Aurélien Belot

Ten-Year Survival Results of a Randomized Trial of Irradiation of Internal Mammary Nodes After Mastectomy

PURPOSE To evaluate the efficacy of irradiation of internal mammary nodes (IMN) on 10-year overall survival in breast cancer patients after mastectomy. METHODS AND PATIENTS This multicenter phase 3 study enrolled patients with positive axillary nodes (pN+) or central/medial tumors with or without pN+. Other inclusion criteria were age <75 and a Karnofsky index ≥70. All patients received postoperative irradiation of the chest wall and supraclavicular nodes and were randomly assigned to receive IMN irradiation or not. Randomization was stratified by tumor location (medial/central or lateral), axillary lymph node status, and adjuvant therapy (chemotherapy vs no chemotherapy). The prescribed dose of irradiation to the target volumes was 50 Gy or equivalent. The first 5 intercostal spaces were included in the IMN target volume, and two-thirds of the dose (31.5 Gy) was given by electrons. The primary outcome was overall survival at 10 years. Disease-free survival and toxicity were secondary outcomes. RESULTS T total of 1334 patients were analyzed after a median follow-up of 11.3 years among the survivors. No benefit of IMN irradiation on the overall survival could be demonstrated: the 10-year overall survival was 59.3% in the IMN-nonirradiated group versus 62.6% in the IMN-irradiated group (P=.8). According to stratification factors, we defined 6 subgroups (medial/central or lateral tumor, pN0 [only for medial/central] or pN+, and chemotherapy or not). In all these subgroups, IMN irradiation did not significantly improve overall survival. CONCLUSIONS In patients treated with 2-dimensional techniques, we failed to demonstrate a survival benefit for IMN irradiation. This study cannot rule out a moderate benefit, especially with more modern, conformal techniques applied to a higher risk population.

Incidence of HIV-Related Anal Cancer Remains Increased Despite Long-Term Combined Antiretroviral Treatment: Results From the French Hospital Database on HIV

PURPOSE To study recent trends in the incidence of anal cancer in HIV-infected patients receiving long-term combined antiretroviral treatment (cART) compared with the general population. PATIENTS AND METHODS From the French Hospital Database on HIV, we identified 263 cases of invasive anal squamous cell carcinoma confirmed histologically between 1992 and 2008. We compared incidence rates of anal cancer across four calendar periods: 1992-1996 (pre-cART period), 1997-2000 (early cART period), and 2001-2004 and 2005-2008 (recent cART periods). Standardized incidence ratios (SIRs) were calculated by using general population incidence data from the French Network of Cancer Registries. RESULTS In HIV-infected patients, the hazard ratio (HR) in the cART periods versus the pre-cART period was 2.5 (95% CI, 1.28 to 4.98). No difference was observed across the cART calendar periods (HR, 0.9; 95% CI, 0.6 to 1.3). In 2005-2008, HIV-infected patients compared with the general population had an excess risk of anal cancer, with SIRs of 109.8 (95% CI, 84.6 to 140.3), 49.2 (95% CI, 33.2 to 70.3), and 13.1 (95% CI, 6.8 to 22.8) for men who have sex with men (MSM), other men, and women, respectively. Among patients with CD4 cell counts above 500/μL for at least 2 years, SIRs were 67.5 (95% CI, 41.2 to 104.3) when the CD4 nadir was less than 200/μL for more than 2 years and 24.5 (95% CI, 17.1 to 34.1) when the CD4 nadir was more than 200/μL. CONCLUSION Relative to that in the general population, the risk of anal cancer in HIV-infected patients is still extremely high, even in patients with high current CD4 cell counts. cART appears to have no preventive effect on anal cancer, particularly in MSM.

Descriptive epidemiology of upper aerodigestive tract cancers in France: Incidence over 1980–2005 and projection to 2010

Over the 1998-2002 period, some French Départements have been shown to have the worlds highest incidence of upper aerodigestive tract (UADT) cancers in men. The objectives were to describe the changes in UADT cancer incidence in France over the 1980-2005 period, present projections for 2010, and describe the anatomical and histological characteristics of these tumours. The trend of cancer-incidence over 1980-2005 and projection up to 2010 were obtained using age-period-cohort models (data from eleven cancer registries) and incidence/mortality ratios in the area covered by these registries. The description of UADT cancers by anatomical and histological characteristics concerned data collected between 1980 and 2004 in eleven cancer registries. In men, cancer incidence decreased in all cancer sites and the world-standardized incidence rates decreased by 42.9% for lip-oral cavity-pharynx (LOCP) cancers and 50.4% for larynx cancer. In women, the world-standardized incidence rates increased by 48.6% for LOCP cancers and 66.7% for larynx cancer. Incidence increased the most for oropharynx, palate, and hypopharynx cancers. Incidence analysis by one-year cohorts revealed a progressive shift of the incidence peak towards younger and younger generations, with no change as yet in the mean age at diagnosis. In France, the incidence of these cancers is still higher than in other European and North American countries. This urges actions towards reducing the major risk factors for those cancers, namely alcohol and tobacco consumption, especially among young people, and reducing exposure to risk factors due to social inequalities.

Estimating net survival: the importance of allowing for informative censoring

Net survival, the one that would be observed if cancer were the only cause of death, is the most appropriate indicator to compare cancer mortality between areas or countries. Several parametric and non-parametric methods have been developed to estimate net survival, particularly when the cause of death is unknown. These methods are based either on the relative survival ratio or on the additive excess hazard model, the latter using the general population mortality hazard to estimate the excess mortality hazard (the hazard related to net survival). The present work used simulations to compare estimator abilities to estimate net survival in different settings such as the presence/absence of an age effect on the excess mortality hazard or on the potential time of follow-up, knowing that this covariate has an effect on the general population mortality hazard too. It showed that when age affected the excess mortality hazard, most estimators, including specific survival, were biased. Only two estimators were appropriate to estimate net survival. The first is based on a multivariable excess hazard model that includes age as covariate. The second is non-parametric and is based on the inverse probability weighting. These estimators take differently into account the informative censoring induced by the expected mortality process. The former offers great flexibility whereas the latter requires neither the assumption of a specific distribution nor a model-building strategy. Because of its simplicity and availability in commonly used software, the nonparametric estimator should be considered by cancer registries for population-based studies.

Cancer net survival on registry data: use of the new unbiased Pohar-Perme estimator and magnitude of the bias with the classical methods.

Net survival, the survival which might occur if cancer was the only cause of death, is a major epidemiological indicator required for international or temporal comparisons. Recent findings have shown that all classical methods used for routine estimation of net survival from cancer‐registry data, sometimes called “relative‐survival methods,” provide biased estimates. Meanwhile, an unbiased estimator, the Pohar‐Perme estimator (PPE), was recently proposed. Using real data, we investigated the magnitude of the errors made by four “relative‐survival” methods (Ederer I, Hakulinen, Ederer II and a univariable regression model) vs. PPE as reference and examined the influence of time of follow‐up, cancer prognosis, and age on the errors made. The data concerned seven cancer sites (2,51,316 cases) collected by FRANCIM cancer registries. Net survivals were estimated at 5, 10 and 15 years postdiagnosis. At 5 years, the errors were generally small. At 10 years, in good‐prognosis cancers, the errors made in nonstandardized estimates with all classical methods were generally great (+2.7 to +9% points in prostate cancer) and increased in age‐class estimations (vs. 5‐year ones). At 15 years, in bad‐ or average‐prognosis cancers, the errors were often substantial whatever the nature of the estimation. In good‐prognosis cancers, the errors in nonstandardized estimates of all classical methods were great and sometimes very important. With all classical methods, great errors occurred in age‐class estimates resulting in errors in age‐standardized estimates (+0.4 to +3.2% points in breast cancer). In estimating net survival, cancer registries should abandon all classical methods and adopt the new Pohar‐Perme estimator.

The EUROCARE-5 study on cancer survival in Europe 1999–2007: Database, quality checks and statistical analysis methods

BACKGROUND Since 25years the EUROCARE study monitors the survival of cancer patients in Europe through centralised collection, quality check and statistical analysis of population-based cancer registries (CRs) data. The European population covered by the study increased remarkably in the latest round. The study design and statistical methods were also changed to improve timeliness and comparability of survival estimates. To interpret the EUROCARE-5 results on adult cancer patients better here we assess the impact of these changes on data quality and on survival comparisons. METHODS In EUROCARE-5 the survival differences by area were studied applying the complete cohort approach to data on nearly nine million cancer patients diagnosed in 2000-2007 and followed up to 2008. Survival time trends were analysed applying the period approach to data on about 10 million cancer cases diagnosed from 1995 to 2007 and followed up to 2008. Differently from EUROCARE-4, multiple primary cancers were included and relative survival was estimated with the Ederer II method. RESULTS EUROCARE-5 covered a population of 232 million resident persons, corresponding to 50% of the 29 participating countries. The population coverage increased particularly in Eastern Europe. Cases identified from death certificate only (DCO) were on average 2.9%, range 0-12%. Microscopically confirmed cases amounted to over 85% in most CRs. Compared to previous methods, including multiple cancers and using the Ederer II estimator reduced survival estimates by 0.4 and 0.3 absolute percentage points, on average. CONCLUSIONS The increased population size and registration coverage of the EUROCARE-5 study ensures more robust and comparable estimates across European countries. This enlargement did not impact on data quality, which was generally satisfactory. Estimates may be slightly inflated in countries with high or null DCO proportions, especially for poor prognosis cancers. The updated methods improved the comparability of survival estimates between recently and long-term established registries and reduced biases due to informative censoring.

Thyroid cancer: is the incidence rise abating?

OBJECTIVE The aim of the present study was to determine recent trends in thyroid cancer incidence rates and to analyze histopathological characteristics and geographical distribution. METHODS Histologically proven 5367 cases were collected over the period 1998-2006 in France from the Rhône-Alpes thyroid cancer registry. Geographical variations of incidence were analyzed using a mixed Poisson model. RESULTS The average incidence rates, age standardized to the world population, were 3.9/100,000 in men and 12.3/100,000 in women, higher than those previously reported in France. After an initial increase during the first 3 years, a steady level of incidence was observed for the period 2001-2006. The annual incidence rate of microcarcinomas was correlated with that of all cancers in men and women (r=0.78 and 0.89; P<0.01) respectively. Papillary microcarcinomas represented 38% of tumors and two-thirds of them measured less than 5 mm in diameter. They were fortuitously discovered after thyroidectomy for benign diseases in 64% of cases. Histological marks of aggressiveness differed according to the size of the tumor. Despite recent advances in diagnosis, 13% of tumors were diagnosed at advanced stage especially in men. Geographical distribution of incidence based on subregional administrative entities showed lower incidence rates in rural than in urban zones in men (relative rate: 0.72; 95% CI: 0.62-0.84) and women (relative rate: 0.85; 95% CI: 0.73-0.93). CONCLUSION The present study suggests that the rise in thyroid cancer incidence is now abating. It could reflect standardization in diagnostic procedures. Further studies, performed on a more prolonged period, are necessary to confirm these data.

Unbiased estimates of long-term net survival of hematological malignancy patients detailed by major subtypes in France.

Long‐term population‐based survival data detailed by cancer subtype are important to measure the overall outcomes of malignancy managements. We provide net survival estimates at 1, 3, 5 and 10‐year postdiagnosis on 37,549 hematological malignancy (HM) patients whose ages were >15 years, diagnosed between 1989 and 2004 and actively followed until 2008 by French population‐based cancer registries. These are, to our knowledge, the first unbiased estimates of 10‐year net survival in HMs detailed by subtypes. HMs were classified according to the International Classification of Diseases‐Oncology 3. Net survival was estimated with the unbiased Pohar‐Perme method. The results are reported by sex and age classes. The changes of these indicators by periods of diagnosis were tabulated and the trends of the net mortality rates over time since diagnosis graphed. In all, 5‐ and 10‐year age‐standardized net survivals after HMs varied widely from 81 and 76% for classical Hodgkin lymphoma (CHL) to 18 and 14% for acute myeloid leukemia (AML). Even in HMs with the most favorable prognoses, the net survival decreased between 5‐ and 10‐year postdiagnosis. Women had better prognoses than men and age at diagnosis was an unfavorable prognostic factor for most HMs. In patients <55 years old, the net mortality rate decreased to null values 5‐year postdiagnosis in AML and 10‐year postdiagnosis in CHL, precursor non‐HL, chronic myelogenous leukemia, diffuse large B‐cell lymphoma and follicular lymphoma. The prognoses improved for various HMs over the study period. The obtained unbiased indicators are important to evaluate national cancer plans.

Trends in the incidence of digestive cancers in France between 1980 and 2005 and projections for the year 2010.

The aim of this study was to present estimates of national trends in the incidence of the most frequent digestive cancers over the period 1980–2005 and to provide projections up to 2010. World age-standardised estimates of national incidence were modelled using data from the French cancer registries and the incidence/mortality ratios observed in the area covered by the contributing registries, using an age–period–cohort model. The incidence of oesophageal cancers in men strongly decreased over time from 15.3 in 1980 to 7.9 per 100 000 in 2005, whereas the incidence in women slowly increased. A steadily decreasing trend in gastric cancer was found in both sexes. After a steady increase until 1995, the incidence of colorectal cancer stabilised in both sexes, with a slight decrease in men. In 2010, the projected incidence was 36.5 per 100 000 in men and 24.4 in women. The incidence of liver cancer showed the highest increase over time. In men, this increase was steeper until 1995 than later. The projected incidence in 2010 was 10.9 per 100 000 in men and 2.4 in women. The incidence of pancreatic cancer increased slowly between 1980 and 1990 and increased steeply after 1990, reaching an estimated 7.6 per 100 000 in men and 4.7 in women in 2005. This study on trends in the incidence of digestive cancers in France showed large changes between 1980 and 2010. The increase in the incidence of primary liver cancer and pancreatic cancer was striking. Colorectal cancer incidence is stabilising.

Trends in survival after cancer diagnosis among HIV-infected individuals between 1992 and 2009. Results from the FHDH-ANRS CO4 cohort

Although the decline in cancer mortality rates with the advent of combination antiretroviral therapy (cART) in HIV‐infected individuals can be mostly explained by a decrease in cancers incidence, we looked here if improved survival after cancer diagnosis could also contribute to this decline. Survival trends were analyzed for most frequent cancers in the HIV‐infected population followed in the French Hospital Database on HIV: 979 and 2,760 cases of visceral and non‐visceral Kaposis sarcoma (KS), 2,339 and 461 cases of non‐Hodgkin lymphoma (NHL) and Hodgkins lymphoma (HL), 446 lung, 312 liver and 257 anal cancers. Five‐year Kaplan–Meier survival rates were estimated for four periods: 1992–1996, 1997–2000, 2001–2004 and 2005–2009. Cox proportional hazard models were used to compare survival across the periods, after adjustment for confounding factors. For 2001–2004, survival was compared to the general population after standardization on age and sex. Between the pre‐cART (1992–1996) and early‐cART (1997–2000) periods, survival improved after KS, NHL, HL and anal cancer and remained stable after lung and liver cancers. During the cART era, 5‐year survival improved after visceral and non‐visceral KS, NHL, HL and liver cancer, being 83, 92, 65, 87 and 19% in 2005–2009, respectively, and remained stable after lung and anal cancers, being 16 and 65%, respectively. Compared with the general population, survival in HIV‐infected individuals in 2001–2004 was poorer for hematological malignancies and similar for solid tumors. For hematological malignancies, survival continues to improve after 2004, suggesting that the gap between the HIV‐infected and general populations will close in the future.