Mary Lesperance

PIECEWISE REGRESSION: A TOOL FOR IDENTIFYING ECOLOGICAL THRESHOLDS

We demonstrate the use of piecewise regression as a statistical technique to model ecological thresholds. Recommended procedures for analysis are illustrated with a case study examining the width of edge effects in two understory plant communities. Piece-wise regression models are “broken-stick” models, where two or more lines are joined at unknown points, called “breakpoints.” Breakpoints can be used as estimates of thresholds and are used here to determine the width of edge effects. We compare a sharp-transition model with three models incorporating smooth transitions: the hyperbolic-tangent, bent-hyperbola, and bent-cable models. We also calculate three types of confidence intervals for the breakpoint estimate: an interval based on the computed standard error of the estimate from the fitting procedure, an empirical bootstrap confidence interval, and a confidence interval derived from an inverted F test. We recommend use of the inverted F test confidence interval when sample sizes are large, and cautious use of bootstrapped confidence intervals when sample sizes are smaller. Our analysis demonstrates the need for a careful study of the likelihood surface when fitting and interpreting the results from piecewise-regression models.

DO AGE AND COMORBIDITY IMPACT TREATMENT ALLOCATION AND OUTCOMES IN LIMITED STAGE SMALL-CELL LUNG CANCER? A COMMUNITY-BASED POPULATION ANALYSIS

PURPOSE The effects of age and comorbidity on treatment and outcomes for patients with limited stage small-cell lung cancer (L-SCLC) are unclear. This study analyzes relapse and survival in a community-based population with L-SCLC according to age and comorbidity. METHODS A retrospective review was performed on 174 patients with L-SCLC referred to the British Columbia Cancer Agency, Vancouver Island Centre, between January 1991 and December 1999. Patient and treatment characteristics, disease response, relapse, and survival were compared among three age cohorts: <65 years (n = 55, 32%), 65-74 years (n = 76, 44%), and > or =75 years (n = 43, 25%); and according to Charlson comorbidity scores 0, 1, and > or =2. Multivariate analysis was performed to identify independent prognostic factors associated with treatment response and survival. RESULTS Patient factors that significantly differed with age were functional status classified by Eastern Cooperative Oncology Group performance status and number of comorbidities. Increasing age was significantly associated with fewer diagnostic scans. Combined modality chemoradiotherapy (CRT) was given in 86%, 66%, and 40% of patients ages <65, 65-74, and > or =75 years, respectively, (p <0.0001). Thoracic irradiation use was comparable among the age cohorts (p >0.05), but chemotherapy use varied significantly with less intensive regimens, fewer cycles, and lower total doses with advancing age (p <0.05). Prophylactic cranial irradiation (PCI) was used in 41 patients, only 3 of whom were age >70 years. Overall response rates to primary treatment significantly decreased with advancing age: 91%, 79%, and 74% in patients ages <65, 65-74, and > or =75 years, respectively (p = 0.014). Treatment toxicity and relapse patterns were similar across the age cohorts. Overall 2-year survival rates were significantly lower with advancing age: 37%, 22%, and 19% (p = 0.003), with corresponding median survivals of 17, 12, and 7 months among patients ages <65, 65-74, and > or =75 years, respectively. On multivariate analysis, age and Charlson comorbidity scores were not significantly associated with treatment response and survival. Independent prognostic factors favorably associated with survival were good performance status, normal lactate dehydrogenase, absence of pleural effusion, and > or =four cycles of chemotherapy. CONCLUSION Increasing age was associated with decreased performance status and increased comorbidity. Older patients with L-SCLC were less likely to be treated with CRT, intensive chemotherapy, and PCI. Treatment response and survival rates were lower with advancing age, but this may be attributed to poor performance status and suboptimal treatment rather than age.

Mega-dose vitamins and minerals in the treatment of non-metastatic breast cancer: an historical cohort study

AbstractBackground. Alternative therapies such as mega-dose vitamins and minerals are commonly used by women with breast cancer, but their effect on recurrence and survival have rarely been evaluated. Methods. Survival and recurrence outcomes for 90 women with unilateral non-metastatic breast cancer diagnosed between 1989 and 1998, and who had been prescribed mega-doses of beta-carotene, vitamin C, niacin, selenium, coenzyme Q10, and zinc in addition to standard therapies were compared with matched controls. The 90 treated patients were prescribed combinations from three to six of the vitamins and minerals listed above. The controls were matched (2:1) to the vitamin/mineral patients for age at diagnosis, presence of axillary lymph node metastasis, tumor stage, grade, estrogen receptor status, year of diagnosis, and prescription of systemic therapy. All subjects were patients of the British Columbia Cancer Agency, Vancouver Island Centre. Findings. Median follow-up of surviving patients was 68 months (minimum 20 months, 133 months maximum). The vitamin/mineral patients and controls were well matched. Two endpoints were considered. Breast cancer-specific survival (p = 0.19) and disease-free survival (p = 0.08) times for the vitamin/mineral treated group were shorter, after adjusting for diagnostic variables using a Cox proportional hazards model. The hazard ratios for the vitamin/mineral treated group versus the control group were estimated at 1.75 (95% CI = 0.83–2.69) for disease-specific survival and 1.55 (95% CI = 0.94–2.54) for disease-free survival. Overall survival was similar for the two groups (log-rank test, p = 0.36). Interpretation. Breast cancer-specific survival and disease-free survival times were not improved for the vitamin/mineral treated group over those for the controls.

A reliability and validity study of the Palliative Performance Scale

BackgroundThe Palliative Performance Scale (PPS) was first introduced in1996 as a new tool for measurement of performance status in palliative care. PPS has been used in many countries and has been translated into other languages.MethodsThis study evaluated the reliability and validity of PPS. A web-based, case scenarios study with a test-retest format was used to determine reliability. Fifty-three participants were recruited and randomly divided into two groups, each evaluating 11 cases at two time points. The validity study was based on the content validation of 15 palliative care experts conducted over telephone interviews, with discussion on five themes: PPS as clinical assessment tool, the usefulness of PPS, PPS scores affecting decision making, the problems in using PPS, and the adequacy of PPS instruction.ResultsThe intraclass correlation coefficients for absolute agreement were 0.959 and 0.964 for Group 1, at Time-1 and Time-2; 0.951 and 0.931 for Group 2, at Time-1 and Time-2 respectively. Results showed that the participants were consistent in their scoring over the two times, with a mean Cohens kappa of 0.67 for Group 1 and 0.71 for Group 2. In the validity study, all experts agreed that PPS is a valuable clinical assessment tool in palliative care. Many of them have already incorporated PPS as part of their practice standard.ConclusionThe results of the reliability study demonstrated that PPS is a reliable tool. The validity study found that most experts did not feel a need to further modify PPS and, only two experts requested that some performance status measures be defined more clearly. Areas of PPS use include prognostication, disease monitoring, care planning, hospital resource allocation, clinical teaching and research. PPS is also a good communication tool between palliative care workers.

Use of the Palliative Performance Scale (PPS) for End-of-Life Prognostication in a Palliative Medicine Consultation Service

This study examines the use of the Palliative Performance Scale (PPS) in end-of-life prognostication within a regional palliative care program in a Canadian province. The analysis was done on a prospective cohort of 513 patients assessed by a palliative care consult team as part of an initial community/hospital-based consult. The variables used were initial PPS score, age, gender, diagnosis, cancer type, and survival time. The findings revealed initial PPS to be a significant predictor of survival, along with age, diagnosis, cancer type and site, but not gender. The survival curves were distinct for PPS 10%, 20%, and 30% individually, and for 40%-60% and > or =70% as bands. This is consistent with earlier findings of the ambiguity and difficulty when assessing patients at higher PPS levels because of the subjective nature of the tool. We advocate the use of median survival and survival rates based on a local cohort where feasible, when reporting individual survival estimates.

A review of semiparametric mixture models

The literature on semiparametric mixture models has flourished over the last decade, both in applied and theoretical journals. In this paper, we review examples of important areas of application, and summarize some of the recent developments in maximum likelihood theory, including inference for the mixing distribution and the structural parameters. The theory and applications developed to date suggest that semiparametric mixture models will play an ever expanding role in the field.

Validation of a Web-Based Predictive Nomogram for Ipsilateral Breast Tumor Recurrence After Breast Conserving Therapy

PURPOSE IBTR! version 1.0 is a web-based tool that uses literature-derived relative risk ratios for seven clinicopathologic variables to predict ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT). Preliminary testing demonstrated over-estimation in high-risk subgroups. This study uses two independent population-based datasets to create and validate a modified nomogram, IBTR! version 2.0. METHODS Cox regression modeling was performed on 7,811 patients treated with BCT at the British Columbia Cancer Agency (median follow-up, 9.4 years). Population-based hazard ratios were generated for the seven variables in the original nomogram. A modified nomogram was then tested against 664 patients from Massachusetts General Hospital (median follow-up, 9.3 years). The mean predicted and observed 10-year estimates were compared for the entire cohort and for four groups predefined by nomogram-predicted risks: group 1: less than 3%; group 2: 3% to 5%; group 3: 5% to 10%; and group 4: more than 10%. Results IBTR! version 2.0 predicted an overall 10-year IBTR estimate of 4.0% (95% CI, 3.8 to 4.2), while the observed estimate was 2.8% (95% CI, 1.6 to 4.7; P = .10). The predicted and observed IBTR estimates were: group 1 (n = 283): 2.2% versus 1.3%, P = .40; group 2 (n = 237): 3.8% versus 3.5%, P = .80; group 3 (n = 111): 6.7% versus 3.2%, P = .05; and group 4 (n = 33): 12.5% versus 8.7%, P = .50. CONCLUSION IBTR! version 2.0 is accurate in the majority of patients with a low to moderate risk of in-breast recurrence. The nomogram still overestimates risk in a minority of patients with higher risk features. Validation in a larger prospective data set is warranted.

The effects of age and comorbidity on treatment and outcomes in women with endometrial cancer.

Background:Although the incidence of endometrial cancer increases with age, the effect of patient age on treatment selection and outcomes is unclear. In addition, although aging is associated with increased prevalence of comorbid conditions, the extent to which comorbidities influence endometrial cancer management is not well documented. Methods:This population-based analysis evaluates the effect of age and comorbidity on endometrial cancer treatment and outcome in a cohort of 401 patients referred to the Vancouver Island Centre, British Columbia Cancer Agency from 1989 to 1996. Treatment and 5-year actuarial overall survival (OS) and disease-free survival (DFS) were compared by age at diagnosis (<65, 65–74, and ≥75 years) and comorbidity index (Charlson score 0–1 and ≥2). Results:Median follow-up time was 7.8 years. In this cohort, 148 (37%), 152 (38%), and 101 (25%) were aged <65, 65–74, and ≥75 years, respectively. Charlson comorbidity scores ≥2 were found in 18% of patients. Distributions of disease stage, tumor characteristics, and surgical therapy were similar across age and comorbidity subgroups. Standard surgery in this cohort comprised hysterectomy without routine lymphadenectomy. In stage Ic disease, the use of postoperative RT declined with advanced age (96%, 97%, and 74% in patients aged <65, 65–74, and ≥75 years, respectively, P = 0.05) and with increased comorbidities (91% and 79% in patients with Charlson score 0–1 and ≥2, respectively, P = 0.07). Among stage Ic patients aged ≥75 years, pelvic/vaginal relapse occurred in 2 of 6 patients treated with hysterectomy alone compared with 0 of 20 patients treated with postoperative radiotherapy (P = 0.006). On multivariable Cox modeling, age at diagnosis, performance status, stage, grade, lymphovascular invasion, surgery, and radiotherapy use, but not Charlson comorbidity score, were significant predictors for overall survival. Conclusions:Although surgical therapy for endometrial cancer was not influenced by age or comorbidities, reduced use of postoperative radiotherapy in stage Ic disease was observed among women with advanced age and high comorbidity index. The associated pelvic/vaginal relapse rates were higher in elderly patients not treated with radiotherapy. Chronologic age alone should not preclude patients from consideration of optimal local therapy.

Intervals Longer Than 20 Weeks From Breast-Conserving Surgery to Radiation Therapy Are Associated With Inferior Outcome for Women With Early-Stage Breast Cancer Who Are Not Receiving Chemotherapy

PURPOSE To determine the interval from breast-conserving surgery (BCS) to radiation therapy (RT) that affects local control or survival. PATIENTS AND METHODS The 10-year Kaplan-Meier (KM) local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and breast cancer-specific survival (BCSS) were computed for 6,428 women who had T1 to 2, N0 to 1, M0 breast cancer that was diagnosed in British Columbia between 1989 and 2003, and who were treated with BCS and RT without chemotherapy. Intervals from BCS to RT were grouped by weeks as follows: < or = 4 (n = 83), greater than 4 to 8 (n = 2,288; reference group); greater than 8 to 12 (n = 2,606); greater than 12 to 16 (n = 961); greater than 16 to 20 (n = 358); and greater than 20 weeks (n = 132). Cox proportional hazards models and matching were used to control for confounding variables. RESULTS The median follow-up time was 7.5 years. The 10-year KM outcomes were as follows: LRFS, 95.4%; DRFS, 90.5%; and BCSS, 92.5%. Compared with the greater than 4 to 8 weeks group, hazard ratios (HR) were not significantly different for any outcome among patients who were treated up to 20 weeks after BCS. However, LRFS (hazard ratio [HR], 2.00; P = .15), DRFS (HR, 1.86; P = .02) and BCSS (HR, 2.15; P = .009) were inferior for women with BCS-to-RT intervals greater than 20 weeks compared with those greater than 4 to 8 weeks. The matched analysis yielded similar results. CONCLUSION Outcomes were statistically similar for BCS-to-RT intervals up to 20 weeks, but they were inferior for intervals beyond 20 weeks. Time can be reasonably allowed for the breast to heal and for patients to consider treatment options, but RT should start within 20 weeks of BCS.

Effect of radiotherapy boost and hypofractionation on outcomes in ductal carcinoma in situ.

Boost radiotherapy (RT) improves outcomes for patients with invasive breast cancer, but whether this is applicable to patients with pure ductal carcinoma in situ (DCIS) is unclear. This study examined outcomes from whole breast RT, with or without a boost, and the impact of different dose‐fractionation schedules in a population‐based cohort of women with pure DCIS treated with breast‐conserving surgery (BCS).