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IMPORTANCE: Clinical trials play a critical role in the development of novel cancer therapies, and precise estimates of the frequency with which older adult patients with cancer participate in clinical trials are lacking. OBJECTIVE: To estimate the proportion of older adult Medicare Fee-for-Service (FFS) beneficiaries with cancer who participate in interventional cancer clinical trials, using a novel population-based methodology. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study evaluating clinical trial participation among older adult patients with cancer from January 1, 2014, through June 30, 2020, claims data from Medicare FFS were linked with the ClinicalTrials.gov to determine trial participation through the unique National Clinical Trial (NCT) identifier. The proportion of patients with newly diagnosed or newly recurrent cancer in 2015 participating in an interventional clinical trial and receiving active cancer treatment from January 2014 to June 2020 was estimated. Data analysis was performed from November 18, 2020, to November 1, 2021. EXPOSURES: Patients with cancer aged 65 years or older with Medicare FFS insurance, with and without active cancer treatment. MAIN OUTCOMES AND MEASURES: Enrollment in clinical trials among all patients with cancer 65 years and older and among patients receiving active cancer treatments as defined by the presence of at least 1 NCT identifier corresponding to an interventional cancer clinical trial in Medicare claims. RESULTS: Among 1 150 978 patients (mean [SD] age, 75.7 [8.4] years; 49.9% men and 50.1% women) with newly diagnosed or newly recurrent cancer in 2015, 12 028 (1.0%) patients had a billing claim with an NCT identifier indicating enrollment in an interventional cancer clinical trial between January 2014 and June 2020. In a subset of 429 343 patients with active cancer treatment, 8360 (1.9%) were enrolled in 1 or more interventional trials. Patients enrolled in a trial tended to be younger, male, a race other than Black, and residing in zip codes with high median incomes. CONCLUSIONS AND RELEVANCE: Findings of this cohort study show that clinical trial enrollment among older adult patients with cancer remains low, with only 1.0% to 1.9% of patients with newly diagnosed or recurrent cancer in 2015 participating in an interventional cancer clinical trial as measured by the presence of NCT identifiers in Medicare claims. These data provide a contemporary estimate of trial enrollment, persistent disparities in trial participation, and only limited progress in trial access over the past 2 decades.

Background Medicare managed care may offer enrollees lower out-of-pocket costs and provide benefits that are not available in the traditional fee-for-service Medicare program. However, managed care plans may also restrict provider choice in an effort to control costs. We compared rates of voluntary disenrollment from Medicare managed care to traditional fee-for-service Medicare among Medicare managed care enrollees with and without a cancer diagnosis. Methods We identified Medicare managed care enrollees aged 65 years or older who were diagnosed with a first primary breast (n = 28331), colorectal (n = 26494), prostate (n = 29046), or lung (n = 31 243) cancer from January 1, 1995, through December 31, 2002, in Surveillance, Epidemiology, and End Results (SEER) cancer registry records linked with Medicare enrollment files. Cancer patients were pair-matched to cancerfree enrollees by age, sex, race, and geographic location. We estimated rates of voluntary disenrollment to fee-for-service Medicare in the 2 years after each cancer patient's diagnosis, adjusted for plan characteristics and Medicare managed care penetration, by use of Cox proportional hazards regression. Results In the 2 years after diagnosis, cancer patients were less likely to disenroll from Medicare managed care than their matched cancer-free peers (for breast cancer, adjusted hazard ratio [HR] for disenrollment = 0.78, 95% confidence interval [Cl] = 0.74 to 0.82; for colorectal cancer, HR = 0.84, 95% Cl = 0.80 to 0.88; for prostate cancer, HR = 0.86, 95% Cl = 0.82 to 0.90; and for lung cancer, HR = 0.81, 95% Cl = 0.76 to 0.86). Results were consistent across strata of age, sex, race, SEER registry, and cancer stage. Conclusions A new cancer diagnosis between 1995 and 2002 did not precipitate voluntary disenrollment from Medicare managed care to traditional fee-for-service Medicare.

Background Results from randomized trials indicate that treatment with tamoxifen or chemotherapy for primary breast cancer reduces the risk for contralateral breast cancer. However, less is known about how long the risk is reduced and the impact of factors such as age and menopausal status. Methods The study included 634 women with contralateral breast cancer (case patients) and 1158 women with unilateral breast cancer (control subjects) from the Women's Environment, Cancer and Radiation Epidemiology Study. The women were younger than age 55 when they were first diagnosed with breast cancer during 1985-1999. Rate ratios (RRs) and 95% confidence intervals (CIs) for contralateral breast cancer after treatment with chemotherapy or tamoxifen were assessed by multivariable adjusted conditional logistic regression analyses. Results Chemotherapy was associated with a lower risk for contralateral breast cancer (RR = 0.57, 95% CI = 0.42 to 0.75) than no chemotherapy. A statistically significant association between chemotherapy and reduced risk for contralateral breast cancer persisted up to 10 years after the first breast cancer diagnosis and was stronger among women who became postmenopausal within 1 year of the first breast cancer diagnosis (RR = 0.28, 95% CI = 0.11 to 0.76). Tamoxifen use was also associated with reduced risk for contralateral breast cancer (RR = 0.66, 95% CI = 0.50 to 0.88) compared with no use, and the association was statistically significant for 5 years after the first diagnosis. Conclusion The associations between chemotherapy and tamoxifen treatment and reduced risk for contralateral breast cancer appear to continue for 10 and 5 years, respectively, after the initial breast cancer is diagnosed. Ovarian suppression may have a role in the association between chemotherapy and reduced risk for contralateral breast cancer.

Cancer survivors constitute 3.5% of the United States population, but second primary malignancies among this high-risk group now account for 16% of all cancer incidence. Although few data currently exist regarding the molecular mechanisms for second primary cancers and other late outcomes after cancer treatment, the careful measurement and documentation of potentially carcinogenic treatments (chemotherapy and radiotherapy) provide a unique platform for in vivo research on gene-environment interactions in human carcinogenesis. We review research priorities identified during a National Cancer Institute (NCI)-sponsored workshop entitled 'Cancer Survivorship--Genetic Susceptibility and Second Primary Cancers.' These priorities include 1) development of a national research infrastructure for studies of cancer survivorship; 2) creation of a coordinated system for biospecimen collection; 3) development of new technology, bioinformatics, and biomarkers; 4) design of new epidemiologic methods; and 5) development of evidence-based clinical practice guidelines. Many of the infrastructure resources and design strategies that would facilitate research in this area also provide a foundation for the study of other important nonneoplastic late effects of treatment and psychosocial concerns among cancer survivors. These research areas warrant high priority to promote NCI's goal of eliminating pain and suffering related to cancer.

Background: Germline mutations in the CDKN2A gene have been linked to melanoma incidence in many families with multiple cases of the disease. Previous studies of multiple-case families have indicated that the lifetime risk (i.e., penetrance) of melanoma in CDKN2A mutation carriers is very high, ranging from 58% in Europe to 91% in Australia by age 80 years, in this study, we examined lifetime melanoma risk among CDKN2A mutation carriers using carriers who were identified in a population-based study of melanoma. Methods: Probands for the study were incident case patients with either first or subsequent melanoma who were identified in nine geographic regions in Australia, Canada, the United States, and Italy. A total of 3626 probands (53% participation rate) with adequate DNA for analysis were recruited and genotyped for CDKN2A mutations. From the 3550 probands whose DNA could be amplified by polymerase chain reaction of CDKN2A exons In, 2, and 3 and surrounding regions, 65 mutation carriers were identified. Melanoma histories in first-degree relatives of these probands were used to calculate the lifetime risk in CDKN2A mutation carriers using the kin--cohort method. Results': The risk of melanoma in CDKN2A mutation carriers was approximately 14% (95% CI = 8% to 22%) by age 50 years, 24% (95% CI = 15% to 34%) by age 70 years, and 28% (95% CI = 18% to 40%) by age 80 years. Eighteen probands had three or more first-degree relatives with melanoma, but only one was a carrier of a CDKN2A mutation. Conclusions: CDKN2A mutation carriers in the general population have a much lower risk of melanoma than that suggested by estimates obtained from multiple-case families. The preponderance of familial clustering of melanoma occurs in families without identifiable mutations in CDKN2A.

Study objectives: To develop and validate a model for estimating the risk of lung cancer death in current and former smokers. The model is intended for use in analyzing a [...]

Background: Patients diagnosed with superficial bladder cancer who have not undergone total cystectomy are at high risk for recurrence, and bladder surveillance with cystoscopy is recommended for such patients every 3-6 months. We examined the degree to which bladder cancer patients undergo the recommended surveillance procedures and identified patient and primary care provider characteristics associated with nonadherence to these recommendations. Methods: We used information obtained from the Surveillance, Epidemiology, and End Results (SEER) Program--Medicare-linked database to identify 6717 patients aged 65 years or older who were diagnosed with superficial bladder cancer from 1992 through 1996 and who survived for at least 3 years after diagnosis but did not have a total cystectomy. We used information obtained from Medicare claims forms to examine the frequency with which these patients had a surveillance examination of the bladder during each of five contiguous 6-month intervals from month 7 to month 36 following diagnosis. We examined characteristics of patients and their physicians that were associated with low-intensity surveillance (defined as having an examination during fewer than two of the five possible follow-up intervals). Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results: Only 40% of the entire cohort had an examination during all five intervals; 1216 patients (18.1%) had low-intensity surveillance. Patient characteristics that were independently associated with low-intensity surveillance were being age 75 years or older (adjusted OR = 1.54, 95% CI = 1.35 to 1.74), nonwhite (adjusted OR = 1.94, 95% CI = 1.57 to 2.40), and having favorable tumor histology (adjusted OR = 0.59, 95% CI = 0.48 to 0.72 for poorly differentiated versus referent well-differentiated tumor grade) and high comorbidity (adjusted OR = 1.72, 95% CI = 1.30 to 2.27). Residence in an urban area or in a census tract with low median income was also associated with low-intensity surveillance. Conclusions: The actual practice of surveillance for patients with superficial bladder cancer differs substantially from the standards recommended in clinical guidelines.

Background: Although there is no proven benefit associated with screening for lung cancer, screening programs are attracting many individuals who perceive themselves to be at high risk due to smoking. We sought to determine whether the risk of lung cancer varies predictably among smokers. Methods: We used data on 18172 subjects enrolled in the Carotene and Retinol Efficacy Trial (CARET)--a large, randomized trial of lung cancer prevention--to derive a lung cancer risk prediction model. Model inputs included the subject's age, sex, asbestos exposure history, and smoking history. We assessed the model's calibration by comparing predicted and observed rates of lung cancer across risk deciles and validated it by assessing the extent to which a model estimated on data from five CARET study sites could predict events in the sixth study site. We then applied the model to evaluate the risk of lung cancer among smokers enrolled in a study of lung cancer screening with computed tomography (CT). Results: The model was internally valid and well calibrated. Ten-year lung cancer risk varied greatly among participants in the CT study, from 15% for a 68-year-old man who has smoked two packs per day for 50 years and continues to smoke, to 0.8% for a 51-year-old woman who smoked one pack per day for 28 years before quitting 9 years earlier. Even among the subset of CT study participants who would be eligible for a clinical trial of cancer prevention, risk varied greatly. Conclusions: The risk of lung cancer varies widely among smokers. Accurate risk prediction may help individuals who are contemplating voluntary screening to balance the potential benefits and risks. Risk prediction may also be useful for researchers designing clinical trials of lung cancer prevention. [J Natl Cancer Inst 2003;95:470-8]

Background: Estimating the lifetime risk associated with (i.e., the penetrance of) genetic abnormalities that predispose individuals to cancer is important for genetic counseling. (Penetrance may be estimated from the degree of familial aggregation of cancer, that is, the extent to which cancers cluster in families.) Early penetrance studies of BRCA1 and BRCA2 mutations used high-risk families with multiple cases of breast cancer, a study design that led to very high penetrance estimates. However, such studies were subject to potential ascertainment biases. To offset such biases, recent studies have used data from family members of probands ascertained from population-based incident cases of cancer. The use of case probands is, however, also subject to bias because all risk factors are over-represented in case patients. To draw attention to this problem, literature on the penetrance of breast cancer in BRCA1 and BRCA2 carriers is reviewed. Methods: A theory is presented to show that the use of case probands is itself biased, leading to inflated penetrance estimates. The strategy is unbiased only if all carriers share an identical risk. Any unexplained heterogeneity of risk caused by unknown genetic or shared environmental factors within families leads to an inflated estimate of penetrance. Results: Eight published studies using population-based methods are reviewed. All but one of the family-based studies used case probands. Conclusions: Penetrance estimates from case proband studies must be inflated if other factors influence breast cancer risk in addition to the specific genetic abnormality. Thus, women with such genetic abnormalities and a strong family history of breast cancer are likely to possess a much higher risk for breast cancer than women with such abnormalities but without a strong family history. Methodologic techniques to improve the prediction of cancer risk are needed.

Associations of MC1Rwith BRAFmutations in melanoma have been inconsistent between studies. We sought to determine for 1,227 participants in the international population-based Genes, Environment, and Melanoma (GEM) study whether MC1Rand phenotypes were associated with melanoma BRAF/NRASsubtypes. We used logistic regression adjusted by age, sex, and study design features and examined effect modifications. BRAF+were associated with younger age, blond/light brown hair, increased nevi, and less freckling, and NRAS+with older age relative to the wild type (BRAF–/NRAS–) melanomas (all P< 0.05). Comparing specific BRAFsubtypes to the wild type, BRAFV600E was associated with younger age, blond/light brown hair, and increased nevi and V600K with increased nevi and less freckling (all P< 0.05). MC1Rwas positively associated with BRAFV600E cases but only among individuals with darker phototypes or darker hair (Pinteraction< 0.05) but inversely associated with BRAFV600K (Ptrend = 0.006) with no significant effect modification by phenotypes. These results support distinct etiologies for BRAFV600E, BRAFV600K, NRAS+, and wild-type melanomas. MC1R’s associations with BRAFV600E cases limited to individuals with darker phenotypes indicate that MC1Rgenotypes specifically provide information about BRAFV600E melanoma risk in those not considered high risk based on phenotype. Our results also suggest that melanin pathways deserve further study in BRAFV600E melanomagenesis.

Germline variants in the melanocortin 1 receptor gene (MC1R)might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1Rvariants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1Rvariants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls.

BRAFand NRASmutations arise early in melanoma development, but their associations with low-penetrance melanoma susceptibility loci remain unknown. In the Genes, Environment and Melanoma Study, 1,223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRASmutations and germline DNA genotyped for 47 single-nucleotide polymorphisms identified as low-penetrant melanoma-risk variants. We used multinomial logistic regression to simultaneously examine each single-nucleotide polymorphism’s relationship to BRAFV600E, BRAFV600K, BRAFother, and NRAS+ relative to BRAF–/NRAS–melanoma adjusted for study features. IRF4rs12203592*T was associated with BRAFV600E (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.43–0.79) and V600K (OR = 0.65, 95% CI = 0.41–1.03), but not BRAFother or NRAS+melanoma. A global test of etiologic heterogeneity (Pglobal = 0.001) passed false discovery (Pglobal = 0.0026). PLA2G6rs132985*T was associated with BRAFV600E (OR = 1.32, 95% CI = 1.05–1.67) and BRAFother (OR = 1.82, 95% CI = 1.11–2.98), but not BRAFV600K or NRAS+melanoma. The test for etiologic heterogeneity (Pglobal) was 0.005. The IRF4rs12203592 associations were slightly attenuated after adjustment for melanoma-risk phenotypes. The PLA2G6rs132985 associations were independent of phenotypes. IRF4and PLA2G6inherited genotypes may influence melanoma BRAF/NRASsubtype development.

Background: Randomized trials have established that 5-fluorouracil-based adjuvant chemotherapy following resection of stage III colon cancer reduces subsequent mortality by as much as 30%. However, the extent to which adjuvant therapy is used outside the clinical trial setting, particularly among the elderly, is unknown. Methods: A retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results/Medicare-linked database identified 6262 patients aged 65 years and older with resected stage III colon cancer. The primary outcome was chemotherapy use within 3 months of surgery, as ascertained from Medicare claims. We examined the extent to which age at diagnosis was associated with adjuvant chemotherapy usage, and we adjusted for potential confounding based on differences in other patient characteristics with the use of multiple logistic regression. All P values were two-sided. Results: Age at diagnosis was the strongest determinant of chemotherapy: 78% of patients aged 65-69 years, 74% of those aged 70-74 years, 58% of those aged 75-79 years, 34% of those aged 80-84 years, and 11% of those aged 85-89 years received postoperative chemotherapy. The age trend remained pronounced after adjustment for potential confounding based on variation in patients' demographic and clinical characteristics and after exclusion of patients with any evident comorbidity (all P values [is less than] .001). Conclusions: Adjuvant chemotherapy for stage III colon cancer is used extensively, especially for patients under the age of 75 years. However, treatment rates decline dramatically with chronologic age. Because patients in their 70s and even 80s have a reasonable life expectancy, further efforts are needed to ensure that elderly patients have the opportunity to make informed decisions regarding this potentially curative treatment. [J Natl Cancer Inst 2001; 93:850-7]

IMPORTANCE: We previously reported that survival is poorer from histopathologically amelanotic than pigmented melanoma because of more advanced stage at diagnosis. Identifying patients at risk of amelanotic melanoma might enable earlier diagnosis and improved survival; however, the phenotypic characteristics and underlying genetics associated with amelanotic melanoma are unknown. OBJECTIVE: To determine whether phenotypic characteristics, carriage of MC1R variants, and history of amelanotic melanoma are associated with histopathologically amelanotic melanoma. DESIGN, SETTING, AND PARTICIPANTS: The Genes, Environment, and Melanoma (GEM) study is an international cohort study that enrolled patients with incident primary cutaneous melanomas from population-based and hospital-based cancer registries (1998 to 2003). The GEM participants included here were 2387 patients with data for phenotypes, MC1R genotype, and primary melanomas scored for histopathologic pigmentation. Of these 2387 patients with incident melanomas scored for pigmentation, 527 had prior primary melanomas also scored for pigmentation. MAIN OUTCOMES AND MEASURES: Associations of phenotypic characteristics (freckles, nevi, phenotypic index) and MC1R status with incident amelanotic melanomas were evaluated using logistic regression models adjusted for age, sex, study center, and primary status (single or multiple primary melanoma); odds ratios (ORs) and 95% CIs are reported. Association of histopathologic pigmentation between incident and prior melanomas was analyzed using an exact logistic regression model. RESULTS: This study included 2387 patients (1065 women, 1322 men; mean [SD] age at diagnosis, 58.3 [16.1] years) and 2917 primary melanomas. In a multivariable model including phenotypic characteristics, absence of back nevi, presence of many freckles, and a sun-sensitive phenotypic index were independently associated with amelanotic melanoma. Carriage of MC1R variants was associated with amelanotic melanoma but lost statistical significance in a model with phenotype. Further, patients with incident primary amelanotic melanomas were more likely to have had a prior primary amelanotic melanoma (OR, 4.62; 95% CI, 1.25-14.13) than those with incident primary pigmented melanomas. CONCLUSIONS AND RELEVANCE: Absence of back nevi, presence of many freckles, a sun-sensitive phenotypic index, and prior amelanotic melanoma increase odds for development of amelanotic melanoma. An increased index of suspicion for melanoma in presenting nonpigmented lesions and more careful examination for signs of amelanotic melanoma during periodic skin examination in patients at increased odds of amelanotic melanoma might lead to earlier diagnosis and improved survival.

Supplemental Digital Content is available in the text.The Lorenz curve is a graphical tool that is used widely in econometrics. It represents the spread of a probability distribution, and its traditional use has been to characterize population distributions of wealth or income, or more specifically, inequalities in wealth or income. However, its utility in public health research has not been broadly established. The purpose of this article is to explain its special usefulness for characterizing the population distribution of disease risks, and in particular for identifying the precise disease burden that can be predicted to occur in segments of the population that are known to have especially high (or low) risks, a feature that is important for evaluating the yield of screening or other disease prevention initiatives. We demonstrate that, although the Lorenz curve represents the distribution of predicted risks in a population at risk for the disease, in fact it can be estimated from a case–control study conducted in the population without the need for information on absolute risks. We explore two different estimation strategies and compare their statistical properties using simulations. The Lorenz curve is a statistical tool that deserves wider use in public health research.

Aim:Melanoma survivors can play a pivotal role in raising family melanoma risk awareness, but are not always aware of family risk. This study examines patterns and sources of survivors’ awareness that first-degree relatives (FDRs) face heightened melanoma risk. Patients & methods:Population-based melanoma survivors (n = 170) completed a 15-min telephone interview. Logistic regressions examining covariates were conducted using awareness (yes vs no) of heightened risk to FDRs as the dependent variable. Results:Almost half (41%) were unaware that their FDRs faced heightened melanoma risk. Of those 59% who were aware, most learned this from dermatologists. In multivariable analyses perceived risk and body site remained significant. Conclusion:Many melanoma survivors remain unaware that their FDRs are at melanoma risk. The results underscore the role that dermatologists and other doctors play in fostering risk awareness. Sensitivity to providing family risk information to survivors who have lower risk perceptions, regardless of anatomic site, is warranted.

IMPORTANCE: NRAS and BRAF mutations in melanoma inform current treatment paradigms, but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. OBJECTIVE: To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. DESIGN, SETTING, AND PARTICIPANTS: A population-based study with a median follow-up of 7.6 years (through 2007), including 912 patients from the United States and Australia in the Genes, Environment, and Melanoma (GEM) Study, with first primary cutaneous melanoma diagnosed in the year 2000 and analyzed for NRAS and BRAF mutations. MAIN OUTCOMES AND MEASURES: Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. RESULTS: The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype [WT]). In a multivariable model including clinicopathologic characteristics, relative to WT melanoma (with results reported as odds ratios [95% CIs]), NRAS+ melanoma was associated with presence of mitoses (1.8 [1.0-3.3]), lower tumor-infiltrating lymphocyte (TIL) grade (nonbrisk, 0.5 [0.3-0.8]; and brisk, 0.3 [0.5-0.7] [vs absent TILs]), and anatomic site other than scalp/neck (0.1 [0.01-0.6] for scalp/neck vs trunk/pelvis), and BRAF+ melanoma was associated with younger age (ages 50-69 years, 0.7 [0.5-1.0]; and ages >70 years, 0.5 [0.3-0.8] [vs &lt;50 years]), superficial spreading subtype (nodular, 0.5 [0.2-1.0]; lentigo maligna, 0.4 [0.2-0.7]; and unclassified/other, 0.2 [0.1-0.5] [vs superficial spreading]), and presence of mitoses (1.7 [1.1-2.6]) (P &lt; .05 for all). There was no significant difference in melanoma-specific survival (reported as hazard ratios [95% CIs]) for melanoma harboring mutations in NRAS (1.7 [0.8-3.4]) or BRAF (1.5 [0.8-2.9]) compared with WT melanoma, as adjusted for age, sex, site, American Joint Committee on Cancer (AJCC) tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher-risk (T2b or higher stage) tumors with NRAS (2.9 [1.1-7.7]) or BRAF (3.1 [1.2-8.5]) mutations (P = .04) but not for lower-risk (T2a or lower) tumors with NRAS (0.9 [0.3-3.0]) or BRAF (0.6 [0.2-1.7]) (P = .65), as adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. CONCLUSIONS AND RELEVANCE: Lower TIL grade for NRAS+ melanoma suggests it has a more immunosuppressed microenvironment, which may affect its response to immunotherapies. The approximate 3-fold increased risk of death for higher-risk tumors harboring NRAS or BRAF mutations after adjusting for other prognostic factors compared with WT melanomas indicates that the prognostic implication of these mutations deserves further investigation, particularly in higher–AJCC stage primary melanomas.

IMPORTANCE: Previous studies have reported that histopathologically amelanotic melanoma is associated with poorer survival than pigmented melanoma; however, small numbers of amelanotic melanomas, selected populations, lack of centralized pathologic review, or no adjustment for stage limit the interpretation or generalization of results from prior studies. OBJECTIVE: To compare melanoma-specific survival between patients with histopathologically amelanotic and those with pigmented melanoma in a large international population-based study. DESIGN, SETTING, AND PARTICIPANTS: Survival analysis with a median follow-up of 7.6 years. The study population comprised 2995 patients with 3486 invasive primary melanomas centrally scored for histologic pigmentation from the Genes, Environment, and Melanoma (GEM) Study, which enrolled incident cases of melanoma diagnosed in 1998 through 2003 from international population-based cancer registries. MAIN OUTCOMES AND MEASURES: Clinicopathologic predictors and melanoma-specific survival of histologically amelanotic and pigmented melanoma were compared using generalized estimating equations and Cox regression models, respectively. RESULTS: Of 3467 melanomas, 275 (8%) were histopathologically amelanotic. Female sex, nodular and unclassified or other histologic subtypes, increased Breslow thickness, presence of mitoses, severe solar elastosis, and lack of a coexisting nevus were independently associated with amelanotic melanoma (each P &lt; .05). Amelanotic melanoma was generally of a higher American Joint Committee on Cancer (AJCC) tumor stage at diagnosis (odds ratios [ORs] [95% CIs] between 2.9 [1.8-4.6] and 11.1 [5.8-21.2] for tumor stages between T1b and T3b and ORs [95% CIs] of 24.6 [13.6-44.4] for T4a and 29.1 [15.5-54.9] for T4b relative to T1a; P value for trend, &lt;.001) than pigmented melanoma. Hazard of death from melanoma was higher for amelanotic than for pigmented melanoma (hazard ratio [HR], 2.0; 95% CI, 1.4-3.0) (P &lt; .001), adjusted for age, sex, anatomic site, and study design variables, but survival did not differ once AJCC tumor stage was also taken into account (HR, 0.8; 95% CI, 0.5-1.2) (P = .36). CONCLUSIONS AND RELEVANCE: At the population level, survival after diagnosis of amelanotic melanoma is poorer than after pigmented melanoma because of its more advanced stage at diagnosis. It is probable that amelanotic melanomas present at more advanced tumor stages because they are difficult to diagnose. The association of amelanotic melanoma with presence of mitoses independently of Breslow thickness and other clinicopathologic characteristics suggests that amelanotic melanomas might also grow faster than pigmented melanomas. New strategies for early diagnosis and investigation of the biological properties of amelanotic melanoma are warranted.

PURPOSE: Eligibility for voluntary screening and for prevention and early detection trials in lung cancer is usually determined based on the presence or absence of threshold values of risk factors [...]

Several authors have proposed the use of patients with double primary malignancies affecting the same or contralateral organ as a genetically enriched resource of cases for epidemiologic case–control studies in cancer. Such an approach is based on the assumption that the factors that increase the risk of a second primary are the same ones which influence the risk of a first primary. The advantages for statistical power are premised on the assumption that relative risks in survivors of a first primary cancer are similar to relative risks in the unaffected population. We explore these assumptions theoretically and empirically using published data from breast cancer studies involving bilateral breast cancer.

Cancer at the resection margin (a positive surgical margin) after radical prostatectomy is associated with an increased risk of recurrence even after adjusting for other known risk factors, including pretreatment serum prostate specific antigen (PSA), clinical stage, grade and pathological stage (level of extracapsular extension, seminal vesicle invasion and pelvic lymph node status). Of these prognostic factors only surgical margin status can be influenced by surgical technique. We examined variations in the rate of positive surgical margins among surgeons after controlling for the severity of disease and volume of cases per surgeon.

Summary. The goal of this article is to describe a two‐stage design that maximizes the power to detect gene‐disease associations when the principal design constraint is the total cost, represented by the total number of gene evaluations rather than the total number of individuals. In the first stage, all genes of interest are evaluated on a subset of individuals. The most promising genes are then evaluated on additional subjects in the second stage. This will eliminate wastage of resources on genes unlikely to be associated with disease based on the results of the first stage. We consider the case where the genes are correlated and the case where the genes are independent. Using simulation results, it is shown that, as a general guideline when the genes are independent or when the correlation is small, utilizing 75% of the resources in stage 1 to screen all the markers and evaluating the most promising 10% of the markers with the remaining resources provides near‐optimal power for a broad range of parametric configurations. This translates to screening all the markers on approximately one quarter of the required sample size in stage 1.

Summary. A nonparametric test is derived for comparing treatments with respect to the final endpoint in clinical trials in which the final endpoint has been observed for a random subset of patients, but results are available for a surrogate endpoint for a larger sample of patients. The test is an adaptation of the Wilcoxon–Mann–Whitney two‐sample test, with an adjustment that involves a comparison of the ranks of the surrogate endpoints between patients with and without final endpoints. The validity of the test depends on the assumption that the patients with final endpoints represent a random sample of the patients registered in the study. This assumption is viable in trials in which the final endpoint is evaluated at a “landmark” timepoint in the patients' natural history. A small sample simulation study demonstrates that the test has a size that is close to the nominal value for all configurations evaluated. When compared with the conventional test based only on the final endpoints, the new test delivers substantial increases in power only when the surrogate endpoint is highly correlated with the true endpoint. Our research indicates that, in the absence of modeling assumptions, auxiliary information derived from surrogate endpoints can provide significant additional information only under special circumstances.

The Eastern Cooperative Oncology Group conducted a randomized study to determine the efficacy of consolidation therapy in prolonging the duration of complete remission (CR) in adults with acute nonlymphocytic leukemia (ANLL). Induction chemotherapy with daunorubicin, cytosine arabinoside, and 6-thioguanine (DAT) yielded CR in 65% of 283 patients with ANLL, aged 16-69. For patients aged 60-69, the CR rate was 58%. Of 184 patients in CR, 146 patients were then randomized to receive either maintenance therapy with weekly cytosine arabinoside and 6-thioguanine alone (69 patients) or two courses of reduced doses of DAT 1 mo apart, before commencing the same maintenance program (77 patients). Consolidation therapy resulted in hematologic toxicity, but was not lethal in any of the eligible patients. Patients receiving consolidation plus maintenance therapy experienced a longer CR duration (40 wk) and disease-free survival at 2 yr (28%) than did those patients receiving maintenance therapy alone (34 wk and 14%, respectively). These differences are not statistically significant. These results suggest that approaches to consolidation therapy employing reduced doses of the induction therapy regimen can have, at best, only a small benefit. For consolidation therapy to provide substantial improvement in CR duration, intensive regimens with non-cross-resistant drugs will be required.

The lecithin/sphingomyelin ratio (US) and the measured value of saturated phosphatidyl choline (SPC), amniotic fluid determinations obtained to assess fetal pulmonary maturity, were evaluated with receiver operating characteristic (ROC) curve analysis. The effects of covariates on the ROC curves were analyzed with a regression methodology that took into account all the available data when constructing an ROC curve for each subgroup. To correct for verification bias the authors used a logistic regression analysis to model the probability of verification, thereby permitting correction for verification bias of a fully stratified data set in spite of small cell frequencies. They examined combination testing with prediction rules using prospective logistic modeling, including as variables test results and clinical features. The US was found to be significantly better than SPC for assessing fetal pulmonary maturity. For older gestational age the US and SPC performed better than for younger gestational age. Contamination of the specimen degraded the ROC curves. Correcting for verification bias did not influence the ROC curves significantly but changed the cutoff value of the test variable for any particular operating point. Prediction rules to evaluate combination testing showed that obtaining the SPC level in addition to the US ratio added no significant infor mation compared with the US only. Including gestational age in the prediction rule of either test improved the prediction. Key words:receiver operating characteristic curve; fetal pul monary maturity testing; covariates; verification bias; combination testing. (Med Decis Mak ing 1990;10:201-211)

A method for applying generalized ordinal regression models to categorical rating data to estimate and analyze receiver operating characteristic (ROC) curves is presented. These models permit parsimonious adjustment of ROC curve parameters for relevant covariates through two regression equations that correspond to location and scale. Particular shapes of ROC curves are interpreted in relation to the kind of covariates included in the two regressions. The model is shown to be flexible because it is not restricted to the assumption of binormality that is commonly employed in smoothed ROC curve estimation, although the binormal model is one particular form of the more general model. The new method provides a mechanism for pinpointing the effect that interobserver variability has on the ROC curve. It also allows for the adjustment of ROC curves for temporal variation and case mix, and provides a way to assess the incremental diagnostic value of a test. The new methodology is recommended because it substantially improves the ability to assess diagnostic tests using ROC curves. Key words:ROC curves; ordinal regression; technology assessment; diagnostic tests. (Med Decis Making 8:204-215, 1988)

Concern with the efficacy of diagnostic technologies has stimulated numerous studies aimed at quantifying the discriminatory properties of various tests and procedures. These have focused principally on estimations of the result conditional probabilities, given disease status, eg, the sensitivity and specificity or the ROC curve. A source of bias in estimating these probabilities that is often unavoidable is created by the existence of a nonrandom selection mechanism for determining which patients initially tested will receive definitive verification of disease status. Correction for verification bias requires frequency data on the test results and any symptoms or other factors that influence selection for verification, both in the verified sample and in the source sample of patients tested.

Publication bias, the phenomenon in which studies with positive results are more likely to be published than studies with negative results, is a serious problem in the interpretation of scientific research. Various hypothetical models have been studied which clarify the potential for bias and highlight characteristics which make a study especially susceptible to bias. Empirical investigations have supported the hypothesis that bias exists and have provided a quantitative assessment of the magnitude of the problem. The use of meta‐analysis as a research tool has focused attention on the issue, since naive methodologies in this area are especially susceptible to bias. In this paper we review the available research, discuss alternative suggestions for conducting unbiased meta‐analysis and suggest some scientific policy measures which could improve the quality of published data in the long term.

In an attempt to clarify appropriate treatment options for women with stage IV breast cancer, we studied the survival experience of a large dataset of patients treated on Cancer and Leukemia Group B (CALGB) protocols. The study, restricted to women who had had no prior chemotherapy for metastatic disease, demonstrated a surprisingly poor prognosis, with an estimated median survival of 1.6 years and only 26% alive at 3 years. Analysis of prognostic factors permitted the identification of subsets with even shorter survival, such as women with estrogen receptor negative tumor in more than one metastatic site and prior adjuvant chemotherapy. We feel that an evaluation of intensive investigational treatment approaches, such as trials using autologous bone marrow transplantation, is justified for most stage IV breast cancer patients, in view of their poor prognosis.

A retrospective review revealed a 42% error rate between computed tomographic scan reports and thoracotomy findings; therefore, a prospective study was designed to compare the value of computed tomographic scans, video-assisted thoracoscopic exploration, and open thoracotomy in the management of pulmonary metastases.

In an effort to understand the difference between melanomas diagnosed in Australia (New South Wales) and Canada, where the incidence in New South Wales is almost three times greater than in Canada, and mortality is twice as high although survival is slightly more favorable, we had one pathologist review 1,271 melanomas from British Columbia and Ontario, Canada, to compare these to melanomas in New South Wales, Australia. We hypothesized that histopathologic characteristics might provide insight into divergent pathways to melanoma development. We found a number of differences in risk factors and tumor characteristics between the two geographic areas. There were higher mole counts and darker phenotypes in the Canadian patients, while the Australian patients had greater solar elastosis, more lentigo maligna melanomas, and more tumor infiltrating lymphocytes. We hypothesize that the differences observed may illustrate different etiologies – the cumulative exposure pathway among Australian patients and the nevus pathway among Canadian patients. This is one of the largest studies investigating the divergent pathway hypothesis and is particularly robust due to the evaluation of all lesions by one dermatopathologist.