Context Of Clinical Trials Research Articles

A retrospective study of the use of cisplatinum-5-fluorouracil neoadjuvant chemotherapy in cervical-node-positive nasopharyngeal carcinoma (NPC).

A retrospective study on 422 nasopharyngeal carcinoma (NPC) patients with cervical nodal metastases treated between 1984 and 1987 was performed. 169 received neoadjuvant chemotherapy (CHEMO) with cisplatinum and 5-fluorouracil for two or three courses prior to definitive radiotherapy and 253 were treated by radical radiotherapy alone (NCHEMO). While the primary tumour (T-stage) prognosticators had been comparable between the two groups, CHEMO had significantly more advanced cervical nodal metastases with bulkier nodes and more low-cervical and supraclavicular nodes (P < 0.05) which could account for its overall worse survival, poorer regional tumour control and a trend towards worse systemic tumour control. The worse regional control in CHEMO for Ho's N1 could be the result of more bulky nodes and more tumours infiltrating the skull base and/or causing cranial nerve(s) palsy. There was no statistical or apparent difference between CHEMO and NCHEMO for the same Ho's overall stages of NPC with comparable nodal and primary tumour characteristics for the clinical endpoints of actuarial survival rate (ASR), disease-free survival rate (DFS), free of local failure survival rate (FLF), and free from distant metastases survival rate (FDM), despite the presence of significantly more fixed nodes and bulky nodes. This suggests a possible beneficial effect of the neoadjuvant chemotherapy. However, multivariate analysis has not shown the administration of the neoadjuvant chemotherapy to be of prognostic significance. Even though the chemotherapy was well tolerated with little toxicity, we recommend against the routine use of neoadjuvant chemotherapy in cervical-node-positive NPC outside the context of a prospective randomised clinical trial.

Symptom distress in newly diagnosed ambulatory cancer patients and as a predictor of survival in lung cancer

Levels of symptom distress are most often measured in a clinical trial context rather than in general ambulatory populations. The purpose of this paper is to report levels of symptom distress in such a population, and to describe the factors associated with this distress. Over a 6-month period, a consecutive sample of 434 newly diagnosed patients, including 82 patients with lung cancer, were tested with the symptom distress scale at two tertiary oncology clinics serving the population of one Canadian prairie province. While levels of symptom distress in this population were generally low, the most problematic symptoms for patients were fatigue and insomnia, with 40% and 30% having moderate or high scores on these symptoms, respectively. Patients with advanced disease reported more distress than those with early stage disease; women reported more distress than men; older patients had less distress than younger patients; distress was highest in lung cancer patients and lowest in men with genitourinary cancers. Consistent with the findings of four previous studies, the single measure of symptom distress was a significant predictor of survival in lung cancer patients, with the exception of three patients who had substantial post-thoracotomy symptoms.

Quality-of-life assessment in clinical trials.

Within the context of clinical trials, quality of life (QOL) is a multidimensional concept that encompasses health-related constructs, but excludes other dimensions such as economics, housing, or education. Most QOL research has been based on the World Health Organization (WHO) definition of health [1]: ‘Health is not only the absence of infirmity and disease but also a state of physical, mental and social well-being.’ Thus QOL encompasses all health-related outcomes beyond those of survival and physiological responses. Diseases and their treatments affect not only patients’ physical functioning and level of pain, but also their cognitive, emotional, and social functioning. QOL measures have also included assessments of sexual functioning, family and marital relationships, role performance, vitality, sleep, health perceptions, general life satisfaction, and symptoms such as nausea and fatigue. QOL assessment has been employed in developing individual patient treatment plans, performing cost-benefit analyses, making health policy decisions, and conducting clinical trial evaluations. Health status, functional status, and health-related quality of life have become synonyms for QOL in the clinical trials literature.

Esophageal Cancer: Neoadjuvant therapy for squamous cell esophageal carcinoma

A number of studies have demonstrated that preoperative chemotherapy (CTx) and combination radiochemotherapy (RTx/CTx) in patients with potentially resectable and locally advanced squamous cell esophageal carcinoma is feasible. In patients with potentially resectable tumors, neoadjuvant therapy followed by surgical resection has, however, so far not shown an increase in the resection rate, rate of complete macroscopic and microscopic tumor resections, i.e. R0-resections according to the UICC, or survival time as compared to patients who had surgical resection alone. In this situation a survival benefit, if at all, can be expected only in those who respond to preoperative therapy. At the present time preoperative CTx or RTx/CTx in patients with potentially resectable esophageal carcinoma must therefore be considered investigational and should not be performed outside the context of clinical trials. In patients with locally advanced esophageal carcinoma, neoadjuvant therapy markedly increases the rate of R0-resections and appears to prolong survival. Combined modality therapy in this context is, however, associated with a substantial perioperative mortality and morbidity. Open questions that have to be addressed by randomized studies include the role, extent and timing of surgical resection in the combined modality approach to patients with locally advanced squamous cell esophageal carcinoma. Research has to focus on preoperative staging modalities and the development of more effective and less toxic preoperative therapy regimen to improve identification of patients that might benefit from combined modality therapy and to more effectively combat systemic recurrences.

Methotrexate in rheumatoid arthritis. An update.

Methotrexate has been approved for the treatment of refractory rheumatoid arthritis by several regulatory agencies, including the Food and Drug Administration. The tendency is now to prescribe it at earlier stages of the disease. Methotrexate is a well known antifolate. Its exact mechanism of action in rheumatoid arthritis remains uncertain. The polyglutamated derivatives of methotrexate are potent inhibitors of various enzymes, including dihydrofolate reductase and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase. Inhibitory effects on cytokines, particularly interleukin-1, and on arachidonic acid metabolism, as well as effects on proteolytic enzymes, have been reported. Some of them may be linked to the antifolate properties of methotrexate. Overall, the drug appears to act in rheumatoid arthritis as an anti-inflammatory agent with subtle immunomodulating properties. Direct inhibitory effects on rapidly proliferating cells in the synovium have also been suggested. Methotrexate is usually given orally. Marked interindividual variation in its bioavailability has been found. Food intake has no significant effect on the pharmacokinetics of oral methotrexate. Methotrexate undergoes significant metabolism. The functionally important metabolites are the polyglutamated derivatives of methotrexate, which are selectively retained in the cells. Less than 10% of a dose of methotrexate is oxidised to 7-hydroxy-methotrexate, irrespective of the route of administration. This metabolite is extensively (91 to 93%) bound to plasma proteins, in contrast to the parent drug (35 to 50% bound). Methotrexate is mainly excreted by the kidneys. It undergoes tubular secretion and may thereby compete with various organic acid compounds. Early placebo-controlled trials demonstrated that weekly low dosage methotrexate produced early symptomatic improvement in most rheumatoid arthritis patients. Two meta-analyses showed that methotrexate is among the most efficacious of slow-acting antirheumatic agents, together with parenteral gold (sodium aurothiomalate), penicillamine and sulfasalazine. Furthermore, in the short term context of clinical trials, methotrexate has one of the best efficacy/toxicity ratios. There is little evidence that methotrexate, or any available slow-acting antirheumatic agent, is a true disease-modifying drug. However, the probability that a patient will continue methotrexate therapy over time appears quite favourable compared with any other slow-acting antirheumatic drug. Combination therapy with slow-acting drugs has been advised for the management of rheumatoid arthritis, but the evidence currently available does not support general use of combination therapy including methotrexate. Almost all investigations indicated that toxic effects, rather than lack of response, were the major reason for discontinuing methotrexate therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Symptom Distress Checklists as a Component of Quality of Life Measurement: Comparing Prompted Reports by Patient and Physician with Concurrent Adverse Event Reports via the Physician

The official definition of “safety” in a clinical trials context relies upon the physician to detect signs of illness or injury, and upon the patient to volunteer adverse event data to the physician. For regulatory purposes, this convention works. But patient and physician filter and perhaps distort information.In two parallel randomized, double-blind, multicenter clinical comparisons of quality of life under treatment with antihypertensive agents, the following were collected concurrently: 1. the usual adverse event information through physician interviews and laboratory reports, 2. the responses of 1,018 patients to a Symptom Distress Checklist (SDC) administered at five office visits, and 3. concurrent physician responses to a parallel form of the SDC. The SDC required the respondent to state for each of 51 symptoms (A) whether the patient had experienced it during the past month; (B) if so, how often; and (C) with how much associated distress.Of the symptoms to which the typical patient confessed in h...

Evaluating Health-Related Quality of Life Measures for Cross-National Research

The interest in including health-related quality of life (HRQOL) as an outcome measure in therapeutic clinical trials has spread to countries throughout the world. Because clinical research within the pharmaceutical industry is increasingly international in scope, the demand for reliable, valid, and sensitive HRQOL measures that can be used in the same trial cross nationally has become acute. Criteria by which HRQOL measures are evaluated for inclusion in international clinical trials have yet to be precisely defined. Moreover, experts in the quality of life field do not always agree on whether an HRQOL measure is applicable for crossnational research. Thus, clear guidelines for identifying existing measures for use in international trials do not exist. This paper identifies guidelines by which existing HRQOL measures can be evaluated for cross-national clinical research. The paper includes a review of the HRQOL concept, a description of basic principles of psychometric measurement, and an examination of the clinical trial context in which these instruments are frequently employed.

Practical Application of ISO 9000 and EC Good Clinical Practice in Validating Clinical Data Management Systems

The development of customized application programs by the end users of data management systems requires special consideration when computer validation is being discussed. These customized programs are produced to capture, tabulate, and analyze data within the context of a specific clinical trial. They may be numerous and in a busy department may be produced on a frequent basis. This paper considers the application of computer validation principles—EC GCP requirements and the principles of the ISO 9000 quality assurance standards—to the validation of these programs. The validation procedure needs to be stringent but straightforward and its documentation practical in order to ensure compliance. It should ensure audit friendly documented evidence that proper validation has taken place. Validation of these end user developed applications is of particular importance in assuring accurate data transformation. It can be effective and is proactive in providing for high quality clinical trial report production.

Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials.

Preferred drugs for rheumatoid arthritis (RA) should be those that have maximal efficacy with the least toxicity. We evaluated the efficacy and toxicity tradeoffs for drugs frequently used in the treatment of RA. We updated 2 metaanalyses of published clinical trials, by adding trials published through 1990 and trials of azathioprine (AZA). We tested 3 different definitions of efficacy, each plotted against 3 different toxicity measures, for antimalarial drugs, methotrexate (MTX), auranofin, injectable gold, D-penicillamine, sulfasalazine (SSZ), AZA, and placebo. Efficacy measures included composite efficacy (a combination of joint count, grip strength, and erythrocyte sedimentation rate), tender joint count alone, and a measure based on how many patients dropped out due to inefficacy. Toxicity measures were the proportion dropping out due to toxicity, the same dropouts with side effects weighted for severity using a modification of a published toxicity index, and the proportion with severe toxicities (defined as a score of at least 7 of 10 on the toxicity index). The latter were usually organ toxicities (e.g., cytopenias and renal involvement). All 9 efficacy/toxicity tradeoff plots suggested that MTX and antimalarial drugs had the highest efficacy relative to toxicity. MTX scored among the most efficacious of the drugs and, of these, had the least toxicity. Antimalarial drugs, though showing only moderate efficacy, had the lowest toxicity rate of all the drugs. SSZ scored close to MTX but was, in general, slightly more toxic. In the short-term context of clinical trials, antimalarial drugs and MTX have the best efficacy/toxicity tradeoffs and may, therefore, be the preferred drugs.

Future horizons for calcitonin: A U.S. perspective

Injectable salmon calcitonin has been in use in the United States for more than a decade for the treatment of patients with postmenopausal osteoporosis, Paget's disease, and hypercalcemia. Sandoz Pharmaceuticals Corp. is currently in the process of developing a nasal formulation of salmon calcitonin. Studies are in progress to compare the efficacy of this nasal formulation with that of the injectable hormone in preventing bone loss and restoring bone, as well as in reducing pain associated with bone diseases. The rationale for development of a nasal formulation is to attempt to reduce the incidence of systemic side effects, inconvenience, and resulting noncompliance associated with the injectable product. In studies to date, the nasal form of calcitonin has been well tolerated by most subjects and was not notably associated with nasal irritation. The tolerability seen within the context of clinical trials suggests that a nasal formulation might be well accepted, even among asymptomatic osteoporotic patients. Asymptomatic patients with secondary osteoporosis due to steroid administration or solid organ transplantation may also be studied as possible candidates for the prophylactic use of this drug. Additional future research includes the development of an oral calcitonin agent.

Concepts in limb-sparing treatment of adult soft tissue sarcomas.

Pretreatment assessment of patients with soft tissue sarcomas of the extremities requires careful attention to a biopsy approach that will establish the precise diagnosis and will not compromise the subsequent definitive operative procedure. Also, staging procedures are required to evaluate the status of both local and distant sites. Limb-sparing surgery for high grade extremity soft tissue sarcomas is a feasible and appropriate approach in approximately 90% of patients with such lesions. Wide gross surgical margins around the sarcoma are the optimal operative approach. Circumstantial evidence is convincing that local treatment failure can be reduced by adjuvant regional radiation treatment when surgical margins are narrow, and end results appear to be equal to those obtained by more extensive surgical resection alone. Adjuvant radiation following operation with optimal gross surgical margins has not been established as adding benefit. Although some groups treating soft tissue sarcomas do use intraarterial chemotherapy in conjunction with these other modalities, there is, as yet, no convincing evidence that this aspect of the multimodality treatment adds to local and/or systemic disease control. The efficacy of adjuvant systemic chemotherapy for high grade soft tissue sarcomas remains to be established within the context of prospective clinical trials.

Comparison of sampling methods for choosing the best binomial population with delayed observations

We consider the problem of choosing the best of k binomial populations when the time to response is non zero. Several sampling schemes are discussed, with an aim to making as few trials as possible with the poorer treatments, as would be a desideraturm in the context of clinical trials. The stopping rule is based on a likelihood ratio. For k = 2 populations, it is shown that for a fixed difference in success probabilities, alternate sampling (ABABA…) leads to a smaller number of trials with the poorer treatment when the mean success probability is roughly less than 0.7. When the mean success probability is greater than 0.7, a generalization of the play-the-winner rule (Robbins, 1956, Zelen, 1969) is more efficient. For k> 2 populations, it is shown to be useful to have some method of eliminating poor treatments before the full trial is completed. It is further shown that the use of an adaptive patient assignment technique can, in some circumstances, lead to a significant reduction in the number of patient...