Five-alpha-reductase Inhibitors for prostate cancer prevention.

BACKGROUND: Five-alpha-reductase inhibitors (5ARI) are frequently used to treat bothersome lower urinary tract symptoms associated with benign prostatic hyperplasia and male androgenic alopecia. They have potential as chemopreventive agents. OBJECTIVES: We sought to estimate the effectiveness and harms of 5ARI in preventing prostate cancer. SEARCH STRATEGY: MEDLINE, PreMEDLINE, and the Cochrane Collaboration Library were searched through April 2007 to identify randomized trials. SELECTION CRITERIA: For prostate cancer outcomes we included randomized controlled trials of at least 1 year in duration published after 1984. For non-prostate cancer outcomes, randomized trials were included if: they were at least 6 months in duration published after 1999. DATA COLLECTION AND ANALYSIS: The primary outcome was prostate cancer period-prevalence "for-cause." "For-cause" was defined as prostate cancer clinically detected based on symptoms, an abnormal digital rectal exam, or detected as a result of an abnormal prostate specific antigen value. Trials were categorized as long (> 2 year), mid (1-2 years) and short (< 1 year) term. MAIN RESULTS: Nine trials reported prostate cancer period-prevalence. Three trials using finasteride lasted 4 years or longer but only one (the Prostate Cancer Prevention Trial) was specifically designed to assess the impact of 5ARI on prostate cancer period-prevalence. The mean age of enrollees was 64.6 years, 91% were white, mean PSA was 2.1 ng/mL. For-cause prostate cancers comprised 54% of all cancers detected. Finasteride was associated with a 26% relative risk reduction in prostate cancers detected for-cause among all randomized subjects (relative risk 0.74 [95% CI 0.67 to 0.83]; absolute risk reduction = 1.4% (3.5% versus 4.9%). Six trials assessed prostate cancers detected overall with a pooled 26% relative reduction favoring 5ARI (relative risk 0.74 [95% CI 0.55 to1.00]; 2.9% absolute reduction (6.3% versus 9.2%). Reductions were observed regardless of age, race or family history of prostate cancer but not among men with baseline PSA > 4.0 ng/mL. A greater number of high Gleason score tumors (7-10 or 8-10) occurred in men on finasteride in the PCPT. Impaired sexual or erectile function or endocrine effects were more common with finasteride than placebo. AUTHORS' CONCLUSIONS: 5ARI reduce prostate cancer risk but may increase the risk of high-grade disease in men who are undergoing regular screening for prostate cancer using prostate specific antigen and digital rectal examination. Effects are consistent across race, family history and age and possibly 5ARI but were limited to men with baseline PSA values <4.0 ng/mL. The impact of 5ARI on absolute or relative rates of prostate cancer in men who are not being regularly screened is not clear. Information is inadequate to assess the impact of 5ARI on mortality.

Analysis of the role of cancer prevention and control measures in reducing cancer mortality.

One goal of the war against cancer is to create declines in cancer mortality rates. A decrease in these rates can only occur in two ways: 1) a decrease in incidence rates and 2) a real increase in overall survival rates. Reductions in incidence rates can be envisioned to occur through three mechanisms (in order of the time course of cancer): 1) reduction or amelioration of environmental or lifestyle risk factors, 2) use of agents that prevent the occurrence of cancer by blocking the progression to cancer, and 3) early detection at a preneoplastic state combined with treatment that prevents or delays progression to invasive cancer. "True" increases in overall survival can occur by two mechanisms (in order of the time course of cancer): 1) early detection of cancer by screening tests and subsequent effective treatment and 2) advancements in treatment. Unique patterns or "fingerprints" of stage-specific incidence and overall incidence and of survival rates characterize the various cancer prevention and control mechanisms that can decrease mortality rates. The rates are presented for five organ sites that have shown reduced cancer mortality. The patterns of rates for breast cancer for women under the age of 65 years were most consistent with early detection. The testicular cancer fingerprints were most consistent with advances in treatment, whereas cervical cancer rates were most consistent with the detection of preneoplastic lesions. The stomach cancer fingerprints were indicative of reductions in lifestyle or environmental risks, and colorectal cancer rates were indicative of a combination of treatment advances and early detection. These fingerprint patterns can be extended to other situations in which mortality trends are changing in order to suggest possible causes of observed changes. Limitations of this model are also discussed.

Potential role of tamoxifen in prevention of breast cancer.

Despite advances in early detection and treatment of breast cancer, primary prevention has not been well explored, especially for women at increased risk of disease due to reproductive factors and family history. There are, however, suggestions that primary prevention of breast cancer may be a realistic objective. Randomized clinical trials of adjuvant therapy for early-stage breast cancer have demonstrated a 35% decrease in contralateral breast cancers among women receiving tamoxifen compared with controls, suggesting a potential role for tamoxifen in chemoprevention of breast cancer in women at increased risk of the disease. Adjuvant therapy studies also demonstrate that tamoxifen is well tolerated by most patients and suggest additional health benefits from alterations in plasma lipid levels and stabilization of bone mineral loss in women receiving tamoxifen. Aspects of tamoxifen pharmacology, laboratory research, and clinical experience which support its investigation as a chemopreventive agent for breast cancer are summarized, and potential toxic effects are discussed.

Tobacco addiction: implications for treatment and cancer prevention.

The American Society of Clinical Oncology and the National Cancer Institute convened a symposium in June 1996 on tobacco addiction. Additional support for the symposium was provided by the American Medical Women's Association and the American Society of Preventive Oncology. The goals of this conference were to describe the burden and public health consequences of tobacco addiction, to describe the state of science for the treatment of nicotine dependence, and to explore new strategies to increase quit rates and to prevent the uptake of tobacco use. This article summarizes and integrates the meeting presentations on tobacco addiction and includes the topics of smoking prevalence; psychobiologic aspects of nicotine dependence; and implications for disease, treatment, and prevention. Comments on regulatory approaches and national strategies for reducing dependence are also summarized in presentations by Dr. David Kessler, former Food and Drug Administration Commissioner, and Dr. C. Everett Koop, former U.S. Surgeon General.

Chemosensitivity patterns and expression of human multidrug resistance-associated MDR1 gene by human gastric and colorectal carcinoma cell lines.

We compared the in vitro sensitivity patterns to cytotoxic drugs and expression of the multidrug resistance-associated MDR1 gene (also known as PGY1 gene) in four gastric carcinoma cell lines with those obtained in a panel of 11 colorectal carcinoma cell lines. In addition, we tested the effects of leucovorin on enhancement of fluorinated pyrimidine-induced cytotoxicity. We used a semiautomated tetrazolium dye assay [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (tetrazolyl blue)] (MTT) to compare the drug sensitivity of the gastric carcinoma cell lines with that of the colorectal carcinoma cell lines. The gastric carcinoma cell lines were more sensitive to some drugs, including doxorubicin and cisplatin, but not to the fluorinated pyrimidines. Addition of leucovorin at a clinically achievable concentration enhanced the cytotoxic effects of both fluorouracil and floxuridine in colorectal carcinoma cell lines, but it enhanced the effects of only floxuridine in gastric carcinoma cell lines. With the use of a slot blot assay, relatively low levels of MDR1 RNA were present in all four gastric carcinoma cell lines, while intermediate or high levels were present in most of the colorectal carcinoma cell lines. In general, our findings reflect clinical experience and may help in the design of clinical trials.

Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human colorectal carcinoma cell lines.

Reduced folates have been shown to increase the cytotoxicity of 5-fluorouracil (5-FU) by stabilizing the 5-fluoro-2'-deoxyuridine-5'-monophosphate-thymidylate synthase complex, thus increasing the block in the DNA synthetic pathway. Using an in vitro colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxicity assay, we tested the effects of 5-FU and 5-fluoro-2'-deoxyuridine (FdUrd) with and without leucovorin (LV) on a panel of 11 human colorectal carcinoma cell lines. The effect of LV on 5-FU and FdUrd was quantitatively similar. A clinically achievable level of LV (20 microM) increased the cytotoxicity in all three replicate experiments in 10 of the 11 cell lines (P less than .05, binomial test). LV alone at a concentration of 20 microM had no effect on cell survival. In three cell lines, 50% inhibition of growth occurred at a clinically achievable area under the curve of 5-FU alone. With the addition of LV, one additional cell line showed 50% growth inhibition at a clinically achievable level of 5-FU. Hence large clinical trials may be necessary to detect a significant improvement in survival as a result of adding LV to the fluorinated pyrimidines.

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.

Chemosensitivity testing of human colorectal carcinoma cell lines using a tetrazolium-based colorimetric assay.

The in vitro chemosensitivity of 11 human colorectal cell lines to seven chemotherapeutic agents was determined using a semiautomated tetrazolium-based colorimetric assay (MTT assay). Four of the cell lines were from primary tumors and seven from metastases. Eight lines were from patients with no prior chemotherapy. From assay results, we predict 5-fluorouracil (5-FU) to be the sole active agent of the seven tested. This is based on two observations: the range of drug concentrations which produced 50% inhibition of cell growth was greatest with 5-FU (388-fold versus 5- to 30-fold with the other six agents); and the area under the curve (AUC) which produced 50% growth inhibition was within a clinically achievable range only for 5-FU. Since the assay AUC of 5-FU at 50% inhibition was in a clinically achievable range for only two of the 11 cell lines, we performed a multivariate analysis to explore parameters which predict 5-FU sensitivity. In the best fitting model, sensitivity was positively correlated with cloning efficiency in media and with cell surface TAG-72 (a tumor-associated glycoprotein found on epithelial tumors of ovary, lung, colon, and breast origin) expression. If validated with an in vivo test such as the nude mouse model, the MTT assay could be very useful in new drug screening for colorectal carcinoma, for examining combination chemotherapy for synergy, for exploring strategies for biochemical modulation, and perhaps in individualizing therapy when cell lines can be established from a patient.

Lack of in vitro synergy between etoposide and cis-diamminedichloroplatinum(II).

Claims of synergy between etoposide and cisplatin have been based upon preclinical in vivo murine P388 models or upon human clinical trials in tumors such as lung cancer. Such in vivo studies are useful in exploring therapeutic synergy, i.e., an improved therapeutic strategy. The term "synergy" in this context is sometimes, however, taken to imply greater than additive kill of tumor cells. Unfortunately, it is virtually impossible to document supra-additive tumor cell kill in vivo, since in vivo curves of therapeutic effect are not linear and drugs are therefore not additive with themselves. Therapeutic synergy may, in fact, occur when two drugs are merely additive (or even antagonistic) with regard to cytotoxicity if the drugs have nonoverlapping host toxicity. The demonstration of true supra-additive cell kill would imply an interaction of the two agents at a cellular level and would have profound implications for biochemical studies. In order to determine whether the reported therapeutic synergy of etoposide and cisplatin is due, in part, to supra-additive cell kill, we used an in vitro tetrazolium-based colorimetric assay for cytotoxicity (MTT assay) and an isobologram analysis to test combinations of the two drugs against four human small cell and four human non-small cell lung carcinoma lines. Using a rigorous test for in vitro synergy, we could not establish a greater than additive cytotoxic effect on our cell lines. It thus appears that the clinical synergy between etoposide and cisplatin is not due to a supra-additive effect at the cellular level. Our results have implications for a variety of fields in which claims of "synergy" often appear.

Effects of intravenous hyperalimentation during treatment in patients with small-cell lung cancer.

One hundred nineteen patients were entered onto a randomized trial of the role of intravenous hyperalimentation (IVH) in patients with small-cell lung cancer. IVH was given during the first 30 days of induction chemotherapy to 54 patients. IVH did not effect any improvement in response or survival from therapy. In view of the lack of benefits from IVH, an analysis was made of the toxicities suffered by the 54 patients receiving IVH as well as any effects IVH might have made on chemotherapy-induced toxicity. Toxicities observed included mechanical difficulties with the catheter leading to temporary or permanent discontinuation of the IVH (11 patients), subclavian vein thrombosis (one patient), sepsis in nine patients v none of the 62 control patients, fluid overload (27 patients), hyponatremia (25 patients), and hyperglycemia requiring insulin (13 patients). Patients receiving IVH had higher granulocyte counts on days 14 and 21 of the first cycle of chemotherapy. Analysis shows that this difference is likely caused by fever and infection associated with IVH rather than any nutritional effect on granulopoiesis. In this population of patients, IVH had significant complications but did not ameliorate chemotherapy-induced toxicity and it did not effect any clinical benefit. Future studies of adjunctive nutritional therapy must consider the significant risk in this older population and must limit IVH volume or exclude patients with even mild compromise in cardiovascular functions. Further, any new trial must have a significant rationale for adjunctive use to justify the potential risks.

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.

A pilot study of interferon alfa-2a in combination with fluorouracil plus high-dose leucovorin in metastatic gastrointestinal carcinoma.

Thirty-one assessable patients with metastatic adenocarcinoma of the gastrointestinal tract were entered onto a pilot study designed to assess the impact of recombinant interferon alpha-2a (rIFN alpha-2a) on the toxicity and pharmacokinetics of fluorouracil (5-FU) and leucovorin (LV). Patients received an initial cycle of 5-FU (370 or 425 mg/m2/d) with LV (500 mg/m2/d) for 5 days. If tolerated, the patient received the same dose of 5-FU/LV for the second cycle on days 2 to 6, with rIFN alpha-2a at 5 x 10(6) or 10 x 10(6) U/m2/d on days 1 to 7, or with 3 x 10(6) U/m2/d on days 1 to 14. In 26 matched cycles, rIFN alpha-2a administration was associated with an increased incidence of dose-limiting mucositis and diarrhea and a significantly lower median platelet nadir; rIFN alpha-2a did not significantly affect the median WBC or granulocyte nadir. Dose-limiting toxicity occurred in all six patients entered at 425 mg/m2/d of 5-FU/LV within two cycles. The majority of patients treated with 370 mg/m2/d of 5-FU/LV and 10 x 10(6) U/m2/d rIFN alpha-2a experienced grade 3 to 4 mucositis and diarrhea, whereas patients receiving 3 x 10(6) and 5 x 10(6) U/m2/d rIFN alpha-2a had acceptable toxicity. Administration of rIFN alpha-2a was associated with a dose-dependent decrease in 5-FU clearance. The increase in the area under the 5-FU concentration-time curve (AUC) was 1.3-fold and 1.5-fold in patients receiving 5 x 10(6) and 10 x 10(6) U/m2/d rIFN alpha-2a, respectively. Thus, the increase in 5-FU toxicity with rIFN alpha-2a may be explained by alterations in 5-FU pharmacokinetics. In 22 patients without prior 5-FU therapy, three complete (13.6%) and seven partial (31.8%) responses were seen, for an overall response rate of 45.4% (95% confidence interval, 24.4% to 67.8%). Since the 5 x 10(6) U/m2/d dose of rIFN alpha-2a increased the 5-FU drug exposure and was associated with acceptable toxicity, we recommend its further evaluation as given on days 1 to 7 in combination with 5-FU 370 mg/m2/d, with high-dose LV given on days 2 to 6.

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.

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.

An outlier theory of cancer curability. Tumor cell differentiation as a therapeutic goal.

Combinations of cytotoxic agents that cure a substantial percentage of patients with several childhood and adult malignancies are much less efficacious for the majority of solid tumors. Standard approaches for curability that rely solely on the concept of cytotoxicity may not be applicable for most epithelial and mesenchymal solid malignancies. Differentiation may play a more important role in cancer cure than heretofore suspected. Clinical and experimental evidence supports further investigation into models of inducing tumor cell differentiation. The question of why such models could predict for curative modalities of treatment is discussed.

Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients.

Bone marrow transplant recipients were found to have a 10-fold greater incidence of nosocomial Aspergillus infection than other immunocompromised patient populations (p less than 0.001) when housed outside of a high-efficiency particulate air (HEPA) filtered environment. Multivariate analysis demonstrated that number of infections, age, and graft-versus-host disease severe enough to require treatment were independent risk factors for development of nosocomial Aspergillus infection in this group. The use of whole-wall HEPA filtration units with horizontal laminar flow in patient rooms reduced the number of Aspergillus organisms in the air to 0.009 colony-forming units/m3, which was significantly lower than in all other areas of the hospital (p less than or equal to 0.03). No cases of nosocomial Aspergillus infection developed in 39 bone marrow transplant recipients who resided in this environment throughout their transplantation period compared with 14 cases of nosocomial Aspergillus infection in 74 bone marrow transplant recipients who were housed elsewhere (p less than 0.001). Thus, although bone marrow transplant recipients had an order-of-magnitude greater risk of nosocomial Aspergillus infection than other immunocompromised hosts, this risk could be eliminated by using HEPA filters with horizontal laminar airflow.

The management of primary lymphoma of bone.

From October 1962 through April 1982, 21 patients with the diagnosis of primary lymphoma of bone (18 monostotic, stages IE and IIE; 3 polyostotic) were treated with curative intent. A combination of chemotherapy and radiation therapy was used in 11 patients, local treatment alone in 9 patients, and chemotherapy alone in one patient. Overall 5-year survival for the patients treated with curative intent was 56%. Standard work-up has changed over the 20-year study period. Five-year survival for the subset of eight stage I and II patients with full pretherapy staging was 83%. Prognosis was significantly correlated with extent of pretherapy staging. Treatment parameters that also seemed to predict outcome were the aggressiveness of chemotherapy and the use of irradiation or surgery for local-regional disease; the only local failure occurred in the patient who received chemotherapy alone. Complications of radiation therapy alone and in combination with chemotherapy are discussed and correlated with irradiation dose. Radiation therapy techniques are described, and a management approach is recommended.

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.

Cancer screening.

Especially in the emotionally charged field of cancer screening, which can have substantial public health implications for large numbers of healthy, asymptomatic people, it is important to achieve strong levels of evidence before promulgating new screening tools. This review of screening study methodology is intended to help the reader weigh such evidence and to evaluate reports which appear in the literature. It is an attempt to go beyond the often-stated intuition that early cancer detection finds cancers when they are easier to treat, at a time when survival is best. Examples tell us that sometimes this assumption has been true, sometimes not. A familiarity with the hidden biases in the supposition can be translated into everyday medical practice for screening tests in general. The practitioner can then match the strength of recommendation with the strength of the evidence behind the recommendation.

Phase III, large-scale chemoprevention trials. Approach to chemoprevention clinical trials and phase III clinical trial of tamoxifen as a chemopreventive for breast cancer--the US National Cancer Institute experience.

Clinical trials to evaluate interventions for cancer prevention are designed as early (phase I, IIa, and IIb) or late-phase studies. Whereas the former are small and generally rely on intermediate endpoint biomarkers of carcinogenesis, the latter are large-scale, long-term, randomized, phase III studies that address endpoints such as cancer incidence. The Breast Cancer Prevention Trial, P-1, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP), is discussed as an example of a large, extended, phase III trial designed to answer the question of whether tamoxifen reduces the incidence of breast cancer in women who are at increased risk for the disease.