Graça M. Dores

Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world.

Efforts to reduce global cancer disparities begin with an understanding of geographic patterns in cancer incidence, mortality, and prevalence. Using the GLOBOCAN (2002) and Cancer Incidence in Five Continents databases, we describe overall cancer incidence, mortality, and prevalence, age-adjusted temporal trends, and age-specific incidence patterns in selected geographic regions of the world. For the eight most common malignancies-cancers of lung, breast, colon and rectum, stomach, prostate, liver, cervix, and esophagus-the most important risk factors, cancer prevention and control measures are briefly reviewed. In 2002, an estimated 11 million new cancer cases and 7 million cancer deaths were reported worldwide; nearly 25 million persons were living with cancer. Among the eight most common cancers, global disparities in cancer incidence, mortality, and prevalence are evident, likely due to complex interactions of nonmodifiable (ie, genetic susceptibility and aging) and modifiable risk factors (ie, tobacco, infectious agents, diet, and physical activity). Indeed, when risk factors among populations are intertwined with differences in individual behaviors, cultural beliefs and practices, socioeconomic conditions, and health care systems, global cancer disparities are inevitable. For the eight most common cancers, priorities for reducing cancer disparities are discussed.

Second Malignant Neoplasms Among Long-Term Survivors of Hodgkin’s Disease: A Population-Based Evaluation Over 25 Years

PURPOSE To quantify the relative and absolute excess risks (AER) of site-specific second cancers, in particular solid tumors, among long-term survivors of Hodgkins disease (HD) and to assess risks according to age at HD diagnosis, attained age, and time since initial treatment. PATIENTS AND METHODS Data from 32,591 HD patients (1,111 25-year survivors) reported to 16 population-based cancer registries in North America and Europe (1935 to 1994) were analyzed. RESULTS Two thousand one hundred fifty-three second cancers (observed-to-expected ratio [O/E] = 2.3; 95% confidence interval [CI] = 2.2 to 2.4), including 1,726 solid tumors (O/E = 2.0; 95% CI, 1.9 to 2.0) were reported. Cancers of the lung (observed [Obs] = 377; O/E = 2.9), digestive tract (Obs = 376; O/E = 1.7), and female breast (Obs = 234; O/E = 2.0) accounted for the largest number of subsequent malignancies. Twenty-five years after HD diagnosis, the actuarial risk of developing a solid tumor was 21.9%. The relative risk of solid neoplasms decreased with increasing age at HD diagnosis, however, patients aged 51 to 60 years at HD diagnosis sustained the highest cancer burden (AER = 79.2/10,000 patients/year). After a progressive rise in relative risk and AER of all solid tumors over time, there was an apparent downturn in risk at 25 years. Temporal trends and treatment group distribution for cancers of the esophagus, stomach, rectum, female breast, bladder, thyroid, and bone/connective tissue were suggestive of a radiogenic effect. CONCLUSION Significantly increased risks of second cancers were observed in all HD age groups. Although significantly elevated risks of stomach, female breast, and uterine cervix cancers persisted for 25 years, an apparent decrease in relative risk and AER of solid tumors at other sites is suggested.

Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007

Since 2001, the World Health Organization classification for hematopoietic and lymphoid neoplasms has provided a framework for defining acute leukemia (AL) subtypes, although few population-based studies have assessed incidence patterns and patient survival accordingly. We assessed AL incidence rates (IRs), IR ratios (IRRs), and relative survival in the United States (2001-2007) in one of the first population-based, comprehensive assessments. Most subtypes of acute myeloid leukemia (AML) and acute lymphoblastic leukemia/lymphoma (ALL/L) predominated among males, from twice higher incidence of T-cell ALL/L among males than among females (IRR = 2.20) to nearly equal IRs of acute promyelocytic leukemia (APL; IRR = 1.08). Compared with non-Hispanic whites, Hispanics had significantly higher incidence of B-cell ALL/L (IRR = 1.64) and APL (IRR = 1.28); blacks had lower IRs of nearly all AL subtypes. All ALL/L but only some AML subtypes were associated with a bimodal age pattern. Among AML subtypes, survival was highest for APL and AML with inv(16). B-cell ALL/L had more favorable survival than T-cell ALL/L among the young; the converse occurred at older ages. Limitations of cancer registry data must be acknowledged, but the distinct AL incidence and survival patterns based on the World Health Organization classification support biologic diversity that should facilitate etiologic discovery, prognostication, and treatment advances.

Long-term solid cancer risk among 5-year survivors of Hodgkin's lymphoma.

PURPOSE Hodgkins lymphoma (HL) survivors are known to be at substantially increased risk of solid cancers (SC). However, no investigation has used multivariate modeling to estimate the relative risk (RR), excess absolute risk (EAR), and cumulative incidence for specific attained ages and ages at HL diagnosis. PATIENTS AND METHODS We identified 18,862 5-year HL survivors from 13 population-based cancer registries in North America and Europe. Poisson regression was used to evaluate the effects of age at diagnosis, attained age, latency, sex, treatment, and year of diagnosis on the RR and EAR of SC. RESULTS Among 1,490 identified SC, 850 were estimated to be in excess. For most cancer sites, both RR and EAR decreased with age at HL diagnosis and showed strong dependencies on attained age. For a patient diagnosed at age 30 years and survived to > or = 40 years, modeled risks were significantly elevated for cancers of the breast (RR = 6.1), other supradiaphragmatic sites (RR = 6.0), and infradiaphragmatic sites (RR = 3.7); the largest RR (20-fold) was observed for malignant mesothelioma. Thirty-year cumulative risks of SC for men and women diagnosed at 30 years were 18% and 26%, respectively, compared with 7% and 9%, respectively, in the general population. For young HL patients, risks of breast and colorectal cancers were elevated 10 to 25 years before the age when routine screening would be recommended in the general population. CONCLUSION Multivariable modeling demonstrates for the first time temporal changes in SC risk not evident in unadjusted analyses, and can facilitate the development of individualized risk assessment and the creation of screening strategies for early detection.

Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview of the descriptive epidemiology

The 2001 World Health Organization classification scheme considers B‐cell chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) in an aggregate category (CLL/SLL) because of shared clinicopathological features. We have estimated age‐adjusted incidence rates (IRs) of CLL and SLL in the population‐based Surveillance, Epidemiology and End Results Program in the United States to analyse patterns of CLL and SLL separately and jointly. Age‐standardized to the 2000 US population, overall IRs were 3·83 per 100 000 person‐years for CLL (n = 15 676) and 1·31 for SLL (n = 5382) during 1993–2004. Incidence of the combined entity, CLL/SLL, was 90% higher among males compared to females, and the male:female IR ratio was significantly higher for CLL (1·98) than for SLL (1·67). CLL/SLL IRs were 25% and 77% lower among Blacks and Asian/Pacific Islanders, respectively, compared to Whites. A significant reporting delay was evident for CLL but not for SLL, so that CLL/SLL temporal trends must be interpreted cautiously. CLL and SLL IRs increased exponentially with age among all gender/race groups, with CLL IRs increasing more steeply with advancing age than SLL. Avenues of future research include assessment of delayed‐ and under‐reporting to cancer registries and exploration of race, gender, and age effects in epidemiological studies.

Plasmacytoma of bone, extramedullary plasmacytoma, and multiple myeloma: incidence and survival in the United States, 1992–2004

Population‐based plasmacytoma incidence and survival data are sparse. We analyzed incidence rates (IRs), IR ratios (IRRs), and 5‐year relative survival for plasmacytoma overall and by site – bone (P‐bone) and extramedullary (P‐extramedullary) – in the Surveillance, Epidemiology and End Results (SEER) Program (1992–2004). For comparison, we included cases of multiple myeloma (MM) diagnosed over the same time period in SEER. Incidence of MM (n = 23 544; IR 5·35/100 000 person‐years) was 16‐times higher than plasmacytoma overall (n = 1543; IR = 0·34), and incidence of P‐bone was 40% higher than P‐extramedullary (P < 0·0001). The male‐to‐female IRRs for P‐bone, P‐extramedullary, and MM were 2·0, 2·6, and 1·5, respectively. For plasmacytoma and MM, IRs were highest in Blacks, intermediate in Whites, and lowest in Asian/Pacific Islanders. Compared with Whites, the Black IR was ∼30% higher for P‐extramedullary and P‐bone and 120% higher for MM. IRs for all neoplasms increased exponentially with advancing age, less prominently at older ages for plasmacytoma than MM. Distinct age, gender, and race incidence patterns of plasma cell disorders suggest underlying differences in clinical detection, susceptibility, disease biology and/or aetiological heterogeneity. Five‐year relative survival for P‐bone, P‐extramedullary, and MM varied significantly by age (<60/60+ years), supporting age‐related differences in disease burden at presentation, disease biology, and/or treatment approaches.

Merkel Cell Carcinoma and Multiple Primary Cancers

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin for which causative factors remain largely unknown. The site-specific risks of multiple primary cancers associated with MCC, which may provide insight into etiologic influences, have not been quantified in large population-based studies. We estimated the long-term risk of subsequent primary tumors after a first primary MCC (1,306 patients) and the risk of second primary MCC following other first primary cancers (2,048,739 patients) within 11 population-based cancer registries which report to the National Cancer Institutes Surveillance, Epidemiology, and End Results Program (1986-2002). Patients with first primary MCC were at significantly increased risk of developing a subsequent cancer [standardized incidence ratio (SIR), 1.22; 95% confidence intervals (95% CI), 1.01-1.45; observed (O = 122)], with significant excesses restricted to the first year after diagnosis (SIR, 1.71; 95% CI, 1.21-2.33; O = 39). Significantly elevated site-specific risks were observed for cancers of salivary gland (SIR, 11.55; 95% CI, 2.32-33.76; O = 3), biliary sites other than liver and gallbladder (SIR, 7.24; 95% CI, 1.46-21.16; O = 3), and non–Hodgkin lymphoma (SIR, 2.56; 95% CI, 1.23-4.71; O = 10). Nonsignificantly increased risks of 2-fold or higher were seen for chronic lymphocytic leukemia, and cancers of the small intestine and brain. A significantly increased 1.36-fold risk (95% CI, 1.19-1.55; O = 221) of MCC as a second primary malignancy was observed among patients with all other first primary cancers taken together. In particular, significant 3- to 7-fold excesses of MCC followed multiple myeloma (SIR, 3.70; 95% CI, 1.01-9.47; O = 4), chronic lymphocytic leukemia (SIR, 6.89; 95% CI, 3.77-11.57; O = 14), non–Hodgkin lymphoma (SIR, 3.37; 95% CI, 1.93-5.47; O = 16), and malignant melanoma (SIR, 3.05; 95% CI, 1.74-4.95; O = 16). Although enhanced medical surveillance may play a role, increased reciprocal risks suggest that MCC may share etiologic influences with other malignancies. Heightened awareness of the associations of lymphohematopoietic malignancies with MCC may facilitate early clinical recognition. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1545–9)

Comparison of Age Distribution Patterns for Different Histopathologic Types of Breast Carcinoma

Background: Historically, female breast carcinoma has been viewed as an etiologically homogeneous disease associated with rapidly increasing incidence rates until age 50 years, followed by a slower rate of increase among older women. More recent studies, however, have shown distinct age incidence patterns for female breast cancer when stratified by estrogen receptor (ER) expression and/or histopathologic subtypes, suggesting etiologic heterogeneity. Materials and Methods: To determine if different age incidence patterns reflect etiologic heterogeneity (more than one breast cancer type within the general breast carcinoma), we applied “smoothed” age histograms at diagnosis (density plots) and a two-component statistical mixture model to all breast carcinoma cases (n = 270,124) in the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. These overall patterns were then reevaluated according to histopathologic type, race, and ER expression. Results: A bimodal age distribution at diagnosis provided a better fit to the data than a single density for all breast carcinoma populations, except for medullary carcinoma. Medullary carcinomas showed a single age distribution at diagnosis irrespective of race and/or ER expression. Conclusions: Distinct age-specific incidence patterns reflected bimodal breast cancer populations for breast carcinoma overall as well as for histopathologic subtypes, race, and ER expression. The one exception was medullary carcinoma. Of note, medullary carcinomas are rare tumors, which are associated with germ-line mutations in the BRCA1 gene. These descriptive and model-based results support emerging molecular data, suggesting two main types of breast carcinoma in the overall breast cancer population. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1899–905)

Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975-2008.

Therapy-related acute myeloid leukemia (tAML) is a rare but highly fatal complication of cytotoxic chemotherapy. Despite major changes in cancer treatment, data describing tAML risks over time are sparse. Among 426068 adults initially treated with chemotherapy for first primary malignancy (9 US population-based cancer registries, 1975-2008), we identified 801 tAML cases, 4.70 times more than expected in the general population (P < .001). Over time, tAML risks increased after chemotherapy for non-Hodgkin lymphoma (n = 158; Poisson regression Ptrend < .001), declined for ovarian cancer (n = 72; Ptrend < .001), myeloma (n = 62; Ptrend = .02), and possibly lung cancer (n = 65; Ptrend = .18), and were significantly heterogeneous for breast cancer (n = 223; Phomogeneity = .005) and Hodgkin lymphoma (n = 58; Phomogeneity = .007). tAML risks varied significantly by age at first cancer and latency and were nonsignificantly heightened with radiotherapy for lung, breast, and ovarian cancers. We identified newly emerging elevated tAML risks in patients treated with chemotherapy since 2000 for esophageal, cervical, prostate, and possibly anal cancers; and since the 1990s for bone/joint and endometrial cancers. Using long-term, population-based data, we observed significant variation in tAML risk with time, consistent with changing treatment practices and differential leukemogenicity of specific therapies. tAML risks should be weighed against the benefits of chemotherapy, particularly for new agents and new indications for standard agents.

Incidence of Carcinoma of the Major Salivary Glands According to the WHO Classification, 1992 to 2006: A Population-Based Study in the United States

Background: Carcinomas of the major salivary glands (M-SGC) comprise a morphologically diverse group of rare tumors of largely unknown cause. To gain insight into etiology, we evaluated incidence of M-SGC using the WHO classification schema (WHO-2005). Methods: We calculated age-adjusted incidence rates (IR) and IR ratios (IRR) for M-SGC diagnosed between 1992 and 2006 in the Surveillance, Epidemiology and End Results Program. Results: Overall, 6,391 M-SGC (IR, 11.95/1,000,000 person-years) were diagnosed during 1992 to 2006. Nearly 85% of cases (n = 5,370; IR, 10.00) were encompassed within WHO-2005, and among these, males had higher IRs than females [IRR, 1.51; 95% confidence interval (95% CI), 1.43-1.60]. Squamous cell (IR, 3.44) and mucoepidermoid (IR, 3.23) carcinomas occurred most frequently among males, whereas mucoepidermoid (IR, 2.67), acinic cell (IR, 1.57), and adenoid cystic (IR, 1.40) carcinomas were most common among females. Mucoepidermoid, acinic cell, and adenoid cystic carcinomas predominated in females through age ∼50 years; thereafter, IRs of acinic cell and adenoid cystic carcinomas were nearly equal among females and males, whereas IRs of mucoepidermoid carcinoma among males exceeded IRs among females (IRR, 1.57; 95% CI, 1.38-1.78). Except for mucoepidermoid and adenoid cystic carcinomas, which occurred equally among all races, other subtypes had significantly lower incidence among Blacks and Asians/Pacific Islanders than among Whites. Adenoid cystic carcinoma occurred equally in the submandibular and parotid glands, and other M-SGC histologic subtypes evaluated had 77% to 98% lower IRs in the submandibular gland. Overall M-SGC IRs remained stable during 1992 to 2006. Conclusion: Distinct incidence patterns according to histologic subtype suggest that M-SGC are a diverse group of neoplasms characterized by etiologic and/or biological heterogeneity with varying susceptibility by gender and race. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2899–906)