Showing papers in "Journal of the National Cancer Institute in 2010"

Overdiagnosis in Cancer

Abstract: This article summarizes the phenomenon of cancer overdiagnosis—the diagnosis of a “cancer” that would otherwise not go on to cause symptoms or death. We describe the two prerequisites for cancer overdiagnosis to occur: the existence of a silent disease reservoir and activities leading to its detection (particularly cancer screening). We estimated the magnitude of overdiagnosis from randomized trials: about 25% of mammographically detected breast cancers, 50% of chest x-ray and/or sputum-detected lung cancers, and 60% of prostate-specific antigen–detected prostate cancers. We also review data from observational studies and population-based cancer statistics suggesting overdiagnosis in computed tomography–detected lung cancer, neuroblastoma, thyroid cancer, melanoma, and kidney cancer. To address the problem, patients must be adequately informed of the nature and the magnitude of the trade-off involved with early cancer detection. Equally important, researchers need to work to develop better estimates of the magnitude of overdiagnosis and develop clinical strategies to help minimize it.

Cardiotoxicity of Anticancer Drugs: The Need for Cardio-Oncology and Cardio-Oncological Prevention

Abstract: Due to the aging of the populations of developed countries and a common occurrence of risk factors, it is increasingly probable that a patient may have both cancer and cardiovascular disease. In addition, cytotoxic agents and targeted therapies used to treat cancer, including classic chemotherapeutic agents, monoclonal antibodies that target tyrosine kinase receptors, small molecule tyrosine kinase inhibitors, and even antiangiogenic drugs and chemoprevention agents such as cyclooxygenase-2 inhibitors, all affect the cardiovascular system. One of the reasons is that many agents reach targets in the microenvironment and do not affect only the tumor. Combination therapy often amplifies cardiotoxicity, and radiotherapy can also cause heart problems, particularly when combined with chemotherapy. In the past, cardiotoxic risk was less evident, but it is increasingly an issue, particularly with combination therapy and adjuvant therapy. Today's oncologists must be fully aware of cardiovascular risks to avoid or prevent adverse cardiovascular effects, and cardiologists must now be ready to assist oncologists by performing evaluations relevant to the choice of therapy. There is a need for cooperation between these two areas and for the development of a novel discipline, which could be termed cardio-oncology or onco-cardiology. Here, we summarize the potential cardiovascular toxicities for a range of cancer chemotherapeutic and chemopreventive agents and emphasize the importance of evaluating cardiovascular risk when patients enter into trials and the need to develop guidelines that include collateral effects on the cardiovascular system. We also discuss mechanistic pathways and describe several potential protective agents that could be administered to patients with occult or overt risk for cardiovascular complications.

Therapy-Induced Senescence in Cancer

Abstract: Cellular senescence is a response to nonlethal stress that results in persistent cytostasis with a distinct morphological and biochemical phenotype The senescence phenotype, detected in tumors through the expression of mRNA and protein markers, can be generated in cancer cells lacking functional p53 and retinoblastoma protein Current research suggests that therapy-induced senescence (TIS) represents a novel functional target that may improve cancer therapy TIS can be induced in immortal and transformed cancer cells by selected anticancer compounds or radiation, and accumulating data indicate that TIS may produce reduced toxicity-related side effects and increased tumor-specific immune activity This review examines the current status of TIS-regulated mechanisms, agents, and senescence biomarkers with the goal of encouraging further development of this approach to cancer therapy Remaining hurdles include the lack of efficient senescence-inducing agents and incomplete biological data on tumor response The identification of additional compounds and other targeted approaches to senescence induction will further the development of TIS in the clinical treatment of cancer

Subsequent Neoplasms in 5-Year Survivors of Childhood Cancer: The Childhood Cancer Survivor Study

Abstract: Background The occurrence of subsequent neoplasms has direct impact on the quantity and quality of life in cancer survivors. We have expanded our analysis of these events in the Childhood Cancer Survivor Study (CCSS) to better understand the occurrence of these events as the survivor population ages. Methods The incidence of and risk for subsequent neoplasms occurring 5 years or more after the childhood cancer diagnosis were determined among 14 359 5-year survivors in the CCSS who were treated from 1970 through 1986 and who were at a median age of 30 years (range = 5–56 years) for this analysis. At 30 years after childhood cancer diagnosis, we calculated cumulative incidence at 30 years of subsequent neoplasms and calculated standardized incidence ratios (SIRs), excess absolute risks (EARs) for invasive second malignant neoplasms, and relative risks for subsequent neoplasms by use of multivariable Poisson regression. Results Among 14 359 5-year survivors, 1402 subsequently developed 2703 neoplasms. Cumulative incidence at 30 years after the childhood cancer diagnosis was 20.5% (95% confidence interval [CI] = 19.1% to 21.8%) for all subsequent neoplasms, 7.9% (95% CI = 7.2% to 8.5%) for second malignant neoplasms (excluding nonmelanoma skin cancer), 9.1% (95% CI = 8.1% to 10.1%) for nonmelanoma skin cancer, and 3.1% (95% CI = 2.5% to 3.8%) for meningioma. Excess risk was evident for all primary diagnoses (EAR = 2.6 per 1000 person-years, 95% CI = 2.4 to 2.9 per 1000 person-years; SIR = 6.0, 95% CI = 5.5 to 6.4), with the highest being for Hodgkin lymphoma (SIR = 8.7, 95% CI = 7.7 to 9.8) and Ewing sarcoma (SIR = 8.5, 95% CI = 6.2 to 11.7). In the Poisson multivariable analysis, female sex, older age at diagnosis, earlier treatment era, diagnosis of Hodgkin lymphoma, and treatment with radiation therapy were associated with increased risk of subsequent neoplasm. Conclusions As childhood cancer survivors progress through adulthood, risk of subsequent neoplasms increases. Patients surviving Hodgkin lymphoma are at greatest risk. There is no evidence of risk reduction with increasing duration of follow-up.

Protection From Right- and Left-Sided Colorectal Neoplasms After Colonoscopy: Population-Based Study

Abstract: BACKGROUND: Colonoscopy is used for early detection and prevention of colorectal cancer, but evidence on the magnitude of overall protection and protection according to anatomical site through colonoscopy performed in the community setting is sparse. We assessed whether receiving a colonoscopy in the preceding 10-year period, compared with no colonoscopy, was associated with prevalence of advanced colorectal neoplasms (defined as cancers or advanced adenomas) at various anatomical sites. METHODS: A statewide cross-sectional study was conducted among 3287 participants in screening colonoscopy between May 1, 2005, and December 31, 2007, from the state of Saarland in Germany who were aged 55 years or older. Prevalence of advanced colorectal neoplasms was ascertained by screening colonoscopy and histopathologic examination of any polyps excised. Previous colonoscopy history was obtained by standardized questionnaire, and its association with prevalence of advanced colorectal neoplasms was estimated, after adjustment for potential confounding factors by log-binomial regression. RESULTS: Advanced colorectal neoplasms were detected in 308 (11.4%) of the 2701 participants with no previous colonoscopy compared with 36 (6.1%) of the 586 participants who had undergone colonoscopy within the preceding 10 years. After adjustment, overall and site-specific adjusted prevalence ratios for previous colonoscopy in the previous 10-year period were as follows: overall, 0.52 (95% confidence interval [CI] = 0.37 to 0.73); cecum and ascending colon, 0.99 (95% CI = 0.50 to 1.97); hepatic flexure and transverse colon, 1.21 (95% CI = 0.60 to 2.42); right-sided colon combined (cecum to transverse colon), 1.05 (95% CI = 0.63 to 1.76); splenic flexure and descending colon, 0.36 (95% CI = 0.16 to 0.82); sigmoid colon, 0.29 (95% CI = 0.16 to 0.53); rectum, 0.07 (95% CI = 0.02 to 0.40); left colon and rectum combined (splenic flexure to rectum, referred to as left-sided elsewhere), 0.33 (95% CI = 0.21 to 0.53). CONCLUSION: Prevalence of left-sided advanced colorectal neoplasms, but not right-sided advanced neoplasms, was strongly reduced within a 10-year period after colonoscopy, even in the community setting.

Impact of Human Papillomavirus (HPV)-6/11/16/18 Vaccine on All HPV-Associated Genital Diseases in Young Women

Abstract: Results The average follow-up was 3.6 years (maximum of 4.9 years). In the population that was negative to 14 HPV types, vaccination was up to 100% effective in reducing the risk of HPV16/18-related high-grade cervical, vulvar, and vaginal lesions and of HPV6/11-related genital warts. In the intention-to-treat group, vaccination also statistically significantly reduced the risk of any high-grade cervical lesions (19.0% reduction; rate vaccine = 1.43, rate placebo = 1.76, difference = 0.33, 95% confidence interval [CI] = 0.13 to 0.54), vulvar and vaginal lesions (50.7% reduction; rate vaccine = 0.10, rate placebo = 0.20, difference = 0.10, 95% CI = 0.04 to 0.16), genital warts (62.0% reduction; rate vaccine = 0.44, rate placebo = 1.17, difference = 0.72, 95% CI = 0.58 to 0.87), Pap abnormalities (11.3% reduction; rate vaccine = 10.36, rate placebo = 11.68, difference = 1.32, 95% CI = 0.74 to 1.90), and cervical definitive therapy (23.0% reduction; rate vaccine = 1.97, rate placebo = 2.56, difference = 0.59, 95% CI = 0.35 to 0.83), irrespective of causal HPV type. Conclusions High-coverage HPV vaccination programs among adolescents and young women may result in a rapid reduction of genital warts, cervical cytological abnormalities, and diagnostic and therapeutic procedures. In the longer term, substantial reductions in the rates of cervical, vulvar, and vaginal cancers may follow.

Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy: Observational Study of Veterans With Prostate Cancer

Abstract: Background Previous studies indicate that androgen deprivation therapy for prostate cancer is associated with diabetes and cardiovascular disease among older men. We evaluated the relationship between androgen deprivation therapy and incident diabetes and cardiovascular disease in men of all ages with prostate cancer.

Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes.

Abstract: BACKGROUND The National Institutes of Health Office of Medical Applications of Research commissioned a structured literature review on the incidence, treatment, and outcomes of ductal carcinoma in situ (DCIS) as a background article for the State of the Science Conference on Diagnosis and Management of DCIS. METHODS Published studies were identified and abstracted from MEDLINE and other sources. We include articles published between 1965 and January 31, 2009; 374 publications were identified that addressed DCIS incidence, staging, treatment, and outcomes in adult women. RESULTS In the United States, DCIS incidence rose from 1.87 per 100 000 in 1973-1975 to 32.5 in 2004. Incidence increased in all ages but more so in women older than 50 years. Increased use of mammography explains some but not all of the increased incidence. Risk factors for incident DCIS include older age and family history. Although tamoxifen treatment prevented both invasive breast cancer and DCIS, raloxifene treatment decreased incidence of invasive breast cancer but not DCIS. Among patients with DCIS, magnetic resonance imaging was more sensitive than mammography for detecting multicentric disease and estimating tumor size. Because about 15% of patients with DCIS identified on core needle biopsy are diagnosed with invasive breast cancer after excision or mastectomy, the accuracy of sentinel lymph node biopsy after excision is relevant to surgical management of DCIS. Most studies demonstrated that sentinel lymph node biopsy is feasible after breast-conserving surgery (BCS). Younger age, positive surgical margins, tumor size and grade, and comedo necrosis were consistently related to DCIS recurrence. DCIS outcomes after either mastectomy or BCS plus radiation therapy were superior to BCS alone. Tamoxifen treatment after DCIS diagnosis reduced risk of recurrent disease. CONCLUSIONS Scientific questions deserving further investigation include the relationship between mammography use and DCIS incidence and whether imaging technologies and treatment guidelines can be modified to focus on lesions that are most likely to become clinically problematic.

Improved Endpoints for Cancer Immunotherapy Trials

Abstract: Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan-Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation.

Long-term Absolute Risk of Cervical Intraepithelial Neoplasia Grade 3 or Worse Following Human Papillomavirus Infection: Role of Persistence

Abstract: Background Infection with high-risk human papillomavirus (HPV) is the main cause of high-grade cervical intraepithelial neoplasia (CIN) and cancer. It has been suggested that information about high-risk HPV type–specific infection might make cervical cancer screening more effective. Persistent HPV infection could also be a useful screening marker. We estimated the long-term risk of high-grade CIN after one-time detection of high-risk HPV DNA and after persistent infection with individual high-risk HPV types.

Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism

Abstract: Dysregulation of metabolism is a common phenomenon in cancer cells. The NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) function at a crossroads of cellular metabolism in lipid synthesis, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction. We review the normal functions of the encoded enzymes, frequent mutations of IDH1 and IDH2 recently found in human cancers, and possible roles for the mutated enzymes in human disease. IDH1 and IDH2 mutations occur frequently in some types of World Health Organization grades 2-4 gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. To date, all IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are usually heterozygous in cancer, and they appear to confer a neomorphic enzyme activity for the enzymes to catalyze the production of D-2-hydroxyglutarate. Study of alterations in these metabolic enzymes may provide insights into the metabolism of cancer cells and uncover novel avenues for development of anticancer therapeutics.

Interferon Alpha Adjuvant Therapy in Patients With High-Risk Melanoma: A Systematic Review and Meta-analysis

Abstract: BACKGROUND Based on previous meta-analyses of randomized controlled trials (RCTs), the use of interferon alpha (IFN-alpha) in the adjuvant setting improves disease-free survival (DFS) in patients with high-risk cutaneous melanoma. However, RCTs have yielded conflicting data on the effect of IFN-alpha on overall survival (OS). METHODS We conducted a systematic review and meta-analysis to examine the effect of IFN-alpha on DFS and OS in patients with high-risk cutaneous melanoma. The systematic review was performed by searching MEDLINE, EMBASE, Cancerlit, Cochrane, ISI Web of Science, and ASCO databases. The meta-analysis was performed using time-to-event data from which hazard ratios (HRs) and 95% confidence intervals (CIs) of DFS and OS were estimated. Subgroup and meta-regression analyses to investigate the effect of dose and treatment duration were also performed. Statistical tests were two-sided. RESULTS The meta-analysis included 14 RCTs, published between 1990 and 2008, and involved 8122 patients, of which 4362 patients were allocated to the IFN-alpha arm. IFN-alpha alone was compared with observation in 12 of the 14 trials, and 17 comparisons (IFN-alpha vs comparator) were generated in total. IFN-alpha treatment was associated with a statistically significant improvement in DFS in 10 of the 17 comparisons (HR for disease recurrence = 0.82, 95% CI = 0.77 to 0.87; P < .001) and improved OS in four of the 14 comparisons (HR for death = 0.89, 95% CI = 0.83 to 0.96; P = .002). No between-study heterogeneity in either DFS or OS was observed. No optimal IFN-alpha dose and/or treatment duration or a subset of patients more responsive to adjuvant therapy was identified using subgroup analysis and meta-regression. CONCLUSION In patients with high-risk cutaneous melanoma, IFN-alpha adjuvant treatment showed statistically significant improvement in both DFS and OS.

Assessing Women at High Risk of Breast Cancer: A Review of Risk Assessment Models

Abstract: Women who are at high risk of breast cancer can be offered more intensive surveillance or prophylactic measures, such as surgery or chemoprevention. Central to decisions regarding the level of prevention is accurate and individualized risk assessment. This review aims to distill the diverse literature and provide practicing clinicians with an overview of the available risk assessment methods. Risk assessments fall into two groups: the risk of carrying a mutation in a high-risk gene such as BRCA1 or BRCA2 and the risk of developing breast cancer with or without such a mutation. Knowledge of breast cancer risks, taken together with the risks and benefits of the intervention, is needed to choose an appropriate disease management strategy. A number of models have been developed for assessing these risks, but independent validation of such models has produced variable results. Some models are able to predict both mutation carriage risks and breast cancer risk; however, to date, all are limited by only moderate discriminatory accuracy. Further improvements in the knowledge of how to best integrate both new risk factors and newly discovered genetic variants into these models will allow clinicians to more accurately determine which women are most likely to develop breast cancer. These steady and incremental improvements in models will need to undergo revalidation.

Breast Tissue Composition and Susceptibility to Breast Cancer

Abstract: Breast density, as assessed by mammography, reflects breast tissue composition. Breast epithelium and stroma attenuate x-rays more than fat and thus appear light on mammograms while fat appears dark. In this review, we provide an overview of selected areas of current knowledge about the relationship between breast density and susceptibility to breast cancer. We review the evidence that breast density is a risk factor for breast cancer, the histological and other risk factors that are associated with variations in breast density, and the biological plausibility of the associations with risk of breast cancer. We also discuss the potential for improved risk prediction that might be achieved by using alternative breast imaging methods, such as magnetic resonance or ultrasound. After adjustment for other risk factors, breast density is consistently associated with breast cancer risk, more strongly than most other risk factors for this disease, and extensive breast density may account for a substantial fraction of breast cancer. Breast density is associated with risk of all of the proliferative lesions that are thought to be precursors of breast cancer. Studies of twins have shown that breast density is a highly heritable quantitative trait. Associations between breast density and variations in breast histology, risk of proliferative breast lesions, and risk of breast cancer may be the result of exposures of breast tissue to both mitogens and mutagens. Characterization of breast density by mammography has several limitations, and the uses of breast density in risk prediction and breast cancer prevention may be improved by other methods of imaging, such as magnetic resonance or ultrasound tomography.

Prognostic Significance of Tumorigenic Cells With Mesenchymal Features in Pancreatic Adenocarcinoma

Abstract: Background Specific populations of highly tumorigenic cells are thought to exist in many human tumors, including pancreatic adenocarcinoma. However, the clinical significance of these tumor-initiating (ie, cancer stem) cells remains unclear. Aldehyde dehydrogenase (ALDH) activity can identify tumor-initiating cells and normal stem cells from several human tissues. We examined the prognostic significance and functional features of ALDH expression in pancreatic adenocarcinoma. Methods ALDH expression was analyzed by immunohistochemistry in 269 primary surgical specimens of pancreatic adenocarcinoma and examined for association with clinical outcomes and in paired primary tumors and metastatic lesions from eight pancreatic cancer patients who had participated in a rapid autopsy program. The clonogenic growth potential of ALDH-positive pancreatic adenocarcinoma cells was assessed in vitro by a colony formation assay and by tumor growth in immunodeficient mice (10–14 mice per group). Mesenchymal features of ALDH-positive pancreatic tumor cells were examined by using quantitative reverse transcription– polymerase chain reaction and an in vitro cell invasion assay. Gene expression levels and the invasive potential of ADLH-positive pancreatic cancer cells relative to the bulk cell population were examined by reverse transcription– polymerase chain reaction and an in vitro invasion assays, respectively. All statistical tests were two-sided. Results ALDH-positive tumor cells were detected in 90 of the 269 primary surgical specimens, and their presence was associated with worse survival (median survival for patients with ALDH-positive vs ALDH-negative tumors: 14 vs 18 months, hazard ratio of death = 1.28, 95% confidence interval = 1.02 to 1.68, P = .05). Six (75%) of the eight patients with matched primary and metastatic tumor samples had ALDH-negative primary tumors, and in four (67%) of these six patients, the matched metastatic lesions (located in liver and lung) contained ALDH-positive cells. ALDH-positive cells were approximately five- to 11-fold more clonogenic in vitro and in vivo compared with unsorted or ALHD-negative cells, expressed genes consistent with a mesenchymal state, and had in vitro migratory and invasive potentials that were threefold greater than those of unsorted cells. Conclusions ALDH expression marks pancreatic cancer cells that have stem cell and mesenchymal features. The enhanced clonogenic growth and migratory properties of ALDH-positive pancreatic cancer cells suggest that they play a key role in the development of metastatic disease that negatively affects the overall survival of patients with pancreatic adenocarcinoma.

Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation Into Cancer and Nutrition (EPIC)

Abstract: BACKGROUND: It is widely believed that cancer can be prevented by high intake of fruits and vegetables. However, inconsistent results from many studies have not been able to conclusively establish an inverse association between fruit and vegetable intake and overall cancer risk. METHODS: We conducted a prospective analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to assess relationships between intake of total fruits, total vegetables, and total fruits and vegetables combined and cancer risk during 1992-2000. Detailed information on the dietary habit and lifestyle variables of the cohort was obtained. Cancer incidence and mortality data were ascertained, and hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression models. Analyses were also conducted for cancers associated with tobacco and alcohol after stratification for tobacco smoking and alcohol drinking. RESULTS: Of the initial 142 605 men and 335 873 women included in the study, 9604 men and 21 000 women were identified with cancer after a median follow-up of 8.7 years. The crude cancer incidence rates were 7.9 per 1000 person-years in men and 7.1 per 1000 person-years in women. Associations between reduced cancer risk and increased intake of total fruits and vegetables combined and total vegetables for the entire cohort were similar (200 g/d increased intake of fruits and vegetables combined, HR = 0.97, 95% CI = 0.96 to 0.99; 100 g/d increased intake of total vegetables, HR = 0.98, 95% CI = 0.97 to 0.99); intake of fruits showed a weaker inverse association (100 g/d increased intake of total fruits, HR = 0.99, 95% CI = 0.98 to 1.00). The reduced risk of cancer associated with high vegetable intake was restricted to women (HR = 0.98, 95% CI = 0.97 to 0.99). Stratification by alcohol intake suggested a stronger reduction in risk in heavy drinkers and was confined to cancers caused by smoking and alcohol. CONCLUSIONS: A very small inverse association between intake of total fruits and vegetables and cancer risk was observed in this study. Given the small magnitude of the observed associations, caution should be applied in their interpretation.

Improved Estimates of Cancer-Specific Survival Rates From Population-Based Data

Abstract: Background Accurate estimates of cancer survival are important for assessing optimal patient care and prognosis. Evaluation of these estimates via relative survival (a ratio of observed and expected survival rates) requires a population life table that is matched to the cancer population by age, sex, race and/or ethnicity, socioeconomic status, and ideally risk factors for the cancer under examination. Because life tables for all subgroups in a study may be unavailable, we investigated whether cause-specific survival could be used as an alternative for relative survival.

National Institutes of Health State-of-the-Science Conference Statement: Diagnosis and Management of Ductal Carcinoma In Situ September 22–24, 2009

Abstract: Objective To provide health-care providers, patients, and the general public with a responsible assessment of currently available data on the diagnosis and management of ductal carcinoma in situ (DCIS). Participants A non-Department of Health and Human Services, nonadvocate, 14-member panel representing the fields of oncology, radiology, surgery (general and reconstructive), pathology, radiation oncology, internal medicine, epidemiology, biostatistics, nursing, obstetrics and gynecology, preventative medicine and population health, and social work. In addition, 22 experts from pertinent fields presented data to the panel and conference audience. Evidence Presentations by experts and a systematic review of the literature prepared by the Minnesota Evidence-based Practice Center, through the Agency for Healthcare Research and Quality. Scientific evidence was given precedence over anecdotal experience. Conference process The panel drafted its statement based on scientific evidence presented in open forum and on published scientific literature. The draft statement was presented on the final day of the conference and circulated to the audience for comment. The panel released a revised statement later that day at http://consensus.nih.gov. This statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the Federal Government. Conclusions Clearly, the diagnosis and management of DCIS is highly complex with many unanswered questions, including the fundamental natural history of untreated disease. Because of the noninvasive nature of DCIS, coupled with its favorable prognosis, strong consideration should be given to elimination of the use of the anxiety-producing term "carcinoma" from the description of DCIS. The outcomes in women treated with available therapies are excellent. Thus, the primary question for future research must focus on the accurate identification of patient subsets diagnosed with DCIS, including those persons who may be managed with less therapeutic intervention without sacrificing the excellent outcomes presently achieved. Essential in this quest will be the development and validation of accurate risk stratification methods based on a comprehensive understanding of the clinical, pathological, and biological factors associated with DCIS.

Initial Assessment, Surveillance, and Management of Blood Pressure in Patients Receiving Vascular Endothelial Growth Factor Signaling Pathway Inhibitors

Abstract: Hypertension is a mechanism-based toxic effect of drugs that inhibit the vascular endothelial growth factor signaling pathway (VSP). Substantial evidence exists for managing hypertension as a chronic condition, but there are few prospectively collected data on managing acute hypertension caused by VSP inhibitors. The Investigational Drug Steering Committee of the National Cancer Institute convened an interdisciplinary cardiovascular toxicities expert panel to evaluate this problem, to make recommendations to the Cancer Therapy Evaluation Program on further study, and to structure an approach for safe management by treating physicians. The panel reviewed: the published literature on blood pressure (BP), hypertension, and specific VSP inhibitors; abstracts from major meetings; shared experience with the development of VSP inhibitors; and established principles of hypertension care. The panel generated a consensus report including the recommendations on clinical concerns summarized here. To support the greatest possible number of patients to receive VSP inhibitors safely and effectively, the panel had four recommendations: 1) conduct and document a formal risk assessment for potential cardiovascular complications, 2) recognize that preexisting hypertension will be common in cancer patients and should be identified and addressed before initiation of VSP inhibitor therapy, 3) actively monitor BP throughout treatment with more frequent assessments during the first cycle of treatment, and 4) manage BP with a goal of less than 140/90 mmHg for most patients (and to lower, prespecified goals in patients with specific preexisting cardiovascular risk factors). Proper agent selection, dosing, and scheduling of follow-up should enable maintaining VSP inhibition while avoiding the complications associated with excessive or prolonged elevation in BP.

Longitudinal Study of Human Papillomavirus Persistence and Cervical Intraepithelial Neoplasia Grade 2/3: Critical Role of Duration of Infection

Abstract: Background The natural history of human papillomavirus (HPV) infections in older women is critical for preventive strategies, including vaccination and screening intervals, but is poorly understood. In a 7-year population-based cohort study in Guanacaste, Costa Rica, we examined whether women’s age and the duration of carcinogenic HPV infections influenced subsequent persistence of infection and risk of cervical intraepithelial neoplasia grade 2 (CIN 2) or worse disease.

Cancer Biomarkers: Can We Turn Recent Failures into Success?

Abstract: Disease biomarkers are used widely in medicine. But very few biomarkers are useful for cancer diagnosis and monitoring. Over the past 15 years, major investments have been made to discover and validate cancer biomarkers. Despite such investments, no new major cancer biomarkers have been approved for clinical use for at least 25 years. In the last decade, many reports have described new cancer biomarkers that promised to revolutionize the diagnosis of cancer and the management of cancer patients. However, many initially promising biomarkers have not been validated for clinical use. In this commentary, a plethora of parameters before sample analysis, during sample analysis, and after sample analysis that can complicate biomarker discovery and validation and lead to "false discovery" are discussed. Several examples of biomarker discoveries that were published in high-profile journals are also presented, as well as why they were not validated and the lessons learned from these false discoveries, so that similar mistakes can be avoided in the future.

International Guidelines for Management of Metastatic Breast Cancer: Can Metastatic Breast Cancer Be Cured?

Abstract: A distinctive subset of metastatic breast cancer (MBC) is oligometastatic disease, which is characterized by single or few detectable metastatic lesions. The existing treatment guidelines for patients with localized MBC include surgery, radiotherapy, and regional chemotherapy. The European School of Oncology-Metastatic Breast Cancer Task Force addressed the management of these patients in its first consensus recommendations published in 2007. The Task Force endorsed the possibility of a more aggressive and multidisciplinary approach for patients with oligometastatic disease, stressing also the need for clinical trials in this patient population. At the sixth European Breast Cancer Conference, held in Berlin in March 2008, the second public session on MBC guidelines addressed the controversial issue of whether MBC can be cured. In this commentary, we summarize the discussion and related recommendations regarding the available therapeutic options that are possibly associated with cure in these patients. In particular, data on local (surgery and radiotherapy) and chemotherapy options are discussed. Large retrospective series show an association between surgical removal of the primary tumor or of lung metastases and improved long-term outcome in patients with oligometastatic disease. In the absence of data from prospective randomized studies, removal of the primary tumor or isolated metastatic lesions may be an attractive therapeutic strategy in this subset of patients, offering rapid disease control and potential for survival benefit. Some improvement in outcome may also be achieved with optimization of systemic therapies, possibly in combination with optimal local treatment.

Gene Expression–Based Prognostic Signatures in Lung Cancer: Ready for Clinical Use?

Abstract: A substantial number of studies have reported the development of gene expression–based prognostic signatures for lung cancer. The ultimate aim of such studies should be the development of well-validated clinically useful prognostic signatures that improve therapeutic decision making beyond current practice standards. We critically reviewed published studies reporting the development of gene expression–based prognostic signatures for non–small cell lung cancer to assess the progress made toward this objective. Studies published between January 1, 2002, and February 28, 2009, were identified through a PubMed search. Following hand-screening of abstracts of the identified articles, 16 were selected as relevant. Those publications were evaluated in detail for appropriateness of the study design, statistical validation of the prognostic signature on independent datasets, presentation of results in an unbiased manner, and demonstration of medical utility for the new signature beyond that obtained using existing treatment guidelines. Based on this review, we found little evidence that any of the reported gene expression signatures are ready for clinical application. We also found serious problems in the design and analysis of many of the studies. We suggest a set of guidelines to aid the design, analysis, and evaluation of prognostic signature studies. These guidelines emphasize the importance of focused study planning to address specific medically important questions and the use of unbiased analysis methods to evaluate whether the resulting signatures provide evidence of medical utility beyond standard of care–based prognostic factors.

Biomarker Expression and Risk of Subsequent Tumors After Initial Ductal Carcinoma In Situ Diagnosis

Abstract: mation on subsequent tumors, defined as invasive breast cancer or DCIS diagnosed in the ipsilateral breast containing the initial DCIS lesion or at a regional or distant site greater than 6 months after initial treatment of DCIS (N = 324). We also conducted standardized pathology reviews and immunohistochemical staining for the estrogen receptor (ER), progesterone receptor, Ki67 antigen, p53, p16, epidermal growth factor receptor-2 (ERBB2, HER2/neu oncoprotein), and cyclooxygenase-2 (COX-2) on the initial paraffin-embedded DCIS tissue. Competing risk models were used to determine factors associated with risk of subsequent invasive cancer vs DCIS, and cumulative incidence survival functions were used to estimate 8-year risk. Results Factors associated with subsequent invasive cancer differed from those associated with subsequent DCIS. Eight-year risk of subsequent invasive cancer was statistically significantly (P = .018) higher for women with initial DCIS lesions that were detected by palpation or that were p16, COX-2, and Ki67 triple positive (p16 1 COX2 1 Ki67 1 ) (19.6%, 95% confidence interval [CI] = 18.0% to 21.3%) than for women with initial lesions that were

Randomized Clinical Trials With Biomarkers: Design Issues

Abstract: Clinical biomarker tests that aid in making treatment decisions will play an important role in achieving personalized medicine for cancer patients. Definitive evaluation of the clinical utility of these biomarkers requires conducting large randomized clinical trials (RCTs). Efficient RCT design is therefore crucial for timely introduction of these medical advances into clinical practice, and a variety of designs have been proposed for this purpose. To guide design and interpretation of RCTs evaluating biomarkers, we present an in-depth comparison of advantages and disadvantages of the commonly used designs. Key aspects of the discussion include efficiency comparisons and special interim monitoring issues that arise because of the complexity of these RCTs. Important ongoing and completed trials are used as examples. We conclude that, in most settings, randomized biomarker-stratified designs (ie, designs that use the biomarker to guide analysis but not treatment assignment) should be used to obtain a rigorous assessment of biomarker clinical utility.

Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers

Abstract: Background Germline mutations in MSH6 account for 10%–20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain.

MicroRNA Cluster 221-222 and Estrogen Receptor α Interactions in Breast Cancer

Abstract: Background Several lines of evidence have suggested that estrogen receptor α (ERα)–negative breast tumors, which are highly aggressive and nonresponsive to hormonal therapy, arise from ERα-positive precursors through different molecular pathways. Because microRNAs (miRNAs) modulate gene expression, we hypothesized that they may have a role in ER-negative tumor formation.

A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program

Abstract: A recent Institute of Medicine (IOM) report (1) cited several deficiencies in the Clinical Trials Cooperative Group Program of the National Cancer Institute (NCI), including an inefficient and cumbersome oversight structure and a 20% reduction in funding since 2002. The authors concluded that these and other problems have resulted in start-up times for phase III Cooperative Group trials that range from 1.25 to almost 7 years and a clinical trial completion rate of only 50%. They also noted that clinical trials of cancer treatments are increasingly located outside the United States. Although the oversight structure and funding decline at the NCI may be partially responsible for the observed problems, demographic and market forces are also likely causes. We searched ClinicalTrials.gov for trials registered since 2005 that involved adult cancer patients and found that planned enrollment in NCI-sponsored clinical trials—the number of patients the investigators intended to enroll at the start of the trial—declined from 2.90% of new US cancer cases in 2005 to 1.79% in 2009 (Table 1). During this same time period, planned enrollment for all other (ie, non–NCI-sponsored) US-based adult clinical trials of cancer treatments increased from 3.24% to 4.62% of new US cancer cases. Table 1 Planned US trial enrollment divided by the number of new US cancer patients These trends illustrate the diminishing role of the NCI in the sponsorship of US-based clinical trials in both absolute and relative terms. As planned enrollment in NCI-sponsored trials has decreased, planned enrollment in commercially sponsored trials has increased. Whether a more efficient and better funded NCI would have been able to prevent this trend is debatable. Planned enrollment for all US-based cancer clinical trials averaged more than 6% of all new US cancer cases over this time period, which is more than double the 3% figure the IOM authors cite as the historical average. Considering the slow increase in the number of new US cancer cases per year and the rapid increase in commercially sponsored clinical trials, the observed reduction in enrollment in NCI-sponsored trials might have been unavoidable. Lengthy trial completion times, low trial completion rates, and a shift away from US-based trials would also be likely consequences. For clinical trials of treatments for certain types of cancer, the potentially available participants may be especially scarce. For example, planned enrollment for leukemia trials equaled 12.8% of new US cases from 2005 to 2009. The rate for breast cancer trials equaled 8.9%. As the IOM report authors noted, “publicly funded clinical trials play a vital role by addressing questions that are important to patients but are less likely to be top priorities of industry.” This statement underscores the importance of achieving an optimal mix of publicly and privately funded clinical trials. With the limited number of potential participants in clinical trial in the United States, policy makers will need to consider methods to increase patient participation in cancer clinical trials or, alternatively, ways to allocate enrollment between publicly and privately funded clinical trials with a goal of improving clinical trial completion rates.

Baseline Characteristics of Participants in the Randomized National Lung Screening Trial

Abstract: Background The National Lung Screening Trial (NLST), a randomized study conducted at 33 US sites, is comparing lung cancer mortality among persons screened with reduced dose helical computerized tomography and among persons screened with chest radiograph. In this article, we present characteristics of the study population.

Randomized Trial of Radiotherapy Plus Concurrent–Adjuvant Chemotherapy vs Radiotherapy Alone for Regionally Advanced Nasopharyngeal Carcinoma

Abstract: BACKGROUND Current practice of adding concurrent-adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. METHODS Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m(2)) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg per m(2) per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. RESULTS The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). CONCLUSIONS Adding concurrent-adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.