Incremental costs of enrolling cancer patients in clinical trials: a population-based study.
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BACKGROUND: Payment for care provided as part of clinical research has become less predictable as a result of managed care. Because little is known at present about how entry into cancer trials affects the cost of care for cancer patients, we conducted a matched case-control comparison of the incremental medical costs attributable to participation in cancer treatment trials. METHODS: Case patients were residents of Olmsted County, MN, who entered phase II or phase III cancer treatment trials at the Mayo Clinic from 1988 through 1994. Control patients were patients who did not enter trials but who were eligible on the basis of tumor registry matching and medical record review. Sixty-one matched pairs were followed for up to 5 years after the date of trial entry for case patients or from an equivalent date for control patients. Hospital, physician, and ancillary service costs were estimated from a population-based cost database developed at the Mayo Clinic. RESULTS: Trial enrollees incurred modestly (no more than 10%) higher costs over various follow-up periods. The mean cumulative 5-year cost in 1995 inflation-adjusted U.S. dollars among trial enrollees after adjustment for censoring was $46424 compared with $44 133 for control patients. After 1 year, trial enrollee costs were $24645 compared with $23 964 for control patients. CONCLUSIONS: This study suggests that cancer chemotherapy trials may not imply budget-breaking costs. Cancer itself is a high-cost illness. Clinical protocols may add relatively little to that cost. (+info)
Development of difluoromethylornithine (DFMO) as a chemoprevention agent.
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D,L-alpha-difluoromethylornithine (DFMO) was synthesized over 20 years ago. It was hoped that this enzyme-activated, irreversible inhibitor of ornithine decarboxylase, the first enzyme in polyamine synthesis, would be effective as a chemotherapy for hyperproliferative diseases, including cancer and/or infectious processes. DFMO was generally found to exert cytostatic effects on mammalian cells and tissues, and its effectiveness as a therapeutic agent has been modest. DFMO was also found to cause treatment-limiting (but reversible) ototoxicity at high doses. This side effect, along with its minimal therapeutic activity, contributed to the loss of interest by many clinicians in further developing DFMO as a cancer therapeutic agent. However, DFMO was subsequently shown to inhibit carcinogen-induced cancer development in a number of rodent models, and interest in developing this compound as a preventive agent has increased. The rationale for the inhibition of ornithine decarboxylase as a cancer chemopreventive agent has been strengthened in recent years because this enzyme has been shown to be transactivated by the c-myc oncogene in certain cell/tissue types and to cooperate with the ras oncogene in malignant transformation of epithelial tissues. Recent clinical cancer chemoprevention trials, using dose de-escalation designs, indicate that DFMO can be given over long periods of time at low doses that suppress polyamine contents in gastrointestinal and other epithelial tissues but cause no detectable hearing loss or other side effects. Current clinical chemoprevention trials are investigating the efficacy of DFMO to suppress surrogate end point biomarkers (e.g., colon polyp recurrence) of carcinogenesis in patient populations at elevated risk for the development of specific epithelial cancers, including colon, esophageal, breast, cutaneous, and prostate malignancies. (+info)
Preclinical and early clinical development of keratinocyte growth factor, an epithelial-specific tissue growth factor.
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Keratinocyte growth factor (KGF) is a 28-kDa heparin-binding member of the fibroblast growth factor (FGF) family (alternative designation = FGF-7) that specifically binds to the KGF receptor, a splice variant of FGF receptor 2, which is expressed only in epithelial tissues. KGF has been identified as an important paracrine mediator of proliferation and differentiation in a wide variety of epithelial cells, including hepatocytes and gastrointestinal epithelial cells, type II pneumocytes, transitional urothelial cells, and keratinocytes in all stratified squamous epithelia. Systemic administration of recombinant human KGF (rHuKGF) provides significant cytoprotection to epithelial tissues in a number of different animal models of epithelial/mucosal damage, including models of injury to the gastrointestinal tract, lung, urinary bladder, and hair follicles. The results obtained with these preclinical models prompted an investigation of the use of rHuKGF as a cytoprotective agent against radiation- and/or chemotherapy-induced oral and gastrointestinal mucositis. Several dose- and time-variable studies were conducted in normal rhesus macaques to determine the lowest dose and shortest duration of rHuKGF administration required to induce oral mucosal proliferation without other significant systemic effects. Numerous studies were also conducted in murine models of chemotherapy-induced mucositis to fine-tune the dosing schedule. These studies showed that 2-3 days of rHuKGF administration were sufficient to induce significant oral mucosal proliferation and to protect against gastrointestinal mucositis when administered prior to the initiation of chemotherapy. The results from these models were used to design a phase I study in normal human volunteers to evaluate the safety of rHuKGF and its ability to induce oral mucosal proliferation. rHuKGF was well tolerated and induced a significant increase in markers of oral mucosal proliferation following 3 days of administration at the highest doses. Phase I/II studies to evaluate the safety and efficacy of rHuKGF in the prevention of chemotherapy-induced mucositis are currently in progress. (+info)
Safety and tolerability of fluconazole in children.
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The safety profile of fluconazole was assessed for 562 children (ages, 0 to 17 years) comprising 323 males and 239 females. The data are derived from 12 clinical studies of fluconazole as prophylaxis or treatment for a variety of fungal infections in predominantly immunocompromised patients. Most children received multiple doses of fluconazole in the range of 1 to 12 mg/kg of body weight; a few received single doses. Administration was mainly by oral suspension or intravenous injection. Overall, 58 (10.3%) children reported 80 treatment-related side effects. The most common side effects were associated with the gastrointestinal tract (7.7%) or skin (1.2%). Self-limiting, treatment-related side effects affecting the liver and biliary system were reported in three patients (0.5%). Overall, 18 patients (3.2%) discontinued treatment due to side effects, mainly gastrointestinal symptoms. Dose and age did not appear to influence the incidence and pattern of side effects. Treatment-related laboratory abnormalities were uncommon, the most frequent being transient elevated alanine aminotransferase (4.9%), aspartate aminotransferase (2.7%), and alkaline phosphatase (2.3%) levels. Although 98.6% of patients were taking concomitant medications, no clinical or laboratory interactions were observed. The safety profile of fluconazole was compared with those of other antifungal agents, mostly oral polyenes, by using a subset of data from five controlled studies. Side effects were reported by more patients treated with fluconazole (45 of 382; 11.8%) than by those patients treated with comparable agents (25 of 381; 6.6%); vomiting and diarrhea were the most common events in both groups. The incidence and type of treatment-related laboratory abnormalities were similar for the two groups. In conclusion, fluconazole was well tolerated by the pediatric population, many of whom were suffering from severe underlying disease and were taking a variety of concurrent medications. The safety profile of fluconazole in children mirrors the excellent safety profile seen in adults. (+info)
The induction of spermidine/spermine N1-acetyltransferase (SSAT) is a common event in the response of human primary non-small cell lung carcinomas to exposure to the new antitumor polyamine analogue N1,N11-bis(ethyl)norspermine.
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Several new polyamine analogues have been developed for the treatment of human solid tumors. The phenotype-specific activity of some of these analogues has been associated with the superinduction of the rate-limiting enzyme in polyamine catabolism spermidine/spermine N1-acetyltransferase (SSAT). Using immunohistochemistry, we found a majority (64%) of human primary lung cancer explants to exhibit high expression of SSAT after treatment with 10 microM N1,N11-bis(ethyl)norspermine, an agent currently undergoing Phase II clinical trials against several important human solid tumors. The staining of SSAT was found specifically in the tumor tissue and not in the neighboring normal lung tissue. These results demonstrate the ability to detect induction of SSAT in clinical specimens and suggest the potential of this test as a prognostic indicator of drug response. (+info)
Progressive disease rate as a surrogate endpoint of phase II trials for non-small-cell lung cancer.
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BACKGROUND: Although the potential activity of anticancer agents has been traditionally assessed by the response rate (RR) in phase II trials, there is an increasing need to identify alternative endpoints to evaluate the efficacy of novel types of antineoplastic agents such as cytostatic agents. However, none of the proposed alternatives have been validated. DESIGN: RR, rate of progressive disease (PD), and median survival time (MST) were obtained from 44 treatment arms in 42 single-agent phase II trials for non-small-cell lung cancer (NSCLC). Correlations between these parameters and their significance in selection of promising drugs were evaluated. RESULTS: The median (range) RR and PD rate per treatment arm were 17% (0%-40%) and 41% (8%-93%), respectively. The PD rate correlated more closely with MST (correlation coefficient (r) = 0.80, P < 0.001) than did the RR (r = 0.62, P < 0.001). The RR of active agents against NSCLC ranged broadly from 7% to 40%, whereas their PD rates were all 50% or less. In addition, all treatment arms with a PD rate over 50% had a poor MST of six months or shorter. CONCLUSIONS: The PD rate was potentially as good an endpoint as RR, and it may be a good candidate for the primary endpoint of phase II trials for novel types of anticancer agents. (+info)
Valuing clinical strategies early in development: a cost analysis of allogeneic peripheral blood stem cell transplantation.
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Allogeneic peripheral blood stem cell transplantation (alloPBSCT) is an emerging technology. As this technology develops, transplant centers are concerned with looking for technologic advances that will result in improvements in clinical outcomes and lower costs. We provide comparative estimates of costs and resource use for alloPBSCT in comparison to allogeneic bone marrow transplantation (alloBMT) for persons with hematologic malignancies from the time of harvest to 100 days post transplant. A retrospective, cost-identification analysis was conducted for patients in two consecutive phase II clinical trials at the University of Nebraska Medical Center. Identical preparative regimens, graft-versus-host disease prophylaxis, post-transplant hematopoietic colony-stimulating factor treatment regimens, and discharge criteria were used. Total median costs were $18,304 lower for alloPBSCT, with lower costs during recovery; specifically for hospitalization, platelet products, hematopoietic growth factors, intravenous hyperalimentation, supportive care agents, supplies, and antibacterial agents. This study provides preliminary evidence for short-term cost savings associated with alloPBSCT. However, concerns exist over the potential for higher costs due to preliminary reports of higher rates of chronic graft-versus-host disease, as well as more intensive induction regimens that may result in lower relapse rates. The premature adoption of new technologies based on short-term economic factors, in the absence of adequate clinical trial data, may prove to be ill-advised, particularly for complex medical treatments such as allogeneic transplantation. (+info)
Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group.
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PURPOSE: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. RESULT: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. CONCLUSION: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point. (+info)