Outlier robust modeling of survival curves in the presence of potentially time-varying coefficients.

In time to event studies, censoring often occurs and models that take this into account are wide-spread. In the presence of outliers, standard estimators of model parameters may be affected such that results and conclusions are not reliable anymore. This in turn also hampers the detection of these outliers due to masking effects. To cope with outliers when using proportional hazard models, we propose to use the Brier score as a loss function. Since the coefficients often vary over time, we focus on the piecewise constant hazard model, which can flexibly model time-varying coefficients if a large number of cut-points is used. To prevent overfitting, we add a penalty term that potentially shrinks time-varying effects to constant effects. By fitting the coefficients of the piecewise constant hazard model using a penalized Brier score loss, we obtain a robust model that can handle time-varying coefficients. Its good performance is illustrated in a simulation study and using two datasets from practice.

Relapse Risk and Loss of Lifetime After Modern Combined Modality Treatment of Young Patients With Hodgkin Lymphoma: A Nordic Lymphoma Epidemiology Group Study.

PURPOSE: Estimates of short- and long-term survival for young patients with classic Hodgkin lymphoma (cHL) are of considerable interest. We investigated cHL prognosis in the era of contemporary treatment at different milestones during the follow-up. PATIENTS AND METHODS: On the basis of a Nordic cohort of 2,582 patients diagnosed at ages 18 to 49 years between 2000 and 2013, 5-year relapse risks and 5-year restricted losses in expectation of lifetime were estimated for all patients and for patients who achieved event-free survival (EFS) for 12 (EFS12), 24 (EFS24), 36 (EFS36) or 60 (EFS60) months. The median follow-up time was 9 years (range, 2.9 to 16.8 years). RESULTS: The 5-year overall survival was 95% (95% CI, 94% to 96%). The 5-year risk of relapse was 13.4% (95% CI, 12.1% to 14.8%) overall but decreased to 4.2% (95% CI, 3.8% to 4.6%) given that patients reached EFS24. Relapse risk for patients treated with six to eight courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) was comparable to that of patients treated with six to eight courses of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) despite more adverse risk criteria among patients treated with BEACOPP. Both from diagnosis and if EFS24 was reached, the losses in expectation of lifetime during the following 5 years were small (from diagnosis, 45 days [95% CI, 35 to 54 days] and for patients who reached EFS24, 13 days [95% CI, 7 to 20 days]). In stage-stratified analyses of 5-year restricted loss in expectation of lifetime, patients with stages I to IIA disease had no noteworthy excess risk of death after they reached EFS24, whereas risk remained measurable for patients with stages IIB to IV cHL. CONCLUSION: Real-world data on young patients with cHL from the Nordic countries show excellent outcomes. The outlook is particularly favorable for patients who reach EFS24, which supports limited relapse-oriented clinical follow-up.

Limited value of routine follow-up visits in chronic lymphocytic leukemia managed initially by watch and wait: A North Denmark population-based study.

INTRODUCTION: The majority of newly diagnosed chronic lymphocytic leukemia (CLL) patients are followed initially by watch and wait (WAW). Clinical practice varies and the value of frequent follow-up visits remains unclear. Thus, in this study we investigated the clinical value of follow-up visits for patients with CLL. METHODS: We collected data from diagnosis and follow-up visits for patients diagnosed with CLL and managed by WAW in the North Denmark Region between 2007-2014. High- and low-risk group patients were determined by Binet stage, IgVH status, and cytogenetics at diagnosis. The effect of risk group allocation on the probability of receiving CLL-directed treatment within two years was included in a multivariable logistic regression model adjusted for age and blood test results. RESULTS: 273 patients were included in the study with a median follow-up of 3 years (IQR: 1.6-5.4). Overall, the median interval between follow-up visits was 98 days (95% CI: 96-100) (high-risk patients: 91 days [95% CI: 86-95] vs. low-risk patients: 105 days [95% CI: 100-110]). Among 2,312 follow-up visits, only 387 (17%) were associated with interventions. At the following time points: 6 months, 1 year, and 1.5 years, patients with low-risk CLL had significantly lower odds of initiating treatment compared to patients with high-risk CLL. CONCLUSION: WAW plays an important role in managing CLL. Interventions at follow-up visits were infrequent and low-risk patients had significantly lower risk of treatment initiation. We question the value of routine follow-up in CLL in the absence of changes in symptoms and/or blood test results.