Is screening for prostate cancer the current gold standard?--"no".
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Biomarkers, Tumor↗
Biomedical subjects
B S Kramer
Publications and source records attributed to B S Kramer.
Induced abortion, bias, and breast cancer: why epidemiology hasn't reached its limit.
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Abortion, Induced↗
Evaluation of in vitro chemosensitivity using human lung cancer cell lines.
The use of well-characterized human lung cancer cell lines has allowed for new opportunities in preclinical and clinical drug evaluation. Development of semiautomated tests of in vitro cytotoxicity such as the MTT assay, which utilizes the formazan salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), has allowed for preclinical evaluation of novel chemotherapeutic agents and drug combinations. In addition, techniques such as this make possible the testing of sufficient data sets to allow determination of true biochemical drug synergy. Assessment of drug combinations which possess in vitro synergy or supraadditive effects can suggest chemotherapeutic regimens for further clinical testing. Using the MTT assay in conjunction with isobolographic analysis, it is possible to test commonly used regimens which are based on presumed or apparent in vivo drug synergy, such as the combination of etoposide and cis-platinum. This frequently prescribed combination was found to lack in vitro biochemical synergy when tested with human lung cancer cell lines, indicating that the observed clinical benefits of this drug combination may be due to factors in the tumor microenvironment, drug metabolism, or non-overlapping toxicities. Finally, although it remains to be determined if a significant role for in vitro drug testing will be found in direct clinical applications, preclinical drug evaluation during the drug development process using cultured tumor cell lines may ultimately allow for disease or patient specific therapies for testing.
Animals↗
Dipyridamole mediated enhanced antiproliferative activity of 10-ethyl-10-deazaaminopterin (10-EDAM) against human lung cancer cell lines.
10-ethyl-10-deazaaminopterin (10-EDAM) is a rationally designed derivative of the antifolate, methotrexate (MTX). In a number of tumor models these design features have resulted in an improved spectrum of antiproliferative activity as compared with the parent compound. Using an MTT growth assay, we compared in vitro antiproliferative activity of 10-EDAM with MTX in eight lung cancer cell lines. Growth was inhibited in all lines tested by clinically achievable concentrations of 10-EDAM (0.1-1,000 nM). 10-EDAM was more cytotoxic than MTX at the same concentrations in all eight lung cancer cell lines. In an effort to enhance the antiproliferative effect, we evaluated the addition of dipyridamole (DPM), an inhibitor of nucleoside transport, to 10-EDAM (0.1-10 microns). DPM decreased the concentration of 10-EDAM required to cause 50% growth inhibition (IC50) in all eight cell lines tested. This suppression was statistically significant by 2-sided sign test (P = .0078). By contrast, the IC50 of MTX was decreased in only two of the eight cell lines when DPM was added (0.1-10 microM). In defined thymidine depleted media, cell kill by the combination of 10-EDAM and DPM was no greater than 10-EDAM alone, consistent with the possibility that DPM exerts some of its effect by inhibition of extrinsic nucleoside salvage. In consideration of the published activity of 10-EDAM in lung cancer and the modest clinical toxicity of DPM based biochemical modulation, we conclude the current in vitro data provide justification for clinical evaluation of this combination in patients with lung cancer.
Aminopterin↗
Prostate cancer screening: current issues.
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Cost-Benefit Analysis↗
The role of increasing detection in the rising incidence of prostate cancer.
OBJECTIVE: To assess the reasons for the dramatic surge in prostate cancer incidence from 1986 to 1991. DESIGN: Population-based study of incidence rates and procedures used to detect and diagnose prostate cancer derived from Medicare claims data and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program from 1986 to 1991. SETTING: Four SEER areas (Connecticut; Atlanta, Ga; Detroit, Mich; and Seattle--Puget Sound, Wash) covering approximately 6% of the US population. PARTICIPANTS: A 5% random sample of male fee-for-service Medicare beneficiaries aged 65 years and older without cancer, and all men with prostate cancer diagnosed at 65 years of age and older residing in the four areas. MAIN OUTCOME MEASURES: The age-adjusted rates of prostate cancer incidence, prostate needle biopsy, transurethral resection of the prostate, serum prostate-specific antigen (PSA) testing, and transrectal ultrasound. RESULTS: The age-adjusted incidence rate of prostate cancer among men aged 65 years and older in the four SEER areas rose 82% from 1986 to 1991, with the largest annual increases occurring in 1990 (20%) and 1991 (19%). Prostate needle biopsy rates increased while the use of transurethral resection of the prostate declined from 1986 to 1991. The rising needle biopsy rate has been driven by an exponential increase in PSA testing in the general population from 1988 to 1991 and, to a much lesser extent, the increasing use of transrectal ultrasound since 1986. The use of PSA or transrectal ultrasound has increased across age and race groups and in different geographic areas. However, there remain wide geographic variations in the use of PSA screening. CONCLUSIONS: The recent dramatic epidemic of prostate cancer is likely the result of the increasing detection of tumors resulting from increased PSA screening. The magnitude and rapidity of the incidence rise suggest that changes in the intensity of medical surveillance is the most plausible explanation for this trend. IMPLICATIONS: The rapid diffusion of screening interventions that have the ability to detect latent asymptomatic disease leads to important concerns regarding costs and patient quality of life for men aged 65 years and older. Geographic variability in the adoption of PSA testing underscores uncertainty and disagreement about its value for reducing prostate cancer mortality. More research is required to determine the effectiveness of screening for prostate cancer.
Age Distribution↗
Genetics of lung cancer: implications for early detection and prevention.
Human lung cancer is a complex disease originating in different cell types. In general, tumorigenesis in the lung appears to involve a complex series of molecular, genetic, and histopathologic events, leading to the transformation of normal cells to malignant cells. It is generally believed that it is the accumulation of biologic changes, not necessarily the order in which they occur, that could best describe the transformation of cells. Our knowledge of genetic changes during tumorigenesis in the lung is limited and comes from studies involving animal models and frankly malignant lung tissues. Such studies can be questioned as to their applicability in primary prevention. A vast majority of genetic changes occurring during the preclinical stage are yet to be documented. Study of these preclinical changes would offer a better opportunity for early detection and prevention. Oncogenes and tumor suppressor genes have potential for use as biomarkers in identifying high-risk groups and in early detection. The interaction between nature and nurture is nowhere as evident as in cancers of the lung, which are influenced by environmental exposure, familial inheritance, and metabolic phenotypes. The gene-environment interaction provides several targets for prevention and early detection. Biomarkers, if validated for specificity, sensitivity, and predictive values, could act as markers of exposure, susceptibility, progression, and disease. Validation of these markers, however, would require well-characterized, prospectively collected samples, representing normal, premalignant, malignant, invasive, and metastatic conditions. The NCI has started an initiative for a tissue bank of prostate, bladder, colorectum, head and neck, and lung cancers. Clinical and epidemiological information are also collected for each sample. Study of genetic and molecular changes in collected samples should shed light on the involvement of these changes in the transformation of normal to malignant tissues.
Biomarkers, Tumor↗
Design of the Prostate Cancer Prevention Trial (PCPT).
The PCPT is a chemoprevention trial of finasteride with a primary endpoint of biopsy-proven presence or absence of prostate cancer. A total of 18,000 healthy men, aged 55 years and older, will be randomized. Half will receive finasteride (5 mg/day) and half will receive placebo (one matching tablet per day) for 7 years. The trial is designed to have 92% power to detect a 25% reduction in period prevalence of biopsy-proven disease using a two-sided test with alpha = 0.05. The trial is complicated by the known impact of finasteride on the major screening test for prostate cancer, prostate specific antigen (PSA). This paper describes the PCPT design with reference to alternatives that were considered. The chosen design depends on five critical assumptions that must be monitored closely throughout the 9-year trial.
Aged↗
The potential for hormonal prevention trials.
Breast and prostate cancer are significant causes of morbidity and mortality and are very similar in etiology, epidemiology, and modalities of treatment. Investigational strategies in the prevention of these malignancies also have strong parallels. The National Cancer Institute is sponsoring several large scale clinical trials involving hormonal manipulation and cancer prevention. In the Breast Cancer Prevention Trial, 16,000 women at high risk for breast cancer are being randomized to receive the antiestrogen agent tamoxifen or placebo for 5 years in an effort to determine if breast cancer development can be inhibited. In a similar trial, the Prostate Cancer Prevention Trial, 18,000 men older than 55 years of age will be randomized to receive finasteride, a 5-alpha-reductase inhibitor, or placebo to determine if inhibition of dihydrotestosterone synthesis in the prostate over a prolonged period will lead to a decreased incidence of prostate cancer. Both clinical trials offer the possibility of demonstrating that a hormonal intervention can decrease an individual's risk of developing breast or prostate cancer. They also have the potential of providing critical information about cancer risk, etiology, screening, and genetics, as well as quantifying the risks and benefits of specific preventive interventions.
5-alpha Reductase Inhibitors↗
NIH Consensus 1994: screening.
Frequently, the medical and lay community has assumed that earlier diagnosis of cancer of any type automatically confers benefit and that any diagnostic test that can identify early stages of disease must therefore be useful for screening. However, there is an emerging science of screening which affords a more rigorous approach to public health recommendations in the application of new technologies to screening and early detection. A number of public health groups and agencies are using an evidence-based approach in making recommendations. Using this approach, early detection methods for ovarian cancer would meet only the weakest level of evidence to support their routine application in asymptomatic women. For this reason, the National Cancer Institute has recently launched a large randomized clinical trial to test the effectiveness of screening for ovarian cancer.
Aged↗
Integrated clinical and basic studies related to circumventing non-small cell lung cancer drug resistance.
Consideration of a range of clinical and basic studies conducted at the National Cancer Institute which explore the nature of the tumor biology of lung identify the limitations of using chemotherapy for the treatment of advanced lung cancer. No single mechanistic explanation for lung cancer's chemoresistance is apparent, although considerable information about the biology of lung cancer and some of its clinical consequences have been elucidated. In contrast to previous works from our group, this presentation will focus principally on studies of the nature of drug resistance with non-small cell cancer. An alternative combined modality strategy for lung cancer control is to focus on epithelial progression of lung cancer using local modalities while it is still confined to the bronchial epithelium. Particular high risk populations may be appropriate to determine if local tools such as photodynamic laser therapy can be effective in this application. To deal with the underlying biochemical perturbations resulting from critical exposure of the bronchial epithelium to carcinogens, rational biochemical intervention with 13 cis retinoic acid are being evaluated in several clinical trials. An evolution towards more effective lung cancer control may involve the combined modalities of laser ablation of accessible dysplastic epithelium and chronic administration of intervention agents, such as retinoids, to neutralize cancer promotion dynamics in the more remote areas of the lung epithelium.
Antineoplastic Agents↗
Prostate cancer screening in the prostate, lung, colorectal and ovarian cancer screening trial of the National Cancer Institute.
Screening for prostate cancer and subsequent treatment is of unknown benefit but carries known treatment related morbidity and mortality risks. The recent enthusiasm for screening in the United States contrasts sharply with the more cautious attitudes of the European and Canadian medical communities. Current data from screening series without randomization and controls are inadequate to determine screening benefit. The prostate, lung, colorectal and ovarian cancer (randomized, controlled) screening trial of the National Cancer Institute, to include 74,000 men (and 74,000 women) 60 to 74 years old, has a design power of 90% to determine a 20% reduction of prostate cancer mortality from a baseline and 3 subsequent annual screens using prostate specific antigen and digital rectal examination. Randomization of participants into this trial began on November 16, 1993. Ten screening centers nationwide, a coordinating center, a laboratory and a biorepository are participating under contract.
Aged↗
Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer.
PURPOSE: We performed a prospective randomized clinical trial to determine whether higher doses of etoposide and cisplatin (EP) yield more complete responses or longer survival in small-cell lung cancer (SCLC) patients. PATIENTS AND METHODS: Ninety patients with previously untreated extensive-stage SCLC fulfilled criteria for randomization to standard-dose versus high-dose EP. Another 25 patients at risk of excessive toxicity from high-dose treatment were given standard-dose therapy. During cycles 1 and 2 of EP, patients on standard-dose treatment received intravenous etoposide 80 mg/m2 on days 1 to 3 and cisplatin 80 mg/m2 on day 1 every 3 weeks; high-dose treatment consisted of etoposide 80 mg/m2 on days 1 to 5 and cisplatin 27 mg/m2 on days 1 to 5 every 3 weeks. All patients received standard-dose EP in cycles 3 and 4. In cycles 5 through 8, completely responding patients continued standard-dose EP; all other patients received either cyclophosphamide, doxorubicin, and vincristine, or (if possible) a combination drug program based on in vitro drug sensitivity testing of tumor-cell lines established from individual patients. RESULTS: Despite 68% higher doses and a 46% higher dose-rate intensity actually given to patients randomized to receive high-dose relative to those randomized to receive standard-dose EP, complete response rates (23% v 22%; P = .99) and median survival durations (10.7 and 11.4 months, respectively; P = .68) were virtually identical. Complete responses occurred in 4% of patients and the median survival duration was 5.8 months in nonrandomized patients. Leukopenia (P < .0001), thrombocytopenia (P < .0001), febrile neutropenia (P = .01), and weight loss (P = .02) were significantly more common in patients randomized to receive high-dose compared with standard-dose EP. CONCLUSION: No therapeutic benefits resulted from increasing planned doses by 67% for the first two cycles of EP in patients with extensive-stage SCLC. Higher doses were associated with substantially worse toxicities.
Adult↗
After a treatment breakthrough: a comparison of trial and population-based data for advanced testicular cancer.
PURPOSE: To determine to what extent the benefits of cisplatin-based combination chemotherapy have been disseminated to all American men diagnosed with advanced testicular cancer. PATIENTS AND METHODS: One hundred seventy-two advanced testicular cancer cases from five population-based registries of the Surveillance, Epidemiology, and End Results (SEER) Program diagnosed from 1978 to 1984 were compared with 133 diagnostically comparable cases from the Memorial Sloan-Kettering Cancer Center (MSKCC) vinblastine, dactinomycin, and bleomycin (VAB) regimens 7 through 9. Exclusions were made in both series for cases with elevated markers only, abdominal disease only, or extragonadal tumors. Ratings of extent of disease using the Indiana University system (minimal/moderate or advanced) were available for the MSKCC cases, and were determined retrospectively on the SEER cases based on information abstracted from medical records. RESULTS: Among the SEER cases, 89% reported receiving chemotherapy, and 95% of these received cisplatin-containing regimens. Survival among the MSKCC patients was significantly better than for the SEER cases in the minimal/moderate extent of disease category (95% and 73% 3-year survival rate, respectively); however, the difference for advanced cases was only marginally significant (52% and 40% 3-year survival rates, respectively). Survival did not vary significantly by year of diagnosis in either series. CONCLUSION: Although most of the patients in the SEER series received cisplatin-based chemotherapy, this alone did not produce results equivalent to that in the MSKCC series. Since the patients were selected to be as diagnostically comparable as possible at baseline, remaining differences in survival may be due to adherence to a fixed regimen and level of dose-intensity, adequacy of diagnostic work-up, implementation of salvage therapies and debulking surgery, and unknown factors related to who is willing and able to travel to a tertiary care center for treatment. Whatever the reason for not achieving optimal results in the SEER series, the very modest survival improvements over the time period 1978 to 1984 indicates that the differences in outcome between the two series were basically stable over the study period.
Adolescent↗
5-Alpha-reductase inhibition and prostate cancer prevention.
Studies of prostate biology support the concept that dihydrotestosterone is the principal androgen responsible for normal and hyperplastic growth of the prostate gland. Cancer is a process of malignant transformation evolving over time, involving cellular growth and division. Therefore, an altered endocrine state, such as suppression of dihydrotestosterone activity, may have an impact on prostate cells inhibiting carcinogenic transformation. In vitro and in vivo preclinical observations support this hypothesis. A placebo-controlled randomized trial using finasteride, an inhibitor of the enzyme that converts testosterone to dihydrotestosterone, is planned. The endpoint of this trial will be reduction of prostate cancer incidence.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Prostate cancer screening: what we know and what we need to know.
OBJECTIVE: To critically evaluate the evidence for recommending the screening of asymptomatic men for prostate cancer with a blood test to detect a prostate-specific antigen (PSA). DATA SOURCES: Relevant articles on screening for prostate cancer were identified from MEDLINE searches, from the authors' files, and from the bibliographies of identified articles. STUDY SELECTION: In the absence of controlled prospective trials, the studies are primarily retrospective and contain information about the sensitivity, specificity, and predictive values of tests used to screen for prostate cancer; the natural history of untreated prostate cancer; the morbidity, mortality, and costs of definitive treatment; and reviews of screening study biases. DATA EXTRACTION: Potential treatment-related mortality and costs that could be incurred by screening were estimated using defined assumptions. RESULTS: Although screening for prostate cancer has the potential to save lives, because of possible overdiagnosis, screening and subsequent therapy could actually have a net unfavorable effect on mortality or quality of life or both. Given the performance characteristics of the test, widespread screening efforts would probably cost billions of dollars. CONCLUSIONS: The net benefit from widespread screening is unclear. A randomized prospective study of the effect of screening on prostate cancer mortality has therefore been initiated by the National Cancer Institute.
Aged↗
Vasectomy and increased risk of prostate cancer.
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Humans↗
Combination cytotoxic effects of cis-diamminedichloroplatinum(II) and 5-fluorouracil with and without leucovorin against human non-small cell lung cancer cell lines.
Both cisplatin (CDDP) and leucovorin (LV) have been shown to enhance cytotoxicity of 5-fluorouracil (FUra) against murine and human neoplasms by increasing intracellular reduced folate concentrations. We were interested in their use in a combination to inhibit non-small cell lung cancer (NSCLC) cell growth and therefore conducted an in vitro study to investigate the cytotoxic activities of combinations of CDDP plus FUra, with and without LV (20 microM), against seven NSCLC cell lines. A tetrazolium assay with application of the classical isobole method was used to test drug combinations. We found that LV enhanced FUra but not CDDP cytotoxicity and that the degree of enhancement was negatively correlated with the effect of FUra. There was an overall additive combination effect of CDDP plus FUra, although there may be synergy at higher effect levels. There was synergy to a combination of CDDP, FUra, and LV, presumably primarily related to the synergistic effects of adding LV to FUra. In summary, LV and CDDP enhanced FUra cytotoxicity in a complementary fashion and there was clear synergy of a combination of CDDP, FUra, and LV against a panel of NSCLC cell lines. Our in vitro results provide a rationale for controlled clinical studies of this three-drug regimen in patients with NSCLC.
Carcinoma, Non-Small-Cell Lung↗