Development and application of statistical methods for population-based cancer patient survival

The overarching aim of this work has been to develop and apply statistical methods for estimating cancer patient survival from population-based register data. Particular focus has been on statistical methods that can be used for presenting cancer survival statistics from administrative health data registers in a manner that is relevant for physicians and patients. Study 1: In this study we clarify and discuss the relative merits of estimates of crude and net cancer patient survival, respectively. In addition, we demonstrate how period analysis, applied in a competing risks setting, can be utilised to predict crude survival probabilities applicable to newly diagnosed cancer patients. As a motivating clinical example, we use data from the National Prostate Cancer Register to assess the impact of prognostic factors on the risk of prostate cancer death in relation to death from other causes than prostate cancer, and event-free survival, among recently diagnosed patients. We conclude that the period estimates of crude survival o er a useful basis for risk communication between physicians and clinicians and advocate their use as means to answer prognostic questions. Study 2: Late adverse health e ects in cancer patients are a growing problem given the longer survival seen for most cancers. Deaths that occur as a consequence of treatment toxicity can be regarded as indirect deaths due to cancer. In this methodological study we extend exible parametric survival models for relative survival by partitioning the overall excess mortality from cancer into two component parts; excess mortality from diseases of the circulatory system, DCS, (assumed caused by the treatment), and remaining excess cancer mortality. We present summary measures for quantifying the risk for death from late e ects of treatment relative to the overall risk of dying of breast cancer, or causes unrelated to the cancer. The method is illustrated using data obtained from the Swedish Cancer Register on women diagnosed with breast cancer in Sweden between 1973 and 1992. Study 3: Survival after Hodgkin lymphoma has increased substantially in the past four decades, following the development of e ective multi-agent chemotherapy, introduction of combinedmodality therapy with reductions in radiation eld size and dose, and more apt evaluation of treatment response. The aim of this study was to present clinically interpretable estimates of temporal trends in the burden of fatal excess DCS mortality among Hodgkin lymphoma survivors who were treated in the 1970's through 1990's, and to predict the future clinical burden among patients diagnosed more recently. Using data from the Swedish Cancer Registry we showed how the excess DCS mortality, within 20 years after diagnosis, has decreased continually since the mid-1980s and is expected to further decrease among patients diagnosed in the modern era. However, when accounting for competing causes of death, we found that excess DCS mortality constitutes a relatively small proportion of the overall mortality among Hodgkin lymphoma patients in Sweden. Study 4: In this study we show how recently developed exible parametric cure models, combined with competing risks theory, can be used to estimate crude probabilities that cancer patients who are alive will eventually die from their cancer, or from other causes, respectively. Moreover, we show how to 'update' the prognosis for patients who have survived some time after their diagnosis via the use of conditional probabilities. The method is discussed and demonstrated using data from the Swedish Cancer Register on patients diagnosed with melanoma, colon cancer and acute myeloid leukemia between 1973 and 2007

Estimating and modelling cure in population-based cancer studies within the framework of flexible parametric survival models

<p>Abstract</p> <p>Background</p> <p>When the mortality among a cancer patient group returns to the same level as in the general population, that is, the patients no longer experience excess mortality, the patients still alive are considered "statistically cured". Cure models can be used to estimate the cure proportion as well as the survival function of the "uncured". One limitation of parametric cure models is that the functional form of the survival of the "uncured" has to be specified. It can sometimes be hard to find a survival function flexible enough to fit the observed data, for example, when there is high excess hazard within a few months from diagnosis, which is common among older age groups. This has led to the exclusion of older age groups in population-based cancer studies using cure models.</p> <p>Methods</p> <p>Here we have extended the flexible parametric survival model to incorporate cure as a special case to estimate the cure proportion and the survival of the "uncured". Flexible parametric survival models use splines to model the underlying hazard function, and therefore no parametric distribution has to be specified.</p> <p>Results</p> <p>We have compared the fit from standard cure models to our flexible cure model, using data on colon cancer patients in Finland. This new method gives similar results to a standard cure model, when it is reliable, and better fit when the standard cure model gives biased estimates.</p> <p>Conclusions</p> <p>Cure models within the framework of flexible parametric models enables cure modelling when standard models give biased estimates. These flexible cure models enable inclusion of older age groups and can give stage-specific estimates, which is not always possible from parametric cure models.</p

A multi-state model incorporating estimation of excess hazards and multiple time scales

As cancer patient survival improves, late effects from treatment are becoming the next clinical challenge. Chemotherapy and radiotherapy, for example, potentially increase the risk of both morbidity and mortality from second malignancies and cardiovascular disease. To provide clinically relevant population-level measures of late effects, it is of importance to (1) simultaneously estimate the risks of both morbidity and mortality, (2) partition these risks into the component expected in the absence of cancer and the component due to the cancer and its treatment, and (3) incorporate the multiple time scales of attained age, calendar time, and time since diagnosis. Multi-state models provide a framework for simultaneously studying morbidity and mortality, but do not solve the problem of partitioning the risks. However, this partitioning can be achieved by applying a relative survival framework, by allowing is to directly quantify the excess risk. This paper proposes a combination of these two frameworks, providing one approach to address (1)-(3). Using recently developed methods in multi-state modeling, we incorporate estimation of excess hazards into a multi-state model. Both intermediate and absorbing state risks can be partitioned and different transitions are allowed to have different and/or multiple time scales. We illustrate our approach using data on Hodgkin lymphoma patients and excess risk of diseases of the circulatory system, and provide user-friendly Stata software with accompanying example code

Incidence and time trends of second primary malignancies after non-Hodgkin lymphoma:a Swedish population-based study

Considering treatment changes and an improved prognosis of non-Hodgkin lymphoma (NHL) over time, knowledge regarding long-term health outcomes, including late effects of treatment, has become increasingly important. We report on time trends of second primary malignancies (SPMs) in Swedish NHL patients, encompassing the years before as well as after the introduction of anti-CD20 antibody therapy. We identified NHL patients in the Swedish Cancer Register 1993 to 2014 and matched comparators from the Swedish Total Population Register. The matched cohort was followed through 2017. By linking to the Swedish Lymphoma Register, subcohort analyses by NHL subtype were performed. Flexible parametric survival models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of SPM among patients and comparators. Among 32 100 NHL patients, 3619 solid tumors and 217 myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) cases were observed, corresponding to a 40% higher rate of solid tumors (HR(solid tumors) = 1.4; 95% CI, 1.4-1.5) and a 5-fold higher rate of MDS/AML (HR(MDS/AML )= 5.2; 95% CI, 4.4-6.2) than for comparators. Overall, the observed excess risks for solid tumors or MDS/AML remained stable over the study period, except for follicular lymphoma, where the excess rate of MDS/AML attenuated with time (P for trend = .012). We conclude that NHL survivors have an increased risk of both solid tumors and hematologic malignancies, in particular MDS/AML. Stable excess risks over time indicate that contemporary treatment standards are not associated with modified SPM risk. Encouragingly, decreasing rates of MDS/AML were noted among patients with follicular lymphoma, possibly due to the increasing use of nonchemotherapy-based treatments

Patterns of survival among patients with myeloproliferative neoplasms diagnosed in Sweden from 1973 to 2008: a population-based study.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Reported survival in patients with myeloproliferative neoplasms (MPNs) shows great variation. Patients with primary myelofibrosis (PMF) have substantially reduced life expectancy, whereas patients with polycythemia vera (PV) and essential thrombocythemia (ET) have moderately reduced survival in most, but not all, studies. We conducted a large population-based study to establish patterns of survival in more than 9,000 patients with MPNs. We identified 9,384 patients with MPNs (from the Swedish Cancer Register) diagnosed from 1973 to 2008 (divided into four calendar periods) with follow-up to 2009. Relative survival ratios (RSRs) and excess mortality rate ratios were computed as measures of survival. Patient survival was considerably lower in all MPN subtypes compared with expected survival in the general population, reflected in 10-year RSRs of 0.64 (95% CI, 0.62 to 0.67) in patients with PV, 0.68 (95% CI, 0.64 to 0.71) in those with ET, and 0.21 (95% CI, 0.18 to 0.25) in those with PMF. Excess mortality was observed in patients with any MPN subtype during all four calendar periods (P < .001). Survival improved significantly over time (P < .001); however, the improvement was less pronounced after the year 2000 and was confined to patients with PV and ET. We found patients with any MPN subtype to have significantly reduced life expectancy compared with the general population. The improvement over time is most likely explained by better overall clinical management of patients with MPN. The decreased life expectancy even in the most recent calendar period emphasizes the need for new treatment options for these patients.Swedish Cancer Society CAN 2009/1203 Stockholm County Council SLL 20090201 Karolinska Institutet SLL 20090201 Karolinska Institutet Foundations 2009Fobi0072 Shire Pharmaceuticals Adolf H. Lundin Charitable Foundatio

Маркетинг инноваций как инструмент активизации трансфера знаний

Модель «Тройная спираль» (Triple Helix Model (THM)), основанная на исследовании сложного взаимодействия университетов, бизнеса и власти, является современной моделью развития инновационных систем. В модели ТНМ ведущее значение отводится университетам, которые превращаются в предпринимательские университеты и через собственные каналы для трансфера знаний применяют знания на практике и вкладывают результаты в новые образовательные дисциплины. Университеты все чаще становятся залогом успешного экономического развития региона

Association of varying number of doses of quadrivalent human papillomavirus vaccine with incidence of condyloma

IMPORTANCE Determining vaccine dose-level protection is essential to minimize program costs and increase mass vaccination program feasibility. Currently, a 3-dose vaccination schedule is recommended for both the quadrivalent and bivalent human papillomavirus (HPV) vaccines. Although the primary goal of HPV vaccination programs is to prevent cervical cancer, condyloma related to HPV types 6 and 11 is also prevented with the quadrivalent vaccine and represents the earliest measurable preventable disease outcome for the HPV vaccine. OBJECTIVE To examine the association between quadrivalent HPV vaccination and first occurrence of condyloma in relation to vaccine dose in a population-based setting. DESIGN, SETTING, AND PARTICIPANTS An open cohort of all females aged 10 to 24 years living in Sweden (n = 1 045 165) was followed up between 2006 and 2010 for HPV vaccination and first occurrence of condyloma using the Swedish nationwide population-based health data registers. MAIN OUTCOMES AND MEASURES Incidence rate ratios (IRRs) and incidence rate differences (IRDs) of condyloma were estimated using Poisson regression with vaccine dose as a time-dependent exposure, adjusting for attained age and parental education, and stratified on age at first vaccination. To account for prevalent infections, models included a buffer period of delayed case counting. RESULTS A total of 20 383 incident cases of condyloma were identified during follow-up, including 322 cases after receipt of at least 1 dose of the vaccine. For individuals aged 10 to 16 years at first vaccination, receipt of 3 doses was associated with an IRR of 0.18 (95% CI, 0.15-0.22) for condyloma, whereas receipt of 2 doses was associated with an IRR of 0.29 (95% CI, 0.21-0.40). One dose was associated with an IRR of 0.31 (95% CI, 0.20-0.49), which corresponds to an IRD of 384 cases (95% CI, 305-464) per 100 000 person-years, compared with no vaccination. The corresponding IRDs for 2 doses were 400 cases (95% CI, 346-454) and for 3 doses, 459 cases (95% CI, 437-482). The number of prevented cases between 3 and 2 doses was 59 (95% CI, 2-117) per 100 000 person-years. CONCLUSIONS AND RELEVANCE Although maximum reduction in condyloma risk was seen after receipt of 3 doses of quadrivalent HPV vaccine, receipt of 2 vaccine doses was also associated with a considerable reduction in condyloma risk. The implications of these findings for the relationship between number of vaccine doses and cervical cancer risk require further investigation

Relative and absolute cancer risks among Nordic kidney transplant recipients-a population-based study

Kidney transplant recipients (KTRs) have an increased cancer risk compared to the general population, but absolute risks that better reflect the clinical impact of cancer are seldom estimated. All KTRs in Sweden, Norway, Denmark, and Finland, with a first transplantation between 1995 and 2011, were identified through national registries. Post-transplantation cancer occurrence was assessed through linkage with cancer registries. We estimated standardized incidence ratios (SIR), absolute excess risks (AER), and cumulative incidence of cancer in the presence of competing risks. Overall, 12 984 KTRs developed 2215 cancers. The incidence rate of cancer overall was threefold increased (SIR 3.3, 95% confidence interval [CI]: 3.2-3.4). The AER of any cancer was 1560 cases (95% CI: 1468-1656) per 100 000 person-years. The highest AERs were observed for nonmelanoma skin cancer (838, 95% CI: 778-901), non-Hodgkin lymphoma (145, 95% CI: 119-174), lung cancer (126, 95% CI: 98.2-149), and kidney cancer (122, 95% CI: 98.0-149). The five- and ten-year cumulative incidence of any cancer was 8.1% (95% CI: 7.6-8.6%) and 16.8% (95% CI: 16.0-17.6%), respectively. Excess cancer risks were observed among Nordic KTRs for a wide range of cancers. Overall, 1 in 6 patients developed cancer within ten years, supporting extensive post-transplantation cancer vigilance.Peer reviewe

Risk of diabetes and the impact on preexisting diabetes in patients with lymphoma treated with steroid-containing immunochemotherapy

First-line treatments for lymphomas often include high doses of prednisolone, but the risks of new-onset diabetes mellitus (DM) or worsening of preexisting DM following treatment with cyclic high dose corticosteroids is unknown. This cohort study matched non-Hodgkin lymphoma (NHL) patients treated with steroid-containing immunochemotherapy (ie, R-CHOP[-like] and R-CVP) between 2002 and 2015 to individuals from the Danish population to investigate the risks of new-onset DM. For patients with preexisting DM, the risks of insulin dependency and anthracycline-associated cardiovascular diseases (CVDs) were assessed. In total, 5672 NHL patients and 28 360 matched comparators were included. Time-varying incidence rate ratios (IRRs) showed increased risk of DM in the first year after treatment compared with matched comparators, with the highest IRR being 2.7. The absolute risks were higher among patients in the first 2 years, but the difference was clinically insignificant. NHL patients with preexisting DM had increased risks of insulin prescriptions with 0.5-, 5-, and 10-year cumulative risk differences of insulin treatment of 15.3, 11.8, and 6.0 percentage units as compared with the DM comparators. In a landmark analysis at 1 year, DM patients with lymphoma had decreased risks of insulin dependency compared with comparators. Time-varying IRRs showed a higher CVD risk for NHL patients with DM as compared with comparators in the first year after treatment. NHL patients treated with steroid-containing immunochemotherapy regimens have a clinically insignificant increased risk of DM in the first year following treatment, and patients with preexisting DM have a temporary increased risk of insulin prescriptions and CVD