Summary Background EUROCARE is the largest population-based cooperative study on survival of patients with cancer. The EUROCARE project aims to regularly monitor, analyse, and explain survival trends ...and between-country differences in survival. This report (EUROCARE-4) presents survival data for eight selected cancer sites and for all cancers combined, diagnosed in adult (aged ≥15 years) Europeans in 1995–99 and followed up until the end of 2003. Methods We analysed data from 83 cancer registries in 23 European countries on 2 699 086 adult cancer cases that were diagnosed in 1995–99 and followed up to December, 2003. We calculated country-specific and mean-weighted age-adjusted 5-year relative survival for eight major cancers. Additionally, case-mix-adjusted 5-year survival for all cancers combined was calculated by countries ranked by total national expenditure on health (TNEH). Changes to survival were analysed relative to cases diagnosed in 1990–94. Findings Mean age-adjusted 5-year relative survival for colorectal (53·8% 95% CI 53·3–54·1), lung (12·3% 12·1–12·5), breast (78·9% 78·6–79·2), prostate (75·7% 75·2–76·2), and ovarian (36·3% 35·7–37·0) cancer was highest in Nordic countries (except Denmark) and central Europe, intermediate in southern Europe, lower in the UK and Ireland, and worst in eastern Europe. Survival for melanoma (81·6% 81·0–82·3), cancer of the testis (94·2% 93·4–95·0), and Hodgkin's disease (80·0% 79·0–81·0) varied little with geography. All-cancer survival correlated with TNEH for most countries. Denmark and UK had lower all-cancer survival than countries with similar TNEH; Finland had high all-cancer survival, but moderate TNEH. Survival increased and intercountry survival differences narrowed between the data for 1990–94 and 1995–99 for, notably, Hodgkin's disease (range 66·1–82·9 IQR 72·2–78·6 vs 74·0–83·9 78·6–81·9), colorectal (29·4–56·7 45·8–54·1 vs 38·8–59·7 50·7–57·5), and breast (61·7–82·7 72·3–78·3 vs 69·3–87·6 76·6–82·7) sites. Interpretation Increases in survival and decreases in geographic differences over time, which are mainly due to improvements in health-care services in countries with poor survival, might indicate better cancer care. Wealthy countries with high TNEH generally had good cancer outcomes, but those with conspicuously worse outcomes than those with similar TNEH might not be allocating health resources efficiently.
Summary Background Survival and cure rates for childhood cancers in Europe have greatly improved over the past 40 years and are mostly good, although not in all European countries. The EUROCARE-5 ...survival study estimates survival of children diagnosed with cancer between 2000 and 2007, assesses whether survival differences among European countries have changed, and investigates changes from 1999 to 2007. Methods We analysed survival data for 157 499 children (age 0–14 years) diagnosed between Jan 1, 1978 and Dec 31, 2007. They came from 74 population-based cancer registries in 29 countries. We calculated observed, country-weighted 1-year, 3-year, and 5-year survival for major cancers and all cancers combined. For comparison between countries, we used the corrected group prognosis method to provide survival probabilities adjusted for multiple confounders (sex, age, period of diagnosis, and, for all cancers combined without CNS cancers, casemix). Age-adjusted survival differences by area and calendar period were calculated with period analysis and were given for all cancers combined and the major cancers. Findings We analysed 59 579 cases. For all cancers combined for children diagnosed in 2000–07, 1-year survival was 90·6% (95% CI 90·2–90·9), 3-year survival was 81·0 % (95% CI 80·5–81·4), and 5-year survival was 77·9% (95% CI 77·4–78·3). For all cancers combined, 5-year survival rose from 76·1% (74·4–77·7) for 1999–2001, to 79·1% (77·3–80·7) for 2005–07 (hazard ratio 0·973, 95% CI 0·965–0·982, p<0·0001). The greatest improvements were in eastern Europe, where 5-year survival rose from 65·2% (95% CI 63·1–67·3) in 1999–2001, to 70·2% (67·9–72·3) in 2005–07. Europe-wide average yearly change in mortality (hazard ratio) was 0·939 (95% CI 0·919–0·960) for acute lymphoid leukaemia, 0·959 (0·933–0·986) for acute myeloid leukaemia, and 0·940 (0·897–0·984) for non-Hodgkin lymphoma. Mortality for all of Europe did not change significantly for Hodgkin's lymphoma, Burkitt's lymphoma, CNS tumours, neuroblastoma, Wilms' tumour, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Disparities for 5-year survival persisted between countries and regions, ranging from 70% to 82% (for 2005–07). Interpretation Several reasons might explain persisting inequalities. The lack of health-care resources is probably most important, especially in some eastern European countries with limited drug supply, lack of specialised centres with multidisciplinary teams, delayed diagnosis and treatment, poor management of treatment, and drug toxicity. In the short term, cross-border care and collaborative programmes could help to narrow the survival gaps in Europe. Funding Italian Ministry of Health, European Commission, Compagnia di San Paolo Foundation.
Imatinib, the first tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), improves overall survival (OS), but the introduction of newer TKIs requires the definition of ...the optimal first-line TKI for newly diagnosed Philadelphia chromosome–positive (Ph+) chronic-phase (CP) CML. This systematic review of randomized controlled trials (RCTs) compares the efficacy and safety of imatinib vs second-generation (dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib) in adults with newly diagnosed Ph+ CP CML, concentrating on OS, progression-free survival (PFS), and hematological and nonhematological adverse events. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. Seven RCTs published between 1990 and 2019 (involving 3262 participants) satisfied the eligibility criteria. Two RCTs (imatinib vs nilotinib and imatinib vs dasatinib) found no difference in 5-year OS or PFS. Second- and third-generation TKIs improved 3-month major molecular responses (relative risk RR, 4.28; 95% confidence interval CI, 2.20-8.32) and other efficacy outcomes, decreased accelerated/blastic-phase transformations (RR, 0.44; 95% CI, 0.26-0.74), but were associated with more cases of thrombocytopenia (RR, 1.57; 95% CI, 1.20-2.05), cardiovascular events (RR, 2.54; 95% CI, 1.49-4.33), and pancreatic (RR, 2.29; 95% CI, 1.32-3.96) and hepatic effects (RR, 3.51; 95% CI 1.55-7.92). GRADE showed that the certainty of the evidence ranged from high to moderate. This study shows that, in comparison with imatinib, second- and third-generation TKIs improve clinical responses, but the safer toxicity profile of imatinib may make it a better option for patients with comorbidities.
Changing definitions and classifications of hematologic malignancies (HMs) complicate incidence comparisons. HAEMACARE classified HMs into groupings consistent with the latest World Health ...Organization classification and useful for epidemiologic and public health purposes. We present crude, age-specific and age-standardized incidence rates for European HMs according to these groupings, estimated from 66 371 lymphoid malignancies (LMs) and 21 796 myeloid malignancies (MMs) registered in 2000-2002 by 44 European cancer registries, grouped into 5 regions. Age-standardized incidence rates were 24.5 (per 100 000) for LMs and 7.55 for MMs. The commonest LMs were plasma cell neoplasms (4.62), small B-cell lymphocytic lymphoma/chronic lymphatic leukemia (3.79), diffuse B-cell lymphoma (3.13), and Hodgkin lymphoma (2.41). The commonest MMs were acute myeloid leukemia (2.96), other myeloproliferative neoplasms (1.76), and myelodysplastic syndrome (1.24). Unknown morphology LMs were commonest in Northern Europe (7.53); unknown morphology MMs were commonest in Southern Europe (0.73). Overall incidence was lowest in Eastern Europe and lower in women than in men. For most LMs, incidence was highest in Southern Europe; for MMs incidence was highest in the United Kingdom and Ireland. Differences in diagnostic and registration criteria are an important cause of incidence variation; however, different distribution of HM risk factors also contributes. The quality of population-based HM data needs further improvement.
Summary Background Cancer survival varies widely between countries. The CONCORD study provides survival estimates for 1·9 million adults (aged 15–99 years) diagnosed with a first, primary, invasive ...cancer of the breast (women), colon, rectum, or prostate during 1990–94 and followed up to 1999, by use of individual tumour records from 101 population-based cancer registries in 31 countries on five continents. This is, to our knowledge, the first worldwide analysis of cancer survival, with standard quality-control procedures and identical analytic methods for all datasets. Methods To compensate for wide international differences in general population (background) mortality by age, sex, country, region, calendar period, and (in the USA) ethnic origin, we estimated relative survival, the ratio of survival noted in the patients with cancer, and the survival that would have been expected had they been subject only to the background mortality rates. 2800 life tables were constructed. Survival estimates were also adjusted for differences in the age structure of populations of patients with cancer. Findings Global variation in cancer survival was very wide. 5-year relative survival for breast, colorectal, and prostate cancer was generally higher in North America, Australia, Japan, and northern, western, and southern Europe, and lower in Algeria, Brazil, and eastern Europe. CONCORD has provided the first opportunity to estimate cancer survival in 11 states in USA covered by the National Program of Cancer Registries (NPCR), and the study covers 42% of the US population, four-fold more than previously available. Cancer survival in black men and women was systematically and substantially lower than in white men and women in all 16 states and six metropolitan areas included. Relative survival for all ethnicities combined was 2–4% lower in states covered by NPCR than in areas covered by the Surveillance Epidemiology and End Results (SEER) Program. Age-standardised relative survival by use of the appropriate race-specific and state-specific life tables was up to 2% lower for breast cancer and up to 5% lower for prostate cancer than with the census-derived national life tables used by the SEER Program. These differences in population coverage and analytical method have both contributed to the survival deficit noted between Europe and the USA, from which only SEER data have been available until now. Interpretation Until now, direct comparisons of cancer survival between high-income and low-income countries have not generally been available. The information provided here might therefore be a useful stimulus for change. The findings should eventually facilitate joint assessment of international trends in incidence, survival, and mortality as indicators of cancer control. Funding Centers for Disease Control and Prevention (Atlanta, GA, USA), Department of Health (London, UK), Cancer Research UK (London, UK).
Triple negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options. New opportunities are emerging from current comprehensive characterization of tumor immune infiltration ...and fitness. Therefore, effectiveness of current chemotherapies and novel immunotherapies are partially dictated by host inflammatory and immune profiles. However, further progress in breast cancer immuno-oncology is required to reach a detailed awareness of the immune infiltrate landscape and to determine additional reliable and easily detectable biomarkers. In this study, by analyzing gene expression profiles of 54 TNBC cases we identified three TNBC clusters displaying unique immune features. Deep molecular characterization of immune cells cytolytic-activity and tumor-inflammation status reveled variability in the local composition of the immune infiltrate in the TNBC clusters, reconciled by tumor-infiltrating lymphocytes counts. Platelet-to-lymphocyte ratio (PLR), a blood systemic parameter of inflammation evaluated using pre-surgical blood test data, resulted negatively correlated with local tumoral cytolytic activity and T cell-inflamed microenvironment, whereas tumor aggressiveness score signature positively correlated with PLR values. These data highlighted that systemic inflammation parameters may represent reliable and informative markers of the local immune tumor microenvironment in TNBC patients and could be exploited to decipher tumor infiltrate properties and consequently to select the most appropriate therapies.
Background
The risk of malignancy associated with sequential disease-modifying therapies (DMTs) for patients with multiple sclerosis (MS) is uncertain. The aim of this study was to analyze the risk ...of cancer in patients with MS treated with azathioprine (AZA) and the influence of sequential DMTs on the risk.
Method
We retrospectively enrolled a cohort of AZA-treated MS patients followed in two Italian centers from 1987 to 2019. The ratio between observed and expected cancers in the Italian general population was calculated as standardized incidence ratio (SIR). Associations between AZA and DMTs and cancer were estimated by Cox proportional hazards model.
Results
We identified 500 AZA-treated MS patients, followed for a median time of 9.7 (0.1–45.7) years: 61.8% of them were treated with DMTs. We found 22 cases of cancer (4.4%). The SIR was 1.14 (95% CI 0.98–1.29), not significantly increased in comparison with the general population. However, the risk was significantly higher in the quintiles of age 32–45, SIR 1.21 (95% CI 1.21–1.42), and 46–51, SIR 1.11 (95% CI 1.11–1.32) than in older cases. Age at AZA treatment onset was the only covariate significantly related to cancer incidence (HR = 1.049, 95% CI 1.007–1.093). The exposure to other DMTs did not modify the risk.
Conclusion
The risk of malignancy in MS patients after AZA was similar to that of the general population and did not change with other DMTs sequential treatments. The increased risk in the younger ages should be considered in treatment assessment.
The purpose of this study was to evaluate the impact of breast size on acute and late side effects in breast cancer (BC) patients treated with hypofractionated radiotherapy (Hypo-RT). In this study ...we analyzed patients over 50 years with a diagnosis of early BC, candidate for Hypo-RT after conservative surgery. Acute and late skin toxicities were evaluated in accordance with the RTOG scale. Multivariable logistic analysis was performed using dosimetric/anatomical factors resulted associated with toxicity outcome in univariable analysis. Among patients treated between 2009 and 2015, 425 had at least 5 years of follow-up. At RT end, acute skin toxicity ≥ G2 and edema ≥ G2 occurred in 88 (20.7%) and 4 (0.9%) patients, respectively. The multivariable analysis showed association of skin toxicity with boost administration (
p
< 0.01), treated skin area (TSA) receiving more than 20 Gy (
p
= 0.027) and breast volume receiving 105% of the prescription dose (V105%) (
p
= 0.016), but not breast size. At 5 years after RT, fibrosis ≥ G1 occurred in 89 (20.9%) patients and edema ≥ G1 in 36 (8.5%) patients. Fibrosis resulted associated with breast volume ≥ 1000 cm
3
(
p
= 0.04) and hypertension (
p
= 0.04). As for edema, multivariable logistic analysis showed a correlation with hypertension and logarithm of age, but not with boost administration. Breast volume had an unclear impact (
p
= 0.055). A recurrent association was found between acute and late toxicities and breast V105%, which is correlated with breast size. This may suggest that a more homogenous RT technique may be preferred for patients with larger breast size.
Objectives: Standard care for cutaneous melanoma includes an accurate pathology report (PR) and sentinel lymph node biopsy (SLNB) for staging clinically node-negative >1 mm melanomas. We aimed to ...investigate the frequency of these indicators across European countries, also assessing consequences for survival. Methods: We analyzed 4245 melanoma cases diagnosed in six European countries in 2009−2013. Multivariable logistic regression was used to estimate the Odds Ratio (OR) of receiving complete PR with eight items or SLNB and model-based survival to estimate the five-year relative excess risks of death (RER). Results: Overall, 12% patients received a complete PR (range 2.3%, Estonia—20.1%, Italy); SLNB was performed for 68.8% of those with cN0cM0 stage (range 54.4%, Spain—81.7%, Portugal). The adjusted OR of receiving a complete PR was lower than the mean in Estonia (OR 0.11 (0.06−0.18)) and higher in Italy (OR 6.39 (4.90−8.34)) and Portugal (OR 1.39 (1.02−1.89)); it was higher for patients operated on in specialized than general hospitals (OR 1.42 (1.08−1.42)). In the multivariate models adjusted for age, sex, country and clinical-pathological characteristics, the RER resulted in being higher than the reference for patients not receiving a complete PR with eight items (RER 1.72 (1.08−2.72)), or for those not undergoing SLNB (RER 1.76 (1.26−2.47)) Patients with non-metastatic node-negative thickness >1 mm melanoma who did not undergo SLNB had a higher risk of death (RER (RER 1.69 (1.02−2.80)) than those who did. Conclusions: Accurate pathology profiling and SLNB carried survival benefit. Narrowing down between-countries differences in adhesion to guidelines might achieve better outcomes.
To investigate differences in lung cancer (LC) management and survival using data from European population cancer registries.
We analysed 4,602 lung cancer cases diagnosed in 2010-2013, followed-up ...to 2019 in five countries. Multivariable logistic regression was used to calculate the Odds Ratio (OR) of surgery for stages I-II LC or chemo- or radiotherapy for stages III-IV LC. Relative survival (RS) was estimated by the actuarial method; Relative Excess Risk of death (RER), with 95% CI, was calculated by generalized linear models.
Diagnostic work-up was extensive for 65.9% patients (range 57%, Estonia, Portugal - 85% (Belgium). Sixty-six percent of stages I-II patients underwent surgery; compared to non-operated, their adjusted OR decreased with age and was associated with main bronchus cancer (OR vs. lobes 0.25, CI, 0.08-0.82), stage II (OR vs. stage I: 0.42, CI, 0.29-0.60), comorbidity (OR vs. absent: 0.55, CI, 0.33-0.93), country (ORs: Estonia 1.82, CI, 1.28-2.60; Belgium 0.62, CI, 0.42-0.91; Portugal 0.69, CI, 0.52-0.93).Almost half of stages III-IV patients received chemo- or radiotherapy only; the adjusted OR vs. non receiving decreased with age and was associated with unspecified cancer topography or morphology. The adjusted five-year RER increased with age and stage and was lower for women (0.78, CI, 0.72-0.86), above the reference for main bronchus cancer (1.37, CI, 1.21-1.54) and unspecified morphology (1.17, CI, 1.05-1.30). Surgery carried the lowest mortality (RS 56.9; RER 0.13, CI, 0.11-0.15) with RER above the mean in Estonia (1.20, CI, 1.10-1.30), below it in Portugal (0.88, CI, 0.82-0.93) and Switzerland (0.91, CI, 0.84-0.99). Comorbidity (1.21, CI, 1.09-1.35) and not smoking (0.68, CI, 0.57-0.81) were associated with RER.
The survival benefit of early diagnosis, allowing curative surgery, was evident at the population level. Screening for subjects at risk and adhesion to standard care should be incremented across the EU by funding better equipment and training health personnel.
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