News and Articles on Health. Medical research topics.

Despite this interpretation of the early experience, another generation has passed since the NPCP trials were initiated, without cytotoxic therapy earning a place in the routine management of patients with metastatic prostate cancer. Recent modification of chemotherapy and the introduction of prostate-specific antigen (PSA) testing that permits efficient assessment of ‘response’ have changed this perception.

It is instructive to consider some of the factors contributing to this perception. First, evaluation of clinical response has been difficult. Second, the fact that even patients with disseminated prostate cancer are commonly managed exclusively by urologists has attenuated the experience of medical oncologists in this disease, and very likely has contributed to the slow development of cytotoxic paradigms. Third, there has been an ironic distraction produced by the advent of medical testicular suppression. For some time, clinical research in advanced prostate cancer has seen disproportionate resources expended on randomizing many thousands of patients to variants of hormonal therapies.

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More than a decade of such experience has demonstrated that no matter how complex or expensive we make androgen deprivation, its therapeutic impact is still limited. Finally, the palliative impact of cytotoxic drugs is underappreciated. As pointed out by Slack and Murphy in the quotation above, cytotoxic therapy carefully applied can often provide symptom relief with less morbidity than that associated with narcotics or other palliative
interventions.

Progress towards more routine assessment of the role of chemotherapy has been made because of a number of factors that have been addressed:

(1) Establishment of standardized response criteria;
(2) Closer ties between medical oncologists and urologists in ‘academic centers of
excellence’;
(3) Recognition of the toxicity and therapeutic limitations of androgen ablation;
(4) Inclusion of quality-of-life end-points in clinical research.

Skin cancer is a common cancer in Irish men and is on the increase. Unlike many other types of cancer however, only a small minority of those affected by skin cancer will actually die of the condition.

What Are the Different Types of Skin Cancer?

There are three main types of skin cancer. The most common types of skin cancers are basal cell (BCC) and squamous cell (SCC) skin cancers. These can be disfiguring but are unlikely to spread to other parts of the body and so are rarely fatal. The least common form of skin cancer is also the most dangerous and is called malignant melanoma.

Basal Cell Cancer

This is the most common type of skin cancer and accounts for about 75 per cent of all cases. It often looks like a small, raised pearl-like bump or nodule on a sun-exposed area of skin on the head, face, neck or back of the hands. It can easily be mistaken for a sore that doesn’t heal. This highly treatable cancer tends to start in the top layer of skin and grows very slowly. It commonly occurs among persons with light-coloured eyes, hair and complexion. Untreated, it can eventually spread down through the skin, which is why it has the alternative medical in Canadian Medstore online term of a ‘rodent ulcer’.

Squamous Cell Cancer

This is the second most common form of skin cancer and accounts for about 20 per cent of cases. It often looks like a raised crusted lesion on the sun- exexposed areas of skin. Symptoms may include any spot or sore on the skin that changes or fails to heal, as well as localised scaliness, oozing, bleeding, itching, tenderness or pain at the site of the spot. Squamous cell carcinoma, although more aggressive than basal cell carcinoma, is highly treatable. It may appear as nodules or red, scaly patches of skin, and may be found on the face, ears, lips and mouth. Squamous cell carcinoma, if untreated, can spread to other parts of the body. This type of skin cancer is usually found in fair-skinned people.

Malignant Melanoma

Malignant melanoma is the least common but most dangerous form of skin cancer. It affects about 500 people each year in Ireland and its incidence is on the rise. Risk factors for developing malignant melanoma include a history of melanoma in the family. Those with certain skin types are at increased risk of melanoma, particularly those who are fair-skinned with blue eyes, and men who develop lobster-type skin after a few days in the sun. Having a lot of moles on your skin is termed dysplastic naevus syndrome and is associated with an increased lifetime risk of developing melanoma. Some people are born with very large moles on their bodies that are at increased risk of turning into melanoma over the long term.

Malignant melanoma starts in the melanocyte cells that produce pigment in the skin. It usually begins as a mole that then turns cancerous. This cancer may spread quickly.

We also performed exploratory analyses to investigate treatment effects on sites of first recurrence. After a protocol amendment was approved before the first interim analysis in 2008, we added another secondary end point: invasive-disease–free survival, which was defined according to the Standardized Definitions for Efficacy and End Points in Adjuvant Breast Cancer Trials (STEEP) guidelines. The date of recurrence was defined as the date on which relapse was first suspected, rather than the date on which it was confirmed, to reduce the risk of ascertainment bias. On-site and telephone-based monitoring was performed to ensure that recurrence dates were backdated to the date on which the event was first suspected, when this date preceded clinical, histologic, or imaging confirmation. Viagra Australia website

Study Oversight

The study was sponsored by the University of Sheffield and approved as a United Kingdom national trial by the Clinical Trials Advisory Awards Committee. Grant support was provided by Novartis Pharmaceuticals and was supplemented in the United Kingdom by the infrastructure of the National Cancer Research Network. Novartis Pharmaceuticals donated study supplies of zoledronic acid. The authors developed the study concept, wrote the protocol, and performed and reviewed all analyses. The study was conducted in accordance with the protocol, with amendments to reduce the risk of osteonecrosis of the jaw and to inform both patients and dental practitioners of this risk. The first author wrote the first draft of the manuscript, and all authors were involved in revision and approval of the manuscript. Novartis Pharmaceuticals was given an opportunity to comment on the manuscript, but all decisions on submission of the manuscript for publication were made by the authors and the trial steering committee.

Statistical Analysis

A final analysis was planned after the primary end point (disease-free survival) had occurred in 940 patients, on the basis of the recruitment of 3300 patients during a 3-year period, an anticipated rate of disease-free survival of 75% at 3 years, and a 5% annual rate of loss to follow-up. It was estimated that these numbers would provide a power of 80% to detect a relative reduction of 17% in the rate of disease recurrence or death among patients receiving zoledronic acid, at a two-sided level of significance of 0.05, which would approximate an absolute benefit of 3.7 percentage points.

A single interim analysis was planned after the primary end point had been reached in 470 patients, with a two-sided alpha level of 0.005. After this analysis was performed, on the advice of the independent data and safety monitoring committee, no efficacy data were released. Because the rate of events contributing to the primary end point was lower than predicted (resulting in a combined rate of disease-free survival of 85% at 3 years), an independent statistician who was unaware of the findings and was not involved in the first interim analysis provided revised stopping boundaries for both efficacy and lack of benefit that would allow timely release of a clinically important result. A second interim analysis was planned after the primary end point had occurred in at least 705 patients, along with a 0.5% probability of declaring false positive results (one-sided) or a 5.0% probability of declaring negative results with the use of a group sequential-design method.13 The analysis was carried out on 752 events, resulting in an efficacy boundary for the hazard ratio of 0.833 (lower boundary) and a lack-of-efficacy boundary of 0.936 (upper boundary). At this interim analysis, the lack-of-efficacy boundary was crossed, and the committee recommended the release of results.

Metastasis is a complex process that is dependent on both the biologic features of the primary tumor and cellular interactions within host tissues. In the bone microenvironment, cancer cells stimulate osteoblasts to release receptor activator of nuclear factor κB ligand (RANKL), which binds to its receptor, RANK, on both precursor and mature osteoclasts. The resulting increase in osteoclastic bone resorption leads to the release of bone-derived growth factors that may provide a fertile environment for survival and growth of adjacent cancer cells. Thus, targeting bone-cell function provides a potential additional approach to preventing bone metastases as a component of standard adjuvant therapy. In many in vivo models, bisphosphonates prevent or delay metastasis. In addition, synergistic interactions between aminobisphosphonates and cytotoxic drugs have been shown in preclinical models.

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In patients with early-stage breast cancer, several clinical trials have suggested that the adjuvant use of bisphosphonates reduces rates of recurrence and death.6-8 In addition, despite a lack of regulatory approval in most health care systems, the inclusion of a bisphosphonate as part of adjuvant therapy has become increasingly widespread. In this randomized, controlled, open-label phase 3 study, called the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, we evaluated the adjuvant use of zoledronic acid in a broad population of patients with stage II or III early-stage breast cancer.

Methods

Study Patients

The research protocol and statistical analysis plan are available with the full text of this article at NEJM.org. To be eligible for the study, all the patients had to be at least 18 years of age, have a Karnofsky performance status of at least 80, and have a histologically confirmed breast cancer with axillary lymph-node metastasis (N1) or a T3–T4 primary tumor. Complete primary tumor resection was mandated or intended after neoadjuvant therapy. In addition, patients who were eligible for completion surgery (margin excision, mastectomy, or axillary lymph-node dissection) after completion of adjuvant chemotherapy could be included.

Patients were not eligible if there was clinical or imaging evidence of distant metastases or if complete treatment of the primary breast tumor and regional lymph nodes was not possible. Other exclusion criteria included a cancer diagnosis within the preceding 5 years, use of bisphosphonates during the previous year, or a diagnosis of osteoporosis or other bone disease likely to require bone-targeted treatment. The serum creatinine level had to be less than 1.5 times the upper limit of the normal range. In 2005, after case reports of osteonecrosis of the jaw associated with bisphosphonates,9 an amendment was adopted to exclude patients with clinically significant, active dental problems or planned jaw surgery.

Randomization and Treatment

After providing written informed consent, patients were randomly assigned in a 1:1 ratio to receive standard adjuvant systemic therapy (control group) or standard adjuvant systemic therapy along with zoledronic acid. The zoledronic acid was administered immediately after each cycle of adjuvant chemotherapy in a 4-mg dose by intravenous infusion every 3 to 4 weeks for 6 cycles and then every 3 months for 8 doses, followed by 5 cycles on a 6-month schedule for a total of 5 years. Dose adjustments for renal-function abnormalities were recommended in accordance with the product license. Daily oral supplements containing calcium (400 to 1000 mg) and vitamin D (200 to 500 IU) were recommended for all patients during the first 6 months and were continued thereafter at the discretion of the treating physician.

External-beam radiotherapy to the breast and chest wall, with or without irradiation of regional lymph nodes, and adjuvant cytotoxic and endocrine treatments were given in accordance with standard protocols at each participating institution. After regulatory approval of trastuzumab for adjuvant use, the drug was allowed in patients with HER2-positive tumors.

Other strategies for early detection of lung cancer — in particular, molecular markers in blood, sputum, and urine, which can be studied in specimens that were obtained as part of ACRIN’s NLST activities and are available to the research community — may one day help select persons who are best suited for low-dose CT screening or identify persons with positive low-dose CT screening tests who should undergo more rigorous diagnostic evaluation. management of nodules observed with screening. The observation that low-dose CT screening can reduce the rate of death from lung cancer has generated many questions. Will populations with risk profiles that are different from those of the NLST participants benefit? Are less frequent screening regimens equally effective? For how long should screening continue? Would the use of different criteria for a positive screening result, such as a larger nodule diameter, still result in a benefit? It is unlikely that large, definitive, randomized trials will be undertaken to answer these questions, but modeling and microsimulation can be used to address them. Although some agencies and organizations are contemplating the establishment of lung-cancer screening recommendations on the basis of the findings of the NLST, the current NLST data alone are, in our opinion, insufficient to fully inform such important decisions. Before public policy recommendations are crafted, the cost-effectiveness of low-dose CT screening must be rigorously analyzed. The reduction in lung-cancer mortality must be weighed against the harms from positive screening results and overdiagnosis, as well as the costs. The cost component of low-dose CT screening includes not only the screening examination itself but also the diagnostic follow-up and treatment.

The benefits, harms, and costs of screening will all depend on the way in which low-dose CT screening is implemented, specifically in regard to the eligibility criteria, screening frequency, interpretation threshold, diagnostic follow-up, and treatment. For example, although there are currently only about 7 million persons in the United States who would meet the eligibility criteria for the NLST, there are 94 million current or former smokers6 and many more with secondhand exposure to smoke or other risk factors. The cost-effectiveness of low-dose CT screening must also be considered in the context of competing interventions, particularly smoking cessation. NLST investigators are currently analyzing the quality-of-life effects, costs, and costeffectiveness of screening in the NLST and are planning collaborations with the Cancer Intervention and Surveillance Modeling Network to investigate the potential effect of low-dose CT screening in a wide range of scenarios. Other strategies for early detection of lung cancer — in particular, molecular markers in blood, sputum, and urine, which can be studied in specimens that were obtained as part of ACRIN’s NLST activities and are available to the research community — may one day help select persons who are best suited for low-dose CT screening or identify persons with positive low-dose CT screening tests who should undergo more rigorous diagnostic evaluation.

Radiographic screening rather than community care (care that a participant usually receives) was chosen as the comparator in the NLST because radiographic screening was being evaluated in the PLCO trial at the time the NLST was designed. The designers of the NLST reasoned that if the PLCO trial were to show a reduction in lung-cancer mortality with radiographic screening, a trial of low-dose CT screening in which a communitycare group was the control would be of less value, since the standard of care would have become screening with chest radiography. Nevertheless, the choice of radiography precludes a direct comparison of low-dose CT with community care. Analysis of the subgroup of PLCO participants who met the NLST criteria for age and smoking history indicated that radiography, as compared with community care, does not reduce mortality from lung cancer. Therefore, a similar reduction in lung-cancer mortality would probably have been observed in the NLST if community care had been chosen instead for the control group. In addition to the high rate of false positive results, two other potentially harmful effects of low-dose CT screening must be mentioned. Overdiagnosis, a major source of controversy surrounding low-dose CT lung-cancer screening, results from the detection of cancers that never would have become symptomatic.28 Although additional follow-up would be necessary to measure the magnitude of overdiagnosis in the NLST, a comparison of the number of cancers diagnosed in the two trial groups suggests that the magnitude of overdiagnosis with low-dose CT as compared with radiographic screening is not large. The other harmful effect, the association of low-dose CT with the development of radiation-induced cancers, could not be measured directly, is a longterm phenomenon, and must be assessed in future analyses.

A number of smaller, randomized trials of lowdose CT screening are under way in Europe. Because none of these trials have sufficient statistical power to detect a reduction in lung-cancer mortality of the magnitude seen in the NLST, it is expected that meta-analyses of the findings from these trials will be performed. The European studies are gathering types of data that were not collected by the NLST and will be able to address additional questions about low-dose CT screening, including the best strategies for the overdiagnosis, as well as the costs. The cost component of low-dose CT screening includes not only the screening examination itself but also the diagnostic follow-up and treatment.

The benefits, harms, and costs of screening will all depend on the way in which low-dose CT screening is implemented, specifically in regard to the eligibility criteria, screening frequency, interpretation threshold, diagnostic follow-up, and treatment. For example, although there are currently only about 7 million persons in the United States who would meet the eligibility criteria for the NLST, there are 94 million current or former smokers6 and many more with secondhand exposure to smoke or other risk factors.

The cost-effectiveness of low-dose CT screening must also be considered in the context of competing interventions, particularly smoking cessation. NLST investigators are currently analyzing the quality-of-life effects, costs, and costeffectiveness of screening in the NLST and are planning collaborations with the Cancer Intervention and Surveillance Modeling Network to investigate the potential effect of low-dose CT screening in a wide range of scenarios.

In the NLST, a 20.0% decrease in mortality from lung cancer was observed in the low-dose CT group as compared with the radiography group. The rate of positive results was higher with lowdose CT screening than with radiographic screening by a factor of more than 3, and low-dose CT screening was associated with a high rate of false positive results; however, the vast majority of false positive results were probably due to the presence of benign intrapulmonary lymph nodes or noncalcified granulomas, as confirmed noninvasively by the stability of the findings on follow-up CT scans. Complications from invasive diagnostic evaluation procedures were uncommon, with death or severe complications occurring only rarely, particularly among participants who did not have lung cancer. The decrease in the rate of death from any cause with the use of low-dose CT screening suggests that such screening is not, on the whole, deleterious. A high rate of adherence to the screening, low rates of lung-cancer screening outside the NLST, and thorough ascertainment of lung cancers and deaths contributed to the success of the NLST.
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Moreover, because there was no mandated diagnostic evaluation algorithm, the follow-up of positive screening tests reflected the practice patterns at the participating medical centers. A multidisciplinary team ensured that all aspects of the NLST were conducted rigorously. There are several limitations of the NLST. First, as is possible in any clinical study, the findings may be affected by the “healthy-volunteer” effect, which can bias results such that they are more favorable than those that will be observed when the intervention is implemented in the community. The role of this bias in our results cannot be ascertained at this time. Second, the scanners that are currently used are technologically more advanced than those that were used in the trial. This difference may mean that screening with today’s scanners will result in a larger reduction in the rate of death from lung cancer than was observed in the NLST; however, the ability to detect more abnormalities may result only in higher rates of false positive results.25 Third, the NLST was conducted at a variety of medical institutions, many of which are recognized for their expertise in radiology and in the diagnosis and treatment of cancer. It is possible that community facilities will be less prepared to undertake screening programs and the medical care that must be associated with them. For example, one of the most important factors determining the success of screening will be the mortality associated with surgical resection, which was much lower in the NLST than has been reported previously in the general U.S. population (1% vs. 4%). Finally, the reduction in the rate of death from lung cancer associated with an ongoing low-dose CT screening program was not estimated in the NLST and may be larger than the 20% reduction observed with only three rounds of screening.

In each group, the percentage of stage IA and stage IB lung cancers was highest among cancers that were diagnosed after a positive screening test. Fewer stage IV cancers were seen in the low-dose CT group than in the radiography group at the second and third screening rounds.

Low-dose CT screening identified a preponderance of adenocarcinomas, including bronchioloalveolar carcinomas. Although the use of the term bronchioloalveolar carcinoma is no longer recommended, while the NLST was ongoing, the term was used to denote in situ, minimally invasive, or invasive adenocarcinoma, lepidic predominant (i.e., neoplastic cell growth restricted to preexisting alveolar structure). In both groups, many adenocarcinomas and squamous-cell carcinomas were detected at either stage I or stage II, although the stage distribution was more favorable in the low-dose CT group than in the radiography group. Small-cell lung cancers were, in general, not detected at early stages by either low-dose CT or radiography. A total of 92.5% of stage IA and stage IB cancers in the low-dose CT group and 87.5% of those in the radiography group were treated with surgery alone or surgery combined with chemotherapy, radiation therapy, or both.

Lung-Cancer–Specific Mortality
After the accrual of 144,103 person-years in the low-dose CT group and 143,368 person-years in the radiography group, 356 and 443 deaths from lung cancer in the two groups, respectively, had occurred, corresponding to rates of death from lung cancer of 247 and 309 deaths per 100,000 person-years, respectively, and a relative reduction in the rate of death from lung cancer with lowdose CT screening of 20.0% (95% CI, 6.8 to 26.7; P = 0.004 When only participants who underwent at least one screen-ing test were included, there were 346 deaths from lung cancer among 26,455 participants in the lowdose CT group and 425 deaths among 26,232 participants in the radiography group. The number needed to screen with low-dose CT to prevent one death from lung cancer was 320.

Overall Mortality
There were 1877 deaths in the low-dose CT group, as compared with 2000 deaths in the radiography group, representing a significant reduction with low-dose CT screening of 6.7% (95% CI, 1.2 to 13.6) in the rate of death from any cause (P = 0.02). We were unable to obtain the death certificates for two of the participants in the radiography group who died, but the occurrence of death was confirmed through a review by the end-point verification team. Although lung cancer accounted for 24.1% of all the deaths in the trial, 60.3% of the excess deaths in the radiography group were due to lung cancer. When deaths from lung cancer were excluded from the comparison, the reduction in overall mortality with the use of low-dose CT dropped to 3.2% and was not significant (P = 0.28).

Follow-up of Positive Results
More than 90% of the positive screening tests in the first round of screening (T0) led to a diagnostic evaluation. Lower rates of follow-up were seen at later rounds. The diagnostic evaluation most often consisted of further imaging, and invasive procedures were performed infrequently. Across the three rounds, 96.4% of the positive results in the low-dose CT group and 94.5% of those in the radiography group were false positive results. These percentages varied little by round. Of the total number of low-dose CT screening tests in the three rounds, 24.2% were classified as pos itive and 23.3% had false positive results; of the total number of radiographic screening tests in the three rounds, 6.9% were classified as positive and 6.5% had false positive results.

Adverse Events
Adverse events from the actual screening examinations were few and minor. The rates of complications after a diagnostic evaluation procedure for a positive screening test were low; the rate of at least one complication was 1.4% in the low-dose CT group and 1.6% in the radiography group. A total of 0.06% of the positive screening tests in the low-dose CT group that did not result in a diagnosis of lung cancer and 11.2% of those that did result in a diagnosis of lung cancer were associated with a major complication after an invasive procedure; the corresponding percentages in the radiography group were 0.02% and 8.2%. The frequency of major complications varied according to the type of invasive procedure. A total of 16 participants in the lowdose CT group (10 of whom had lung cancer) and 10 in the radiography group (all of whom had lung cancer) died within 60 days after an invasive diagnostic procedure. Although it is not known whether the complications from the diagnostic procedure caused the deaths, the low frequency of death within 60 days after the procedure suggests that death as a result of the diagnostic evaluation of positive screening tests is a rare occurrence.

Incidence, Characteristics, and Treatment of Lung Cancers
A total of 1060 lung cancers (645 per 100,000 person-years) were diagnosed in the low-dose CT group, as compared with 941 (572 per 100,000 person-years) in the radiography group (rate ratio, 1.13; 95% confidence interval [CI], 1.03 to 1.23). In the low-dose CT group, 649 cancers were diagnosed after a positive screening test, 44 after a negative screening test, and 367 among participants who either missed the screening or received the diagnosis after their trial screening phase was over. In the radiography group, 279 cancers were diagnosed after a positive screening test, 137 after a negative screening test, and 525 among participants who either missed the screening or received the diagnosis after their trial screening phase was over. Detailed calculations of sensitivity, specificity, positive predictive value, and negative predictive value are not reported here.

Interim analyses were performed to monitor the primary end point for efficacy and futility. The analyses involved the use of a weighted logrank statistic, with weights increasing linearly from no weight at randomization to full weight at 4 years and thereafter. Efficacy and futility boundaries were built on the Lan–DeMets approach with an O’Brien–Fleming spending function. Interim analyses were performed annually from 2006 through 2009 and semiannually in 2010.

An independent data and safety monitoring board met every 6 months and reviewed the accumulating data. On October 20, 2010, the board determined that a definitive result had been reached for the primary end point of the trial and recommended that the results be reported. The board’s decision took into consideration that the efficacy boundary for the primary end point had been crossed and that there was no evidence of unforeseen screening effects that warranted acting contrary to the trial’s prespecified monitoring plan. The NCI director accepted the recommendation of the data and safety monitoring board, and the trial results were announced on November 4, 2010.

Characteristics of the Participants
The demographic characteristics and smoking history of the participants were virtually identical in the two groups. As compared with respondents to a 2002–2004 U.S. Census survey of tobacco use22 who met the NLST eligibility criteria for age and smoking history, NLST participants were younger, had a higher level of education, and were more likely to be former smokers. As of December 31, 2009, vital status was known for 97% of the participants in the low-dose CT group and 96% of those in the radiography group. The median duration of follow-up was 6.5 years, with a maximum duration of 7.4 years in each group.

Adherence to Screening
The rate of adherence to the screening protocol across the three rounds was high: 95% in the low-dose CT group and 93% in the radiography group. Among LSS participants in the radiography group, the average annual rate of helical CT screening outside the NLST during the screening phase of the trial was 4.3%, which was well below the 10.0% rate estimated in the trial power calculations.

Results of Screening
In all three rounds, there was a substantially higher rate of positive screening tests in the lowdose CT group than in the radiography group (T0, 27.3% vs. 9.2%; T1, 27.9% vs. 6.2%; and T2, 16.8% vs. 5.0%). The rate of positive tests in both groups was noticeably lower at T2 than at T0 or T1 because the NLST protocol allowed tests showing abnormalities at T2 that were suspicious for cancer but were stable across all three rounds to be categorized as negative with minor abnormalities. During the screening phase of the trial, 39.1% of the participants in the low-dose CT group and 16.0% of those in the radiography group had at least one positive screening result. The percentage of all screening tests that identified a clinically significant abnormality other than an abnormality suspicious for lung cancer was more than three times as high in the low-dose CT group as in the radiography group (7.5% vs. 2.1%).

Results and recommendations from the interpreting radiologist were reported in writing to the participant and his or her health care provider within 4 weeks after the examination. Since there was no standardized, scientifically validated approach to the evaluation of nodules, trial radiologists developed guidelines for diagnostic follow- up, but no specific evaluation approach was mandated.

Medical-Record Abstraction
Medical records documenting diagnostic evaluation procedures and any associated complications were obtained for participants who had positive screening tests and for participants in whom lung cancer was diagnosed. Pathology and tumor-staging reports and records of operative procedures and initial treatment were also obtained for participants with lung cancer. Pathology reports were obtained for other reported cancers to exclude the possibility that such tumors represented lung metastases. Histologic features of the lung cancer were coded according to the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3), and the disease stage was determined according to the sixth edition of the Cancer Staging Manual of the American Joint Committee on Cancer. At ACRIN sites, additional medical records were also obtained for a number of substudies, including studies of health care utilization and cost-effectiveness.

Vital Status
Participants completed a questionnaire regarding vital status either annually (LSS participants) or semiannually (ACRIN participants). The names and Social Security numbers of participants who were lost to follow-up were submitted to the National Death Index to ascertain probable vital status. Death certificates were obtained for participants who were known to have died. An endpoint verification team determined whether the cause of death was lung cancer. Although a distinction was made between a death caused by lung cancer and a death that resulted from the diagnostic evaluation for or treatment of lung cancer, the deaths from the latter causes were counted as lung-cancer deaths in the primary end-point analysis. The members of the team were not aware of the group assignments.

Statistical Analysis
The primary analysis was a comparison of lungcancer mortality between the two screening groups, according to the intention-to-screen principle. We estimated that the study would have 90% power to detect a 21% decrease in mortality from lung cancer in the low-dose CT group, as compared with the radiography group. Secondary analyses compared the rate of death from any cause and the incidence of lung cancer in the two groups. Event rates were defined as the ratio of the number of events to the person-years at risk for the event. For the incidence of lung cancer, person-years were measured from the time of randomization to the date of diagnosis of lung cancer, death, or censoring of data (whichever came first); for the rates of death, person-years were measured from the time of randomization to the date of death or censoring of data (whichever came first). The latest date for the censoring of data on incidence of lung cancer and on death from any cause was December 31, 2009; the latest date for the censoring of data on death from lung cancer for the purpose of the primary endpoint analysis was January 15, 2009. The earlier censoring date for death from lung cancer was established to allow adequate time for the review process for deaths to be performed to the same, thorough extent in each group. We calculated the confidence intervals for incidence ratios assuming a Poisson distribution for the number of events and a normal distribution of the logarithm of the ratio, using asymptotic methods. We calculated the confidence intervals for mortality ratios with the weighted method that was used to monitor the primary end point of the trial, which allows for a varying rate ratio and is adjusted for the design. The number needed to screen to prevent one death from lung cancer was estimated as the reciprocal of the reduction in the absolute risk of death from lung cancer in one group as compared with the other, among participants who had at least one screening test. The analyses were performed with the use of SAS/STAT and R statistical packages.