Evaluating the financial impact of clinical trials in oncology: results from a pilot study from the Association of American Cancer Institutes/Northwestern University clinical trials costs and charges project.

PURPOSE: Medical care for clinical trials is often not reimbursed by insurers, primarily because of concern that medical care as part of clinical trials is expensive and not part of standard medical practice. In June 2000, President Clinton ordered Medicare to reimburse for medical care expenses incurred as part of cancer clinical trials, although many private insurers are concerned about the expense of this effort. To inform this policy debate, the costs and charges of care for patients on clinical trials are being evaluated. In this Association of American Cancer Institutes (AACI) Clinical Trials Costs and Charges pilot study, we describe the results and operational considerations of one of the first completed multisite economic analyses of clinical trials. METHODS: Our pilot effort included assessment of total direct medical charges for 6 months of care for 35 case patients who received care on phase II clinical trials and for 35 matched controls (based on age, sex, disease, stage, and treatment period) at five AACI member cancer centers. Charge data were obtained for hospital and ancillary services from automated claims files at individual study institutions. The analyses were based on the perspective of a third-party payer. RESULTS: The mean age of the phase II clinical trial patients was 58.3 years versus 57.3 years for control patients. The study population included persons with cancer of the breast (n = 24), lung (n = 18), colon (n = 16), prostate (n = 4), and lymphoma (n = 8). The ratio of male-to-female patients was 3:4, with greater than 75% of patients having stage III to IV disease. Total mean charges for treatment from the time of study enrollment through 6 months were similar: $57,542 for clinical trial patients and $63,721 for control patients (1998 US$; P =.4) CONCLUSION: Multisite economic analyses of oncology clinical trials are in progress. Strategies that are not likely to overburden data managers and clinicians are possible to devise. However, these studies require careful planning and coordination among cancer center directors, finance department personnel, economists, and health services researchers.

T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities.

T-cell depletion of donor marrow decreases graft-versus-host disease resulting from transplants from unrelated and human leukocyte antigen (HLA)-mismatched related donors. However, there are diverse strategies for T-cell-depleted transplantation, and it is uncertain whether any improve leukemia-free survival (LFS). To compare strategies for T-cell-depleted alternative donor transplants and to compare T-cell depleted with non-T-cell-depleted transplants, we studied 870 patients with leukemia who received T-cell-depleted transplants from unrelated or HLA-mismatched related donors from 1982 to 1994. Outcomes were compared with those of 998 non-T-cell-depleted transplants. We compared LFS using different strategies for T-cell-depleted transplantation considering T-cell depletion technique, intensity of pretransplant conditioning, and posttransplant immune suppression using proportional hazards regression to adjust for other prognostic variables. Five categories of T-cell depletion techniques were considered: narrow-specificity antibodies, broad-specificity antibodies, Campath antibodies, elutriation, and lectins. Strategies resulting in similar LFS were pooled to compare T-cell-depleted with non-T-cell-depleted transplants. Recipients of transplants T-cell depleted by narrow-specificity antibodies had lower treatment failure risk (higher LFS) than recipients of transplants T-cell depleted by other techniques. Compared with non-T-cell-depleted transplants (5-year probability +/- 95% confidence interval [CI] of LFS, 31% +/- 4%), 5-year LFS was 29% +/- 5% (P = NS) after transplants T-cell depleted by narrow-specificity antibodies and 16% +/- 4% (P <.0001) after transplants T-cell depleted by other techniques. After alternative donor transplantation, T-cell depletion of donor marrow by narrow-specificity antibodies resulted in LFS rates that were higher than those for transplants T-cell depleted using other techniques but similar to those for non-T-cell-depleted transplants. (Blood. 2000;95:3996-4003)

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris.

Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage phiX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.

Assessment of dose proportionality, absolute bioavailability, and immunogenicity response of CTLA4Ig (BMS-188667), a novel immunosuppressive agent, following subcutaneous and intravenous administration to rats.

PURPOSE: The objectives of this study were: to delineate the pharmacokinetics of CTLA4Ig in rats after single and multiple intravenous (IV) and subcutaneous (SC) doses; to assess the relationship of the pharmacokinetic parameters of CTLA4Ig vs dose; to calculate the SC absolute bioavailability; and to assess the antibody response of CTLA4Ig. METHODS: A total of 48 (24 male and 24 female) Sprague Dawley rats were divided into eight treatments with 3 rats per gender in each group: a single dose of 10, 80, or 200 mg/kg of CTLA4Ig given either IV or SC and a repeated dose of 10 mg/kg (once every other day for 7 doses over 13 days) given either SC or IV. Serial blood samples were collected up to 43 days after single dose administration and up to 50 days following the administration of the last multiple dose on day 13. The serum concentration of CTLA4Ig and anti-CTLA4Ig antibodies were measured using ELISA assays. RESULTS: After single IV doses, Cmax and AUCinf increased in a dose proportional manner; CL appeared to be dose independent, while both Vss and T1/2 increased as the administered dose increased. Following single SC doses, Cmax and AUCinf increased in a linear manner but not proportionally; mean Tmax values were prolonged but similar among the three dose levels, while T1/2 increased as the administered dose increased. The absolute SC bioavailability of CTLA4Ig decreased as the dose increased from 10 (62.5%), 80 (55.7%), and 200 mg/kg (41.1%). Comparison of the AUCtau values between the first and last doses suggested an accumulation (3.1-4.7) of CTLA4Ig. However, regardless of the route of dosing, AUCtau after the last dose were comparable to AUCinf values following the single dose. Anti-CTLA4Ig antibodies were detected at the 10 mg/kg dose level after single or multiple doses for both routes of administration. However, regardless of single or multiple doses, antibody titers were relatively greater for the SC compared to the IV administration. CONCLUSIONS: The key findings of this study were: (i) the elimination characteristics of CTLA4Ig were comparable between the SC and IV routes; (ii) the repeated dosing did not alter the pharmacokinetics of CTLA4Ig; (iii) the SC absolute bioavailability tended to decrease as the administered dose increased; and (iv) a greater formation of anti-CTLA4Ig antibodies was observed after SC compared to IV at a single 10 mg/kg dose level; however, after multiple dosing, the formation of antibodies from either of the two routes was relatively slower, and (v) during the study period, no antibodies were observed at either the 80 or 200 mg/kg dose levels regardless of the route of administration.

A sensitive enzyme immunoassay for the quantitation of human CTLA4Ig fusion protein in mouse serum: pharmacokinetic application to optimizing cell line selection.

A sensitive, accurate, and precise enzyme immunoassay (EIA) for the quantitation of human CTLA4Ig in mouse serum was validated. The EIA method employed a technique in which a monoclonal anti-CTLA4 antibody was adsorbed onto 96-well polystyrene microtiter plates and used to capture the CTLA4Ig in mouse serum samples. The captured CTLA4Ig was then detected using a goat anti-human IgGFc antiserum conjugated to the enzyme horseradish peroxidase. The validation included assessments of method accuracy and precision, range of reliable response, lower limit of quantitation (LLQ), inter-analyst robustness, storage stability in mouse serum and assay specificity. The results indicate that this validated assay is precise, accurate, and reproducible. This EIA has a range of reliable response in 10% mouse serum of 0.14-4.58 ng ml-1 resulting in a 100% serum equivalent curve of 1.4-45.8 ng ml-1. Assessment of individual standard curve variations indicated a reproducible response with R2 values of > or = 0.995. The LLQ was established at 1.4 ng ml-1. The accuracy and precision estimates, based on the quality control values, were within 3.8% and 5.2% respectively, for CTLA4Ig. Stability of CTLA4Ig was established in mouse serum for 5 days at both 4 degrees C and room temperature, for 2 months at -70 degrees C and through five freeze-thaw cycles. This validated assay was successfully employed in the assessment of pharmacokinetic characteristics of CTLA4Ig in mice and to aid in the selection of an optimal CTLA4Ig-producing cell line.

Teaching the use of bases and liners: a survey of North American dental schools.

The authors surveyed 64 dental schools in North America about their instruction on the use of bases and liners. Respondents cited the materials being taught at the time of the survey, two years before the survey and four years before the survey. There was no consensus as to the materials being used. Copal varnishes and dentin bonding agents, or DBAs, were used most often in Class II preparations more than 2 millimeters from the pulp, and glass ionomers and DBAs were equally popular for Class II preparations within 1 mm of the pulp. Most schools were pleased with the materials they are currently teaching but continue to review material selection annually.

HLA-identical sibling bone marrow transplants vs chemotherapy for acute myelogenous leukemia in first remission.

There is controversy whether adults with acute myelogenous leukemia (AML) in first remission are best treated with chemotherapy or an HLA-identical sibling bone marrow transplant. We studied 1097 adults, 16-50 years old, with AML in first remission. Results of transplants from HLA-identical siblings reported to the International Bone Marrow Transplant Registry (IBMTR; n = 901) were compared with results of chemotherapy in comparable persons treated by the German AML Cooperative Group (GAMLCG; n = 196). Preliminary analyses identified subject- and disease-related variables differing between the cohorts and associated with treatment outcome within each cohort. We adjusted for these variables and differences in time-to-treatment in subsequent comparisons of treatment-related mortality, relapse, survival and leukemia-free survival (LFS). Five-year probability of treatment-related mortality was greater for transplants than chemotherapy (43% (95% confidence interval, 37-49%) vs 7% (3-11%); P< 0.0001). Five-year relapse probability was less for transplants than chemotherapy (24% (20-28%) vs 63% (55-71%); P< 0.0001). Five-year probability of survival was similar with transplants and chemotherapy (48% (43-53%) vs 42% (33-51%); P = 0.24). Five-year LFS probability was higher for transplants than chemotherapy (46% (42-50%) vs 35% (28-41%); P= 0.01). These data indicate that bone marrow transplants from HLA-identical siblings result in comparable survival but greater LFS than chemotherapy in adults with AML in first remission.

A pharmacokinetic study of intravenous CTLA4Ig, a novel immunosuppressive agent, in mice.

Three skin-intact mice in each group received a single 0.07-, 0.29-, or 0.57-mg dose of CTLA4Ig intravenously (i.v.). Three skin-grafted mice received a single 0.29-mg dose i.v. and another three skin-grafted mice received a 0.29-mg dose once daily for 7 days (the dose was administered via the tail vein). Serial blood samples (0.15 mL) were obtained by retro-orbital bleeds up to 240 h after all single doses and up to 360 h after the last multiple dose. Serum samples were analyzed for CTLA4Ig by a validated enzyme immunoassay method. The concentration data were subjected to noncompartmental pharmacokinetic analysis. Both Cmax and AUCinf values increased in a dose-proportional manner in skin-intact mice. The CLT values were dose independent. The MRT, t1/2, and Vdss values at the 0.07-mg dose level were significantly lower than those obtained for both the 0.29- and 0.57-mg dose levels; however, the respective values between the 0.29- and 0.57-mg dose levels were not significantly different. No significant differences were found in the pharmacokinetic parameters between the skin-intact and skin-grafted mice.

Pharmacokinetics and pharmacodynamics of CTLA4lg (BMS-188667), a novel immunosuppressive agent, in monkeys following multiple doses.

The dose proportionality and multiple dose pharmacokinetics of CTLA4Ig, an immunosuppressive drug under development, were investigated in 12 cynomolgus monkeys in a parallel study. The activity of CTLA4Ig in suppressing the immunoresponses to sheep red blood cell (SRBC) was also assessed. Two monkeys per gender were randomly assigned to one of the three dose levels, 1.0, 2.9, and 8.7 mg/kg of CTLA4Ig. The monkeys in each dose level received the assigned intravenous dose of CTLA4Ig by a bolus injection into a saphenous vein on days 1, 4, 8, 11, 15, and 18. Immediately after the administration of CTLA4Ig on day 1, each monkey was challenged with SRBC. Serial blood samples were collected up to 720 h following administration of CTLA4Ig on day 18 (last dose). In addition, predose blood samples were obtained on days 1, 4, 8, 11, 15, and 18. Serum samples were analyzed for the concentrations of CTLA4Ig using a validated ELISA method. The data obtained were subjected to noncompartmental pharmacokinetic analyses. The serum concentrations of CTLA4Ig attained steady state by day 11 regardless of the dose levels. The mean AUC0-720 values of CTLA4Ig increased in a dose proportional manner. The mean values of Cmax increased in a ratio of 1:3:3:8:5 while the dose administered increased in a ratio of 1:3:9. Predose serum concentrations (Cmin) of CTLA4Ig increased in a dose proportional manner. The mean T1/2 values were not significantly different among the dose groups, suggesting that the elimination characteristics of CTLA4Ig were not altered as the dose increased. Dose-related immunosuppressive activity of CTLA4Ig (78-98% inhibition) was observed in monkeys immunized intravenously with SRBC. In conclusion, CTLA4Ig exhibits linear kinetics and demonstrates significant immunosuppressive activity over a dose range of 1.0-8.7 mg/kg in monkeys.

The role of bone marrow transplantation in the management of advanced local disease.

The applications of bone marrow transplantation for the management of advanced local disease are examined. This review for stage III and inflammatory carcinoma suggests enhanced effectiveness and a progressive decrease in costs for bone marrow transplantation.

Long-term follow-up of a randomized post-induction therapy trial in acute myelogenous leukemia (a Southeastern Cancer Study Group trial).

A phase III clinical trial was designed to determine if more intensive induction and consolidation therapy for acute myeloblastic leukemia increases the remission rate and prolongs survival. A minor objective was to determine if the use of non-cross resistant drugs was more effective than the same drugs used for induction. Patients with untreated leukemia between the ages of 15 and 50 were given daunorubicin 45 mg/m2 for the first 3 days of a 10-day continuous infusion of cytosine arabinoside, initially at a dose of 2000 mg/m2 but reduced to 100 mg/m2 because of toxicity. Those under 36 achieving a complete remission and with an histocompatible donor were assigned to a transplant arm. The rest were randomized to receive one of three consolidation arms: A, cytosine arabinoside, 200 mg/m2 daily for 7 days and daunorubicin 45 mg/m2 daily for 3 days for three courses; B, one course as in Arm A followed by amsacrine, 120 mg/m2 daily for 5 days followed by a 5-day continuous infusion of azacytidine, 150 mg/m2/day; C, thioguanine and cytosine arabinoside, 100 mg/m2 every 12 h and daunorubicin 10 mg/m2 daily for 5 days for three courses followed by four maintenance courses of cytosine arabinoside, 100 mg/m2 daily for 5 days and daunorubicin, 45 mg/m2 for 2 days every 13 weeks. From 1981 to 1986, 398 eligible patients were enrolled and 219 achieved a complete remission. The initial induction dose of cytosine arabinoside was reduced after five of 29 patients exhibited fatal gastrointestinal toxicity. Only 11 patients were assigned to the transplant arm. There were no significant differences in the consolidation arms. The 5 year disease-free survivals were 38, 31 and 27% in arms A, B, and C respectively. Intensive consolidation therapy with the same or different drugs used in induction was as effective as lower dose consolidation followed by maintenance therapy.

Impact of cytogenetic abnormalities on outcome of bone marrow transplants in acute myelogenous leukemia in first remission.

This study analyzed the impact of cytogenetic abnormalities on outcome of 1516 HLA-identical sibling bone marrow transplants for acute myelogenous leukemia (AML) in first remission reported to the International Bone Marrow Transplant Registry by 188 centers. 708 patients (47%) had cytogenetic studies performed. Transplant outcome in these subjects was similar to the 808 in whom cytogenetic studies were not performed. One or more cytogenetic abnormalities were detected in 284 (40%) of subjects studied. Relapse rates were higher and leukemia-free survival lower in patients with poor prognosis abnormalities vs those with no abnormality or with good or intermediate prognosis abnormalities (relative risk of relapse 2.40, P < 0.01; relative risk of treatment failure 1.68, P < 0.03). We conclude that cytogenetic abnormalities correlated with increased relapse in patients treated with chemotherapy. HLA-identical sibling transplants are similar.

Isolation and expression of rat thymidylate synthase cDNA: phylogenetic comparison with human and mouse thymidylate synthases.

Two cDNA clones representing rat hepatoma thymidylate synthase (rTS) were isolated from a lambda ZAP II cDNA library using as a probe a fragment of the human TS cDNA. The two were identical except that one was missing 50 bp and the other 23 bp corresponding to the 5' coding region of the protein. The missing region was obtained by screening a rat genomic library. The open reading frame of rTS cDNA encoded 921 bp encompassing a protein of 307 amino acids with a calculated molecular mass of 35,015 Da. Rat hepatoma TS appears identical to normal rat thymus TS and the two sequences differ from mouse TS in the same eight amino acid residues. Six of these differences are in the first 21 amino acids from the amino-end. The human enzyme differed from rat and mouse TS at 17 residues where the latter two were identical, with most changes being conservative in nature. The three species differed completely at only four sites. Because the mouse TS shares four amino acids with human TS at sites which differ from rTS and a comparable situation does not exist between rTS and human TS, it is suggested that mouse TS is closer to human TS phylogenetically than rTS. The polymerase chain reaction was used to subclone the protein coding region of rTS into a high expression vector, which expressed rTS in Escherichia coli to the extent of 10 to 20% of its cellular protein. Although the amino-end of the amplified TS was unblocked, that isolated from a FUdR-resistant rat hepatoma cell line contained mostly N-acetylmethionine on its N-terminal end, a finding that may have significant regulatory consequences, which are discussed. The TS level in the resistant cell line was 60 to 70-fold higher than normal which was found to be associated with both multiple gene copies and an expanded TS mRNA pool.

Laryngeal preservation.

Laryngeal cancer represents a major medical problem in this state. While early stage tumors are treatable with relatively low morbidity or quality of life sacrifices, advanced stage disease requires a total laryngectomy with its inherent life-style negatives. Recent advances in chemotherapy protocols, specifically induction cisplatin and 5-fluorouracil followed by radiation therapy, have ushered in the era of larynx preservation. This has apparently been accomplished without a sacrifice in survival. While these protocols are experimental, patients may be offered this option at certain centers, and prospective accrual will be important to the long-term efficacy questions of such therapy. The historical background and scientific foundations of laryngeal preservation protocols are discussed, and the relevant trials reviewed. Moreover, specific management issues are covered, and finally, current and future questions of such therapy are explored.

Phase I trial of high-dose melphalan, high-dose etoposide and autologous bone marrow re-infusion in solid tumors: an Eastern Cooperative Oncology Group (ECOG) study.

The purpose of this work was to determine the maximum tolerated (phase II) dose of melphalan and etoposide that can be given in conjunction with autologous BM re-infusion in patients who have refractory or relapsed solid tumors. Twenty-six patients with refractory or relapsed breast cancer (n = 15), small cell lung cancer (n = 1), ovarian cancer (n = 3), colorectal cancer (n = 3) or malignant melanoma (n = 4) were enrolled and treated in this phase I study. Patients ranged in age from 31 to 60 years (median 44.5 years). Melphalan 180 mg/m2 (60 mg/m2/day for 3 consecutive days i.v. over 30 min) and etoposide 1200-3600 mg/m2 (400-1200 mg/m2/day for 3 consecutive days i.v. over 4 h) were given followed by autologous BM infusion 60-72 h after completion of chemotherapy. Ten patients received GM-CSF or G-CSF therapy after marrow re-infusion. Regimen-related toxicities included fever, pancytopenia, mucositis, nausea, vomiting, diarrhea, esophagitis, hepatic dysfunction and infection. Neutrophils recovered to > 500 x 10(6)/l and platelets recovered to > 20 x 10(9)/l (without transfusions) a median of 17 days and 20.5 days after marrow infusion, respectively. Dose-limiting toxicity occurred at an etoposide dose of 3600 mg/m2, since 4 of 6 patients treated at this dose level experienced grade 4 NCI Common Toxicity Criteria (mucositis (n = 3) and infection (n = 1)). Complete responses were noted in 7 patients (breast cancer (n = 5), colorectal cancer (n = 1) and melanoma (n = 1)); partial responses were observed in 5 patients. Melphalan 180 mg/m2 and etoposide 3000 mg/m2 is a potent high-dose chemotherapy regimen with significant antineoplastic activity, particularly for breast cancer, and has acceptable toxicity when administered in conjunction with autologous BM re-infusion.

Quality of life in adult recipients of bone marrow transplantation.

Quality of life, coping styles, and satisfaction with health care were assessed in 32 bone marrow transplant recipients and 22 conventional chemotherapy recipients. Subjects reported having generally good quality of life with no significant differences in quality of life or coping styles between the two groups. Quality of life was not significantly associated with age, socioeconomic status, time since diagnosis, or time since last treatment, although lower scores were associated with a passive coping style. Interestingly, bone marrow transplant recipients reported greater over-all satisfaction with health care and more contentment with the cost and convenience of health-care delivery than did conventional chemotherapy recipients.

Pure red cell aplasia associated with angioimmunoblastic lymphadenopathy with dysproteinemia.

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) can best be described as a disorder of T-cells resulting in amplification of the B-cell response and clinical symptoms of lymphadenopathy, fever, hepatosplenomegaly, and a variety of blood abnormalities. Pure red cell aplasia (PRCA), an autoimmune disorder resulting in selective aplasia of the erythroid series, has only rarely been associated with AILD. Herein we report three cases of AILD and PRCA. Serum from one patient was available for study and contained a dose-dependent inhibitor of the CFU-E but not CFU-GM cultures from normal bone marrow. This activity was found in the globulin fraction after ammonium sulfate precipitation. Patients with AILD are known to make antibodies to many autologous epitopes, and the most well-characterized mechanism of PRCA involves antibodies to red cell precursors. Our serum data are consistent with the hypothesis that such an antibody existed in our patient. Aggressive treatment of these patients resulted in transient improvement in two; however, all three died without achieving a durable complete remission with two dying of infectious complications.