Anthony B. Miller

Reporting results of cancer treatment

On the initiative of the World Health Organization, two meetings on the Standardization of Reporting Results of Cancer Treatment have been held with representatives and members of several organizations. Recommendations have been developed for standardized approaches to the recording of baseline data relating to the patient, the tumor, laboratory and radiologic data, the reporting of treatment, grading of acute and subacute toxicity, reporting of response, recurrence and disease‐free interval, and reporting results of therapy. These recommendations, already endorsed by a number of organizations, are proposed for international acceptance and use to make it possible for investigators to compare validly their results with those of others.

Mortality Results from a Randomized Prostate-Cancer Screening Trial

BACKGROUND The effect of screening with prostate-specific-antigen (PSA) testing and digital rectal examination on the rate of death from prostate cancer is unknown. This is the first report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality. METHODS From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained. RESULTS In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings. CONCLUSIONS After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. (ClinicalTrials.gov number, NCT00002540.)

Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up

BACKGROUND The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was undertaken to determine whether there is a reduction in prostate cancer mortality from screening using serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE). Mortality after 7-10 years of follow-up has been reported previously. We report extended follow-up to 13 years after the trial. METHODS A total of 76 685 men, aged 55-74 years, were enrolled at 10 screening centers between November 1993 and July 2001 and randomly assigned to the intervention (organized screening of annual PSA testing for 6 years and annual DRE for 4 years; 38 340 men) and control (usual care, which sometimes included opportunistic screening; 38 345 men) arms. Screening was completed in October 2006. All incident prostate cancers and deaths from prostate cancer through 13 years of follow-up or through December 31, 2009, were ascertained. Relative risks (RRs) were estimated as the ratio of observed rates in the intervention and control arms, and 95% confidence intervals (CIs) were calculated assuming a Poisson distribution for the number of events. Poisson regression modeling was used to examine the interactions with respect to prostate cancer mortality between trial arm and age, comorbidity status, and pretrial PSA testing. All statistical tests were two-sided. RESULTS Approximately 92% of the study participants were followed to 10 years and 57% to 13 years. At 13 years, 4250 participants had been diagnosed with prostate cancer in the intervention arm compared with 3815 in the control arm. Cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10 000 person-years, respectively, resulting in a relative increase of 12% in the intervention arm (RR = 1.12, 95% CI = 1.07 to 1.17). After 13 years of follow-up, the cumulative mortality rates from prostate cancer in the intervention and control arms were 3.7 and 3.4 deaths per 10 000 person-years, respectively, resulting in a non-statistically significant difference between the two arms (RR = 1.09, 95% CI = 0.87 to 1.36). No statistically significant interactions with respect to prostate cancer mortality were observed between trial arm and age (P(interaction) = .81), pretrial PSA testing (P(interaction) = .52), and comorbidity (P(interaction) = .68). CONCLUSIONS After 13 years of follow-up, there was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing.

Effect of Screening on Ovarian Cancer Mortality: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial

CONTEXT Screening for ovarian cancer with cancer antigen 125 (CA-125) and transvaginal ultrasound has an unknown effect on mortality. OBJECTIVE To evaluate the effect of screening for ovarian cancer on mortality in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of 78,216 women aged 55 to 74 years assigned to undergo either annual screening (n = 39,105) or usual care (n = 39,111) at 10 screening centers across the United States between November 1993 and July 2001. Intervention The intervention group was offered annual screening with CA-125 for 6 years and transvaginal ultrasound for 4 years. Participants and their health care practitioners received the screening test results and managed evaluation of abnormal results. The usual care group was not offered annual screening with CA-125 for 6 years or transvaginal ultrasound but received their usual medical care. Participants were followed up for a maximum of 13 years (median [range], 12.4 years [10.9-13.0 years]) for cancer diagnoses and death until February 28, 2010. MAIN OUTCOME MEASURES Mortality from ovarian cancer, including primary peritoneal and fallopian tube cancers. Secondary outcomes included ovarian cancer incidence and complications associated with screening examinations and diagnostic procedures. RESULTS Ovarian cancer was diagnosed in 212 women (5.7 per 10,000 person-years) in the intervention group and 176 (4.7 per 10,000 person-years) in the usual care group (rate ratio [RR], 1.21; 95% confidence interval [CI], 0.99-1.48). There were 118 deaths caused by ovarian cancer (3.1 per 10,000 person-years) in the intervention group and 100 deaths (2.6 per 10,000 person-years) in the usual care group (mortality RR, 1.18; 95% CI, 0.82-1.71). Of 3285 women with false-positive results, 1080 underwent surgical follow-up; of whom, 163 women experienced at least 1 serious complication (15%). There were 2924 deaths due to other causes (excluding ovarian, colorectal, and lung cancer) (76.6 per 10,000 person-years) in the intervention group and 2914 deaths (76.2 per 10,000 person-years) in the usual care group (RR, 1.01; 95% CI, 0.96-1.06). CONCLUSIONS Among women in the general US population, simultaneous screening with CA-125 and transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality. Diagnostic evaluation following a false-positive screening test result was associated with complications. Trial Registration clinicaltrials.gov Identifier: NCT00002540.

Cohort Studies of Fat Intake and the Risk of Breast Cancer — A Pooled Analysis

BACKGROUND Experiments in animals, international correlation comparisons, and case-control studies support an association between dietary fat intake and the incidence of breast cancer. Most cohort studies do not corroborate the association, but they have been criticized for involving small numbers of cases, homogeneous fat intake, and measurement errors in estimates of fat intake. METHODS We identified seven prospective studies in four countries that met specific criteria and analyzed the primary data in a standardized manner. Pooled estimates of the relation of fat intake to the risk of breast cancer were calculated, and data from study-specific validation studies were used to adjust the results for measurement error. RESULTS Information about 4980 cases from studies including 337,819 women was available. When women in the highest quintile of energy-adjusted total fat intake were compared with women in the lowest quintile, the multivariate pooled relative risk of breast cancer was 1.05 (95 percent confidence interval, 0.94 to 1.16). Relative risks for saturated, monounsaturated, and polyunsaturated fat and for cholesterol, considered individually, were also close to unity. There was little overall association between the percentage of energy intake from fat and the risk of breast cancer, even among women whose energy intake from fat was less than 20 percent. Correcting for error in the measurement of nutrient intake did not materially alter these findings. CONCLUSIONS We found no evidence of a positive association between total dietary fat intake and the risk of breast cancer. There was no reduction in risk even among women whose energy intake from fat was less than 20 percent of total energy intake. In the context of the Western lifestyle, lowering the total intake of fat in midlife is unlikely to reduce the risk of breast cancer substantially.

Colorectal-Cancer Incidence and Mortality with Screening Flexible Sigmoidoscopy

BACKGROUND The benefits of endoscopic testing for colorectal-cancer screening are uncertain. We evaluated the effect of screening with flexible sigmoidoscopy on colorectal-cancer incidence and mortality. METHODS From 1993 through 2001, we randomly assigned 154,900 men and women 55 to 74 years of age either to screening with flexible sigmoidoscopy, with a repeat screening at 3 or 5 years, or to usual care. Cases of colorectal cancer and deaths from the disease were ascertained. RESULTS Of the 77,445 participants randomly assigned to screening (intervention group), 83.5% underwent baseline flexible sigmoidoscopy and 54.0% were screened at 3 or 5 years. The incidence of colorectal cancer after a median follow-up of 11.9 years was 11.9 cases per 10,000 person-years in the intervention group (1012 cases), as compared with 15.2 cases per 10,000 person-years in the usual-care group (1287 cases), which represents a 21% reduction (relative risk, 0.79; 95% confidence interval [CI], 0.72 to 0.85; P<0.001). Significant reductions were observed in the incidence of both distal colorectal cancer (479 cases in the intervention group vs. 669 cases in the usual-care group; relative risk, 0.71; 95% CI, 0.64 to 0.80; P<0.001) and proximal colorectal cancer (512 cases vs. 595 cases; relative risk, 0.86; 95% CI, 0.76 to 0.97; P=0.01). There were 2.9 deaths from colorectal cancer per 10,000 person-years in the intervention group (252 deaths), as compared with 3.9 per 10,000 person-years in the usual-care group (341 deaths), which represents a 26% reduction (relative risk, 0.74; 95% CI, 0.63 to 0.87; P<0.001). Mortality from distal colorectal cancer was reduced by 50% (87 deaths in the intervention group vs. 175 in the usual-care group; relative risk, 0.50; 95% CI, 0.38 to 0.64; P<0.001); mortality from proximal colorectal cancer was unaffected (143 and 147 deaths, respectively; relative risk, 0.97; 95% CI, 0.77 to 1.22; P=0.81). CONCLUSIONS Screening with flexible sigmoidoscopy was associated with a significant decrease in colorectal-cancer incidence (in both the distal and proximal colon) and mortality (distal colon only). (Funded by the National Cancer Institute; PLCO ClinicalTrials.gov number, NCT00002540.).

Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial

Objective To compare breast cancer incidence and mortality up to 25 years in women aged 40-59 who did or did not undergo mammography screening. Design Follow-up of randomised screening trial by centre coordinators, the study’s central office, and linkage to cancer registries and vital statistics databases. Setting 15 screening centres in six Canadian provinces,1980-85 (Nova Scotia, Quebec, Ontario, Manitoba, Alberta, and British Columbia). Participants 89 835 women, aged 40-59, randomly assigned to mammography (five annual mammography screens) or control (no mammography). Interventions Women aged 40-49 in the mammography arm and all women aged 50-59 in both arms received annual physical breast examinations. Women aged 40-49 in the control arm received a single examination followed by usual care in the community. Main outcome measure Deaths from breast cancer. Results During the five year screening period, 666 invasive breast cancers were diagnosed in the mammography arm (n=44 925 participants) and 524 in the controls (n=44 910), and of these, 180 women in the mammography arm and 171 women in the control arm died of breast cancer during the 25 year follow-up period. The overall hazard ratio for death from breast cancer diagnosed during the screening period associated with mammography was 1.05 (95% confidence interval 0.85 to 1.30). The findings for women aged 40-49 and 50-59 were almost identical. During the entire study period, 3250 women in the mammography arm and 3133 in the control arm had a diagnosis of breast cancer, and 500 and 505, respectively, died of breast cancer. Thus the cumulative mortality from breast cancer was similar between women in the mammography arm and in the control arm (hazard ratio 0.99, 95% confidence interval 0.88 to 1.12). After 15 years of follow-up a residual excess of 106 cancers was observed in the mammography arm, attributable to over-diagnosis. Conclusion Annual mammography in women aged 40-59 does not reduce mortality from breast cancer beyond that of physical examination or usual care when adjuvant therapy for breast cancer is freely available. Overall, 22% (106/484) of screen detected invasive breast cancers were over-diagnosed, representing one over-diagnosed breast cancer for every 424 women who received mammography screening in the trial.

Screening by chest radiograph and lung cancer mortality: The Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial

CONTEXT The effect on mortality of screening for lung cancer with modern chest radiographs is unknown. OBJECTIVE To evaluate the effect on mortality of screening for lung cancer using radiographs in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial that involved 154,901 participants aged 55 through 74 years, 77,445 of whom were assigned to annual screenings and 77,456 to usual care at 1 of 10 screening centers across the United States between November 1993 and July 2001. The data from a subset of eligible participants for the National Lung Screening Trial (NLST), which compared chest radiograph with spiral computed tomographic (CT) screening, were analyzed. INTERVENTION Participants in the intervention group were offered annual posteroanterior view chest radiograph for 4 years. Diagnostic follow-up of positive screening results was determined by participants and their health care practitioners. Participants in the usual care group were offered no interventions and received their usual medical care. All diagnosed cancers, deaths, and causes of death were ascertained through the earlier of 13 years of follow-up or until December 31, 2009. MAIN OUTCOME MEASURES Mortality from lung cancer. Secondary outcomes included lung cancer incidence, complications associated with diagnostic procedures, and all-cause mortality. RESULTS Screening adherence was 86.6% at baseline and 79% to 84% at years 1 through 3; the rate of screening use in the usual care group was 11%. Cumulative lung cancer incidence rates through 13 years of follow-up were 20.1 per 10,000 person-years in the intervention group and 19.2 per 10,000 person-years in the usual care group (rate ratio [RR]; 1.05, 95% CI, 0.98-1.12). A total of 1213 lung cancer deaths were observed in the intervention group compared with 1230 in usual care group through 13 years (mortality RR, 0.99; 95% CI, 0.87-1.22). Stage and histology were similar between the 2 groups. The RR of mortality for the subset of participants eligible for the NLST, over the same 6-year follow-up period, was 0.94 (95% CI, 0.81-1.10). CONCLUSION Annual screening with chest radiograph did not reduce lung cancer mortality compared with usual care. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00002540.

The Canadian national Breast screening study-1: Breast cancer mortality after 11 to 16 years of follow-up a: Randomized screening trial of mammography in women age 40 to 49 years

Context Seven- and 10-year results of the Canadian National Breast Screening Study (CNBSS) showed no reduction in breast cancer mortality from five annual mammographies and breast examinations for 40- to 49-year-old women. Some authors have argued that longer follow-up would reveal important benefits. Contribution After 11 to 16 years, the cumulative rate ratios for mammography versus usual care were 0.97 (95% CI, 0.74 to 1.27) for breast cancer mortality without adjustment for nonstudy mammography and 1.06 (CI, 0.80 to 1.40) with adjustment. Clinical Implications The CNBSS suggests that screening 40- to 49-year-old women is unlikely to reduce breast cancer by 20% or more. Controversy will persist because other studies suggest that screening causes small reductions in breast cancer mortality. The Editors The Canadian National Breast Screening Study-1 (CNBSS-1), an individually randomized trial in women 40 to 49 years of age at study entry, evaluated the efficacy of annual mammography, breast physical examination, and instruction on breast self-examination in reducing breast cancer mortality (1). The 7-year (2) and preliminary 10-year (3) mortality results were previously reported. At 7 years, 38 women in the mammography group and 28 women in the usual care group had died of breast cancer, for a rate ratio of 1.36 (95% CI, 0.84 to 2.21) (2). At 10 years, there were 82 breast cancer deaths in the mammography group and 72 in the usual care group (rate ratio, 1.14 [CI, 0.83 to 1.56]) (3). This article reports CNBSS-1 results after an average 13-year follow-up from study entry. Methods Patient Selection and Recruitment Participants were recruited through media publicity, personal invitation letters using population lists (municipal registers and provincial health insurance registers), group mailings, and physicians (4). Eligibility criteria were age 40 to 49 years, no previous diagnosis of breast cancer, not being pregnant, no mammography in the previous 12 months, and signed informed consent. The Human Experimentation Committee of the University of Toronto (Toronto, Ontario, Canada) and Human Experimentation Committees at 15 CNBSS collaborating centers approved the study. A total of 50 430 women age 40 to 49 years were enrolled from January 1980 through March 1985. Randomization Before randomization, all participants received an initial breast physical examination and instruction on breast self-examination. They were then immediately randomly assigned to receive mammography and, thereafter, either annual screening with mammography and breast physical examination (25 214 women in the mammography group were available for analysis) or usual care in the context of the Canadian health care system (25 216 women in the usual care group were available for analysis). Center coordinators randomly assigned participants using prepared allocation lists, independent of breast physical examination findings. This sequence ensured that the conduct and interpretation of the breast physical examination would be unbiased by knowledge of whether mammography would follow. Intervention Screening Schedule In the mammography group, 62% of women received five annual screenings. The remainder, recruited later, received four. Each screening examination comprised mammography, breast physical examination, and instruction and evaluation on breast self-examination. Women in the mammography group completed questionnaires at each rescreening visit. Women in the usual care group were not recalled for rescreening but were mailed annual questionnaires. We expected that these participants would continue their normal pattern of medical care as delivered through Canadas universal health care coverage, including access to mammography for diagnosis. Study Procedures Two-view mammography was done on dedicated mammography units (5), and second readers reviewed mammograms deemed abnormal. Systematic audit procedures were used (6). Nurses provided breast physical examination in 12 centers and physicians in 3 centers in Qubec (7). These providers taught and evaluated breast self-examination while conducting their own examination (8). If findings on breast physical examination or mammography were abnormal, participants were referred to a CNBSS review clinic. The study surgeon discussed mammography findings with the study radiologist, examined the participant, and decided whether further diagnostic procedures should be recommended to the womans physician. The womans physician determined whether and how to implement the study surgeons recommendations. Data Collection Protocol During the screening period, the center coordinators collected surgery and pathology reports for breast-related diagnostic and therapeutic procedures. The CNBSS pathologists reviewed all slides. If the community and CNBSS pathologist disagreed, a panel of three to five CNBSS pathologists blindedly and independently reviewed the slides. Extensive quality control procedures were used during data collection. After the screening centers closed in 1988, the central CNBSS central office annually followed all women known to have breast cancer until 30 June 1996, the cut-off for this analysis. Passive follow-up of all participants through linkage with the National Cancer Registry identified new diagnoses of breast cancer in study participants through 31 December 1993. The central office collected pathology reports for postscreening cases of breast cancer. The community diagnosis was accepted for study purposes. Family members responding to the annual mailed questionnaire identified deaths that occurred before completion of a participants screening schedule. Thereafter, women not known to have cancer were followed only through registry linkage; their mammography experience was not traced. However, for women known to have breast cancer, attending physicians received annual requests for updated clinical information, including death. Attending physicians, who received annual requests for information on women with breast cancer, reported deaths until 30 June 1996. Linkage with the Canadian Mortality Database at Statistics Canada (including deaths in Canadians who resided in the United States at the time of death) identified causes of death in the entire cohort until 31 December 1993. The procedures used to verify deaths from breast cancer were described previously (2). Investigative procedures were initiated for women dying with breast cancer; those whose death certificates mentioned breast cancer; and those whose cause of death was described as unknown, unknown primary, lung cancer, colon cancer, or liver cancer. The reviewers were blinded to study group allocation. All other causes of death were accepted as certified. For the most recent record linkage, more stringent confidentiality requirements exercised by many hospitals hindered verification. Thus, of the breast cancer deaths reported in this paper, a panel reviewed 67% in the mammography group and 77% in the usual care group. The remaining deaths are as reported on death certificates. Study Outcomes Death due to or probably due to breast cancer was the major study outcome. A previous report of the CNBBS-1 noted axillary node status, as assessed by community pathologists, through 7 years of follow-up (2). Subsequently (1993 to 1997), to achieve consistent reporting of tumor size, all available material for screening-detected cancer and cancer detected between screenings was re-collected from originating institutions and reviewed by one of the CNBSS pathologists or a colleague. Slides were obtained for review for nearly 80% of requested cases. For the current analysis, pathologists measured the size of small tumors as observed on the slide or the size of the invasive component for mixed invasive and in situ tumors. Statistical Analysis Sample Size The CNBSS-1 was planned to evaluate whether breast cancer mortality would decrease by 40% in the mammography group compared with the usual care group after 5 years of follow-up, with a required sample size of 50 000 women ( = 0.05; power, 80%) (1). At 5 years, however, too few women had died of breast cancer for the study to achieve the planned power. Thus, for the first report on breast cancer mortality, we extended follow-up to 7 years (2). CNBSS Database The database includes records for 50 430 women, including demographic and risk factor variables and results of screening examinations, diagnostic and therapeutic procedures, pathology results, and causes of death. CNBSS Terminology The terms screen 1, screen 2, through screen 5 denote events associated with screening examinations in the mammography group. The initial breast physical examination received by the usual care group is called screen 1. Screening-detected cancers are those diagnosed after a recommendation made by the study surgeon at the CNBSS review clinic. Interval cancers are cases of cancer that occurred less than 12 months after a screening examination at which no recommendation for diagnostic procedures was made. Incident cancers are cases of cancer that occurred more than 12 months after the previous CNBSS screening examination. Statistical Tests The statistical significance of differences in proportions was determined by using the chi-square test (two-sided = 0.05). For all observed-to-expected ratios, 95% CIs were computed. Death rates were computed by using person-years based on stratification by quinquennium of age; we assumed that all women not known to be dead are alive. Age was defined as age at entry. Because all eligible participants were included in the analysis and follow-up, this is an intention-to-treat analysis. Cox proportional-hazards regression was done to examine variables with the most significant independent influence on survival (9), using the PHREG program in SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Because the variable allocation to screening was our primary interest, it was fo

The Chemotherapy of Plasma-Cell Myeloma and the Incidence of Acute Leukemia

Previously untreated patients with myeloma were randomized to initial treatment with melphalan and prednisone (and to cyclophosphamide or carmustine if relapse or progression occurred)(Group A, 125 patients), melphalan, cyclophosphamide, carmustine and prednisone in alternating (Group B, 123 patients) or concurrent (Group C, 116 patients) schedules. The groups were similar with respect to known prognostic factors. Response rates and survival were also similar. We were unable to identify a subgroup of patients who responded or survived better on melphalan-cyclophosphamide-carmustine and prednisone than on melphalan and prednisone. We conclude that the combination of the four drugs is not better than melphalen and prednisone for inducing responses or prolonging the survival of patients with myeloma. Myelomas producing only gamma chains have a poorer prognosis (P greater than 0.001) than IgG, IgA, or kappa myeloma. Acute leukemia has developed in 14 patients. The actuarial risk of developing acute leukemia, has increased rapidly to 17.4 per cent at 50 months.