Guidelines for publishing papers on cancer clinical trials: responsibilities of editors and authors.

Guidelines are proposed for the reporting of clinical trials. These are meant to be used for both authors and journal editors. Specific proposals are made for: reporting the population under study, actual therapy used, describing the study design, accounting of patients, follow-up statistics, and describing the quality control of the data. Nonrandomized studies require special discussion. Such studies potentially have substantial biases which can lead to incorrect conclusions. Six areas of biases arising in nonrandomized studies are pointed out which should require a discussion in an acceptable published paper. The presentation of statistical results and the reporting of early studies present unusually difficult problems. Guidelines are presented for statistical analyses which, although simple to implement in practice, are not generally used. A proposal is made for the publication of early results of a study which require that the authors agree to follow and periodically report on their trial to the journal editor. If the early conclusions change with additional follow-up, the editor should notify its readers. The adoption of these guidelines can be an important force in raising the scientific level of the reporting of clinical trials.

Screening sensitivity and sojourn time from breast cancer early detection clinical trials: mammograms and physical examinations.

PURPOSE: To estimate sensitivities of breast cancer screening modalities and preclinical duration of the disease from eight breast cancer screening clinical trials. PATIENTS AND METHODS: Screening programs invariably lead to diagnosis of disease before signs or symptoms are present. Two key quantities of screening programs are the sensitivity of the disease detection modality and the mean sojourn time (MST). The observed screening histories in a periodically screened cohort make it possible to estimate these quantities of interest. We applied recently developed statistical methods to data from eight randomized breast cancer screening trials to estimate the sensitivities of early detection modalities and MST. Moreover, when a screening trial involved two screening modalities, our methods enabled the estimation of the individual sensitivity of each screening modality. RESULTS: We analyzed breast cancer data from several screening trials and have relatively complete data from the Health Insurance Plan (HIP), Edinburgh, and two Canadian studies. The screening sensitivity for mammography, physical examination, and MST were, respectively, HIP: 0.39, 0.47, and 2.5 years; Edinburgh: 0.63, 0.40, and 4.3 years; Canadian (age 40 to 49 at entry): 0.61, 0.59, and 1.9 years; Canadian (age 50 to 59 at entry): 0.66, 0.39, and 3.1 years. CONCLUSION: The public debate on early breast cancer detection is mainly centered on mammograms. However, the current study indicates that a physical examination is of comparable importance. Cautious interpretation of trial differences is required as a result of various experimental designs and the age dependency of screening sensitivity and MST.

Exploratory data analysis and the use of the hazard function for interpreting survival data: an investigator's primer.

This report discusses how one can use the hazard function to gain important insights on the patterns of failure in clinical studies when the principal endpoint is a time metric. These new insights may help gain increased understanding into the pathogenesis of a chronic disease and how it is affected by treatment intervention. The qualitative behavior of the hazard function can reveal whether mortality is increasing, decreasing, or is constant over time. Simple graphic plots are all that is necessary to show characteristic failure patterns. These informal procedures are in the spirit of carrying out exploratory analyses on the data. This report discusses the organization of clinical data using a "branch and leaf" plot, outlines the calculation of the hazard function and life table, and uses examples from lung cancer and uveal melanoma to illustrate calculations and ways of interpreting hazard functions.

Referent sampling, family history and relative risk: the role of length-biased sampling.

Familial risk of disease is often assessed using case control studies based on referent databases. A referent database is a collection of family histories of cases typically assembled as a result of one family member being diagnosed with disease. This sampling scheme is equivalent to sampling families proportional to their size. The larger the family, the greater the probability of finding the family in the referent registry. This phenomena is known as length-biased sampling. The consequence of this kind of sampling is to bias the regression estimate associated with family history. The estimate is typically inflated in comparison to what is true for the actual population.

An investigation of a reported cancer cluster in Randolph, Massachusetts.

An increasingly common public health problem is the perception that disease incidence has increased or a cluster of disease has occurred in a community. In most cases, the disease of concern is cancer and a local hazardous waste site or other environmental problem is involved. These problems can be difficult to investigate and public health officials are frequently criticized for their inability to address community concerns. This paper reports a case study of such a situation occurring in the Barlett-Green Acres (BGA) neighborhood of Randolph, Massachusetts. Study data were obtained by interviews in households of persons belonging to a list of alleged cancer cases initially supplied by residents and supplemented using records available in town and state public health offices. One objective of the investigation was to develop methods that may be of value in similar situations arising in other communities. From a list of names compiled prior to and during the investigation, 45 incident cases of cancer were identified and found suitable for analysis. An additional four cases were added from the Massachusetts Cancer Registry. The analysis showed the existence of a cancer cluster, but overall cancer incidence and mortality in the BGA neighborhood were not elevated. Residence history, disease site, and other features of the cancer cases were investigated using methods less sensitive to incomplete reporting than total incidence. No unusual features of the cancer data other than the initiating cluster were identified and no environmental hazard likely to impact the BGA neighborhood was discovered, hence we conclude that the most likely cause of the cancer cluster was random variation in cancer rates.

Immunocompetence, immunodeficiency and prognosis in cancer.

Immunocompetence and prognosis are related in solid tumors, malignant lymphomas, and acute leukemia. Among the parameters of immunocompetence vigorous delayed-type hypersensitivity responses to recall antigens or to primary immunization with Keyhole limpet hemocyanin, vigorous in vitro lymphocyte blastogenic responses to mitogens such as PHA, and relatively high B-lymphocyte levels, all correlate with a good prognosis. The spectrum of immune reactivity as measured by established delayed-type hypersensitivity to recall antigens and in vitro blastogenic responses to mitogens and antigens is similar in melanoma patients and their nontumor-bearing spouses. In melanoma, only patients with widespread inoperable metastatic disease show severe immunological deficiency and this is selective for certain antigens. There are highly significant differences in response to specific antigens when patients with melanoma and lung cancer are compared. Immunotherapy with BCG and C. parvum can boost immunocompetence as measured by recall DTH skin testing. However, the relationship between the initial immunocompetence and prognosis still holds in patients receiving BCG immunotherapy to prevent recurrence of melanoma. These data indicate that a broader survey of immunological reactivity in cancer patients is needed, that immunological testing is useful in cancer prognosis clinically, and that the results of immunological testing can be used to evaluate therapy and to indicate new pathways for improved treatment.

Alternatives to classic randomized trials.

Randomized clinical trials are regarded as the most credible way of generating scientific data that compare the benefits of different therapies. However, randomized trials present difficulties in their execution. Often physicians are unwilling to participate in such studies because they do not wish to inform the patient that the treatment program will be chosen by a chance mechanism. They believe that such a discussion may compromise the physician-patient relationship. Alternatives to classic randomized trials have been discussed. Also considered are some aspects of the strategy of clinical experimentation. It has been pointed out that the initiation of definitive Phase III trials made on the basis of little prior expectation of success ("trying something out") tends to generate false-positive results.

Managing milk leakage in breastfeeding women: a clinical trial evaluating a polyvinyl chloride device versus disposable nursing pads.

The object of this clinical trial was to evaluate the effectiveness and to investigate possible problems associated with the use of a polyvinyl chloride (PVC) device ("blis") compared to a disposable nursing pad, for controlling milk leakage among nursing mothers. Seventy-one women completed the single blind, paired comparison, randomized trial. Among the 28 women having a strong early preference, 21 opted for the PVC device (p = 0.01). Of the 37 women experiencing excessive milk leakage who preferred one of the devices, 24 preferred the PVC device (p = 0.05). There was no evidence that one device caused more problems or feeding complications than the other. This study is important in alleviating anxiety about device safety while promoting breastfeeding in mothers fearful of leaking at inopportune times.

Products liability issues in school asbestos litigation.

The hazards posed by deteriorating friable asbestos in the nation's schools are causing serious concerns for public health officials, school boards, parents and school employees. Reports by both the Environmental Protection Agency and the U.S. Attorney General's Office agree that both school children and school employees stand a substantially increased risk of contracting some form of asbestos-related disease as a result of exposure to deteriorating asbestos materials in school buildings. School systems plagued by the asbestos hazards are now filing suits against asbestos manufacturers alleging causes of action in breach of warranty, negligence and strict products liability in tort. Some plaintiffs in school asbestos litigation seek to recover the costs of EPA-mandated asbestos inspection and abatement programs which have already been completed. Still others request injunctions to compel the manufacturers themselves to conduct inspections and finance abatement. This Note examines the school asbestos situation from a legal perspective and focuses primarily on whether the schools' claims should be considered as economic losses or as property damage. It examines the impact of statutes of limitations on these cases under both contract and tort theories. The Note argues that school asbestos claims should be decided under a strict products liability standard.

Innovations in the design of clinical trials in breast cancer.

The execution of clinical trials is perhaps the most difficult way of carrying out a scientific experiment. This is especially true of chronic diseases, such as breast cancer, which require long-term follow-up and large numbers of patients. As a result, it is necessary to involve many physicians who can contribute patients to these studies. Unfortunately, many physicians are not comfortable participating in randomized studies because they feel the patient-physician relationship may be compromised. This paper discusses new ways of planning randomized clinical trials which do not interfere with the patient-physician relationship. The new designs are called 'randomized consent' or 'prerandomized' designs. The study designs are discussed from the point of view of statistical efficiency and the new ethical problems which may arise.

Biostatistical science as a discipline: a look into the future.

The field of biostatistics is enjoying unparalleled developments. Never before have members of our profession been in such demand. Current applications are significantly influencing the direction of research in statistical methodology. It is not clear whether there is a discipline which can be termed 'biostatistics', but we are part of the emergence of a discipline which is termed 'biostatistical science'. It refers to the applications of statistics, probability, computing and mathematics to the life sciences, with the goal of advancing our knowledge of a subject-matter field in this area. This paper discusses the role of computing, some aspects of training, and future directions of biostatistical science. A special role is envisioned for the Biometric Society to be more active in problems associated with developing countries.