophthalmologists can agree on the qualitative assessment of visible retinal emboli. DESIGN: Inter- and intraobserver agreement study. SETTING: The retina and vitreous subspecialty session at the 1996 Canadian Ophthalmological Society meeting. SUBJECTS: A total of 42 observers, of whom 30 were retinal specialists. OUTCOME MEASURES: The observers viewed 17 fundus photographs of 11 patients with embolic acute retinal artery occlusion and classified the visible retinal emboli into one of three groups: cholesterol, calcific or other. RESULTS: Overall, there was slight agreement for the 17 observations (mean kappa = 0.063). The kappa statistic for all cases ranged from slight to fair agreement. Slight interobserver agreement for the six unique photographs was observed (mean kappa = 0.073). Slight intraobserver agreement was found for the three photographs that were shown in different orientations (mean kappa = 0.041) and for the two photographs shown with differing magnification (mean kappa = 0.102). CONCLUSIONS: Overall both intraobserver and interobserver agreement on the qualitative assessment of retinal emboli was poor. With only slight agreement on the classification of emboli, systemic evaluation of acute retinal artery occlusion should not be based on qualitative assessment of retinal emboli.

Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. International Database on Hodgkin's Disease Overview Study Group.

DESIGN: To perform a meta-analysis of all randomized trials that compared chemotherapy (CT) alone versus combined modality treatment (CT + radiotherapy [RT]) for which individual patient data could be made available. PATIENTS AND METHODS: Data on 1,740 patients treated on 14 different trials that included 16 relevant comparisons have been analysed. Eight comparisons were designed to evaluate the benefit of additional RT after the same CT (CT1 v CT1 + RT; additional RT design). Eight comparisons were designed to evaluate whether RT in a combined modality setting can be substituted by CT using either more cycles of the same CT or regimens that contain additional drugs (CT1 + CT2 v CT1 + RT or CT1 v CT2 + RT; parallel RT/CT design). RESULTS: Additional RT showed an 11% overall improvement in tumor control rate after 10 years (P = .0001; 95% confidence interval [CI], 4% to 18%). No difference could be detected with respect to overall survival (P = .57; 95% CI, -10% to 4%). In contrast, when combined modality treatment was compared with CT alone in the parallel-design trials, no difference could be detected in tumor control rates (P = .43; 95% CI, -6% to 9%), but overall survival was significantly better after 10 years in the group that did not receive RT (P = .045; 8% difference; 95% CI, 1% to 15%). There were significantly fewer fatal events among patients in continuous complete remission (relative risk [RR], 1.73; 95% CI, 1.17 to 2.53; P = .005) if no RT was given. CONCLUSION: Combined modality treatment in patients with advanced-stage Hodgkin's disease overall has a significantly inferior long-term survival outcome than CT alone if CT is given over an appropriate number of cycles. The role of RT in this setting is limited to specific indications.

Fatigue in patients with cancer: results with National Cancer Institute of Canada Clinical Trials Group studies employing the EORTC QLQ-C30.

The purpose of this study was to examine the factors which affect the level of fatigue among patients participating in clinical trials in which this symptom had been assessed with the EORTC QLQ-C30. Data were assembled from 2390 patients in ten clinical trials in which the QLQ-C30 had been used to assess baseline and on-study quality of life. The relationship between the level of fatigue reported by the patients on the fatigue scale of this questionnaire and patient and disease characteristics was assessed in univariate and multivariate cross-sectional analyses. In addition, changes in fatigue scores were compared in a longitudinal analysis among patients on two arms of an anti-emetic trial whose emesis control was markedly different. Baseline fatigue levels differed substantially among patients taking part in the different trials. Factors associated with greater fatigue severity on univariate analysis included: female gender, presence of metastatic disease, and poorer performance status. In addition, on multivariate analyses the oldest patients were found to have less fatigue, as were patients with breast cancer, while patients with ovarian and lung cancer experienced greater fatigue. Patients on the arm of the anti-emetic trial in which emesis was better controlled showed significantly less increase in fatigue after receiving chemotherapy. The fatigue scale of the QLQ-C30 appears to provide a useful approach to assessing this important symptom. The relationships found between fatigue and patient and disease characteristics need further exploration as does the degree to which the QLQ-C30 fully captures this dimension of quality of life.

Phase III double-blind comparison of dolasetron mesylate and ondansetron and an evaluation of the additive role of dexamethasone in the prevention of acute and delayed nausea and vomiting due to moderately emetogenic chemotherapy.

PURPOSE: To compare the efficacy of dolasetron and ondansetron in controlling nausea and vomiting in the first 24 hours; to evaluate the efficacy when dexamethasone is added to either drug in the first 24 hours; and to extend these comparisons over 7 days in patients receiving moderately emetogenic chemotherapy. PATIENTS AND METHODS: This was a multicenter, double-blind, randomized study with six parallel arms that used a 2 x 2 factorial design in chemotherapy-naive patients. In arm 1, dolasetron (2.4 mg/kg) was given intravenously (I.V.) prechemotherapy, followed 24 hours later by oral dolasetron (200 mg once daily) for 6 days. Arms 2 and 3 consisted of dolasetron and dexamethasone 8 mg I.V., followed 24 hours later by oral dexamethasone (8 mg once daily) in one arm, and oral dexamethasone and dolasetron in the other, also for 6 days. In arms 4, 5, and 6, ondansetron (32 mg I.V. or 8 mg orally twice daily) was administered in a similar manner to arms 1, 2, and 3 before and 24 hours after chemotherapy. Mean nausea severity (MNS) was assessed on a visual analog scale (VAS) in a daily diary. RESULTS: Of 703 patients enrolled, 696 were eligible. There were 343 dolasetron- and 353 ondansetron-treated patients; 57% of dolasetron-treated patients had complete protection in the first 24 hours versus 67% of patients who received ondansetron (P = .013). MNS was also more pronounced on the dolasetron arm (P = .051). Sixty-seven percent of patients who received added dexamethasone in the first 24 hours had complete protection, compared with 55% without dexamethasone (P < .001). MNS was significantly reduced with the addition of dexamethasone (P < .001). At 7 days, dolasetron and ondansetron had equivalent complete protection rates (36% and 39%, respectively). With the addition of dexamethasone, 48% of patients compared with 28% had complete protection (P < .001). MNS was significantly improved with added dexamethasone (P < .001). CONCLUSION: At the doses used, dolasetron was significantly less effective than ondansetron at controlling nausea and vomiting in the first 24 hours in patients receiving moderately emetogenic chemotherapy, but there was no demonstrable difference between both drugs over 7 days. The addition of dexamethasone significantly improved the efficacy of both drugs in the first 24 hours and over 7 days.

Extent and variation of omeprazole prescribing in an elderly population of Ontario.

OBJECTIVE: To determine the extent of omeprazole prescribing in the senior population of Ontario over a 1-year period; the variation in omeprazole prescribing for this population according to age group, gender, and geographic region: and the extent of inappropriate prescribing of omeprazole for this population. DESIGN: Retrospective drug utilization review of prescription drug insurance claims. DATA SOURCE: The Ontario Drug Benefit (ODB) program claims database. OUTCOME MEASURES: The following outcomes were measured: the proportion of seniors in Ontario who received a prescription for omeprazole from April 1, 1992 to March 31, 1993: effects of age group, gender, and geographic region of residence on omeprazole prescribing; and the extent of inappropriate omeprazole prescribing according to the ODB criteria for use. Prescribing of omeprazole was defined as inappropriate if a first-line antiulcer drug (i.e., histamine2-receptor antagonist) was not prescribed within 1-6 months of the first prescription claim for omeprazole. RESULTS: A total of 29,936 seniors in Ontario received omeprazole from April 1, 1992 to March 31, 1993 (2.53 recipients per 100 eligible population). The age-gender group most frequently prescribed omeprazole was women 65-74 years, followed by women and men 75 years or older, and then men 65-74 years. Omeprazole prescribing varied widely among the 48 provincial counties (range of 1.66 recipients per 100 eligible population to 4.52 recipients per 100 population, p < 0.001). There was no evidence of a clustering effect in omeprazole prescribing at the county level. Prescribing of omeprazole was considered to be inappropriate for 80.5% of recipients. CONCLUSIONS: This study demonstrated the ineffectiveness of the ODB limited-use program in controlling omeprazole prescribing. Further study should be done to examine determinants of variation in prescribing by geographic region.

Quality of life scores: an independent prognostic variable in a general population of cancer patients receiving chemotherapy. The National Cancer Institute of Canada Clinical Trials Group.

This report examines the prognostic associations between QOL scores measured by the EORTC QLQ-C30 and survival in a large heterogeneous population of cancer patients. Eight hundred and fifty-one cancer patients who were to receive chemotherapy were enrolled in two National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) antiemetic trials. All patients completed the EORTC QLQ-C30 immediately prior to their first chemotherapy. Survival data were available and obtained for 474 of 639 patients (74%). Cox's proportional hazards model was used to assess the independent impact of QOL and demographic variables on survival. Presence of metastatic disease, diagnosis of lung or ovarian cancer, ECOG performance status, global quality of life and emotional functioning were significantly associated with survival. Global QOL was predictive in all patients, in subgroups of patients with metastatic disease, with breast and lung cancer and other tumour types. In patients with low global quality of life scores, patients with low emotional functioning ratings lived longer than did patients with high emotional functioning ratings. Patients with high global QOL live significantly longer than do patients with low global QOL. The relationship between emotional functioning in patients with low global QOL and survival needs confirmation.

The role of the 5-HT3 antagonists ondansetron and dolasetron in the control of delayed onset nausea and vomiting in patients receiving moderately emetogenic chemotherapy.

BACKGROUND: 5-HT3 antagonists are effective in reducing the acute nausea and vomiting caused by cancer chemotherapy. However, it is not clear whether continuing these agents beyond twenty four hours is useful in controlling emesis on days two to seven after chemotherapy. PATIENTS AND METHODS: Four hundred seven patients receiving moderately emetogenic chemotherapy who had been given dexamethasone 8 mg i.v. and either ondansetron 32 mg i.v. or dolasetron 2.4 mg/kg i.v. were randomized to continue either an oral form of their 5-HT3 antagonist (ondansetron 8 mg b.i.d. or dolasetron 200 mg daily) plus dexamethasone 8 mg p.o. daily or dexamethasone alone for days two to seven. Endpoints assessed by self-report were: 1) complete control (no vomiting, no rescue medications, no missing data) of emesis; 2) nausea severity; and 3) quality-of-life as measured by the EORTC QLQ-C30. RESULTS: Continuation of 5-HT3 antagonists improved slightly, but not significantly, the complete control rate (47% vs. 41%: P = 0.24 one-sided) after chemotherapy. However, mean nausea severity was significantly (P = 0.015 one sided) reduced (by 3 mm on a 10 cm scale) on the combined arm. Minimal differences in quality of life were observed. CONCLUSION: The benefit of continuing 5-HT3 antagonists beyond 24 hours is modest and the merits of routine use in these circumstances debatable.

The role of palliative radiotherapy for brain metastases.

Brain metastases (BRM) are common complications of malignancy, frequently associated with disability and death. Clinical trials have addressed a few of the issues arising from treatment options for BRM. Phase III trials have shown superior survival for patients with solitary resectable BRM (SRBRM) when palliative radiation treatment (RT) to the brain is preceded by resection compared to brain RT alone, but no trial has explored resection plus brain RT compared to resection alone. One Phase III trial in patients with solitary unresected BRM comparing lower to higher doses of RT has shown a small survival advantage with higher-dose radiotherapy. All other trials, however, comparing different radiation doses and fractionation schedules have failed to indicate improved outcomes from treatment more intense than 2000 cGy in 5 fractions over 1 week (in any subset of patients with unresected BRM). A panel of radiation oncologists and medical oncologists discussed a literature review and results of Phase III trials of therapy for BRM. The panel was instructed to identify from these trials any evidence for the efficacy, indications, toxicity and fractionation of palliative RT for BRM. The panel concluded that unresected BRM is a possible indication for brain RT. The panel concluded that the benefits and toxicities of brain RT for unresected BRM are not characterized adequately to allow a stronger recommendation. The panel concluded that there is no evidence for superiority for any dose or schedule of brain RT for BRM more protracted or intense than 2000 cGy in 5 fractions over one week. The panel recommended further study in order to characterize the benefits and toxicities of brain RT for unresectable BRM. The panel considered the potential value of conducting a Phase III trial comparing palliative care and strategies that included brain RT to the same strategies excluding brain RT; the panel did not, however, reach consensus on the feasibility of such a trial.