Clinical trials: are they a good buy?

PURPOSE: Concern that clinical trials may be too costly has been used to justify traditionally restrictive insurer policies regarding clinical trials. Additionally, fear of insurer reimbursement denial can be a significant barrier to clinical trial participation. In this study, we reviewed the empirical data on costs of clinical trials versus standard care and summarized the current status of policy initiatives related to clinical trial insurance reimbursement. METHODS: Electronic and print data sources were searched for studies on the costs of oncology clinical trials. Information on policy initiatives for clinical trial reimbursement was obtained from the American Society of Clinical Oncology, the American Society of Hematology, and the Coalition of National Cancer Cooperative Groups and from searches of World Wide Web sites. RESULTS: Five pilot studies provided information for 377 patients on phase II/III clinical trials matched with controls on standard care. Cost estimates ranged from 10% lower to 23% higher costs/charges for clinical trials in comparison to standard medical care. Medicare, 14 states, and several private insurers now cover the costs of patient care in "qualifying" clinical trials. CONCLUSION: Findings from small pilot studies suggest that phase II and III clinical trials result in at most modest increases in cost over standard treatment costs. Also, an increasing number of policy makers have decided to support clinical trial reimbursement initiatives. It is hoped that economic data from large observational studies will facilitate widespread and permanent decisions that support reimbursement for phase I, II, and III clinical trial participation.

Bone marrow transplants from HLA-identical siblings in advanced Hodgkin's disease.

PURPOSE: To determine the outcome of HLA-identical sibling bone marrow transplants in advanced Hodgkin's disease. PATIENTS AND METHODS: We reviewed the data on 100 consecutive patients with Hodgkin's disease who received HLA-identical sibling bone marrow transplants between April 1, 1982 and August 12, 1992, reported to the International Bone Marrow Transplant Registry (IBMTR). The median interval from diagnosis to transplant was 2.5 years (range, < 1 to 14). All had advanced disease. Eighty-nine of 100 patients were not in remission at the time of transplant. Fifty had pretransplant Karnofsky scores less than 90% and 27 had active infection in the week before transplant. Patients received a variety of conditioning regimens; 45 received total-body radiation. RESULTS: The 100-day probability of acute graft-versus-host disease (GVHD) was 35% (95% confidence interval [CI], 26% to 46%); the 3-year probability of chronic GVHD was 45% (95% CI, 31% to 59%). The 3-year probability of relapse was 65% (95% CI, 50% to 78%). The 3-year probability of survival was 21% (95% CI, 14% to 30%). The 3-year disease-free survival rate was 15% (95% CI, 9% to 24%). CONCLUSION: HLA-identical sibling bone marrow transplants have a limited role in advanced Hodgkin's disease.

Rapid eye movement sleep disturbance in posttraumatic stress disorder.

The subjective sleep disturbance in posttraumatic stress disorder (PTSD), including the repetitive, stereotypical anxiety dream, suggests dysfunctional rapid eye movement (REM) sleep mechanisms. The polysomnograms of a group of physically healthy combat veterans with current PTSD were compared with those of an age-appropriate normal control group. Tonic and phasic REM sleep measures in the PTSD subjects were elevated on the second night of recorded sleep. Increased phasic REM sleep activity persisted in the PTSD group on the subsequent night. During the study, an anxiety dream occurred in a PTSD subject in REM sleep. The results are consistent with the view that a dysregulation of the REM sleep control system, particularly phasic event generation, may be involved in the pathogenesis of PTSD. The finding of a specific disturbance of sleep unique to PTSD may have significant implications for the design of effective treatments for PTSD.

Rapid eye movement sleep changes during the adaptation night in combat veterans with posttraumatic stress disorder.

BACKGROUND: Hyperarousal in posttraumatic stress disorder (PTSD) is manifested during sleep as well as waking. Elevated rapid eye movement sleep (REMS) phasic activity, likely signifying central nervous system alerting, has been identified in PTSD. The authors reasoned that PTSD compared to control subjects would show particularly increased REMS phasic activity on the first night of polysomnography, with adaptation to a novel environment. METHODS: First-night polysomnograms of 17 veterans with PTSD were compared with those of 11 control subjects. Sleep was also studied in subsets of both groups over two nights. RESULTS: On the first night, the PTSD subjects had a higher density of rapid eye movements in the first REMS period. This measure was increased on the first compared to the second night, but there was no interaction effect between night and group. CONCLUSIONS: REMS changes are again demonstrated in veterans with PTSD. Introduction to a novel environment activated a REMS phasic process, but not differentially in PTSD compared to control subjects.

Acute lymphoblastic leukemia with eosinophilia.

Acute lymphoblastic leukemia with eosinophilia is a rare but distinctive clinical entity. The eosinophilia in these patients can present before, concomitantly, or after the diagnosis of leukemia. Patients with this syndrome often suffer from the cardiovascular complications of severe eosinophilia, suffering excess morbidity and mortality as a result of their eosinophilia. Treatment of the eosinophilia in this syndrome consists of administration of induction chemotherapy, followed by prednisone and hydroxyurea if required for persistent eosinophilia. Eosinophilia often resolves with remission of leukemia, only to return at the time of relapse in a high percentage of cases. Patients with this syndrome characteristically have cytogenetic abnormalities involving the long arms of chromosomes 5 and 14. These cytogenetic abnormalities are not commonly seen in acute lymphoblastic leukemia and suggest that this syndrome may have a distinct pathophysiology and etiology. The affected region on chromosome 5 contains genes that control hematopoiesis, including eosinophilopoiesis. Further investigations into these cytogenetic abnormalities may provide insight into the etiology of the leukemia and eosinophilia characteristic of this syndrome.

Motor dysfunction during sleep in posttraumatic stress disorder.

A subjective disturbance of sleep, including the occurrence of repetitive, stereotypical anxiety dreams, is characteristic of posttraumatic stress disorder (PTSD). The phenomenology of the PTSD anxiety dream has seemed most consistent with an underlying rapid eye movement (REM) sleep dysfunction. However, motor behavior reportedly can accompany PTSD dreams, and normal REM sleep typically involves a nearly total paralysis of the body musculature. As a means of understanding this discrepancy, anterior tibialis muscle activity during sleep was studied in a group of Vietnam combat veterans with current PTSD and in an age-matched normal control group. The PTSD subjects had a higher percentage of REM sleep epochs with at least one prolonged twitch burst; they also were more likely to have periodic limb movements in sleep, during nonrapid eye movement sleep. Both these forms of muscle activation also have been observed in REM behavior disorder (RBD), a parasomnia characterized by the actual enactment of dream sequences during REM sleep. The identification of RBD-like signs in PTSD adds to the evidence for a fundamental disturbance of REM sleep phasic mechanisms in PTSD.

Tacrolimus and methotrexate for the prophylaxis of acute graft-versus-host disease in allogeneic bone marrow transplantation in patients with hematologic malignancies.

We conducted a study to evaluate the efficacy of the combination of tacrolimus and short-course methotrexate for the prevention of acute GVHD in patients with hematologic malignancies. Patients received preparative regimens specific for their disease category. Twenty-six out of 28 received HLA-identical sibling transplants and the two remaining patients received one-antigen mismatched transplants from a family member. With a median follow-up of 14 months, the Kaplan-Meier estimate of event-free survival was 50 +/- 9%. The probability of grade II-IV GVHD was 15 +/- 7%. Four patients developed GVHD: two had grade II and one each developed grade III and IV GVHD. Administration of methotrexate was associated with severe mucositis and there was no correlation between the distribution of the GVHD grade and the cumulative dose of methotrexate given. Thirteen patients have died; nine from transplant-related complications and four from relapse. The major toxicity of tacrolimus was renal. Nine out of 28 patients (32%) developed renal dysfunction attributed to tacrolimus. The combination of tacrolimus and methotrexate is an effective regimen for GVHD prophylaxis but associated with significant renal and mucosal toxicity. Further studies of tacrolimus as a single agent or in combination with either steroids or with a lower dose of methotrexate or with other antiproliferative drugs to modify the adverse events may improve the therapeutic index of this useful and promising agent.

Double dose-intensive chemotherapy with autologous stem cell support for relapsed and refractory testicular cancer: the University of Michigan experience and literature review.

Testicular cancer patients refractory or in relapse after primary chemotherapy have < or =25% 5-year progression-free survival with salvage. To improve prognosis, patients entered a phase I/II tandem dose-escalation trial of carboplatin (1500-2100 mg/m(2)) and etoposide (1200-2250 mg/m(2)) with ABMT. Patients were eligible for a second cycle if disease progression was absent and performance status allowed. From August 1990 to June 1998, 29 males (25 NSGCT) were treated. At the time of ABMT, 10 were chemosensitive, four were chemoresistant, and 10 were absolutely refractory to platinum. Disease status (no. patients) at transplant: primary refractory disease (six), first relapse (10), second relapse (eight), third relapse (five). Fifteen (52%) received both transplants. Treatment-related mortality was 10%. Best response after ABMT included: two CR, one CR surgically NED, five PR, three PR surgically NED, seven SD, and eight PD. Eight (28%) patients are continuously progression-free a median 60 months (range, 31-93) from first ABMT. Three seminoma patients remain progression-free. Of five long-term NSGCT survivors, four were treated in first relapse with platinum-sensitive disease. Eighteen relapses occurred a median of 4 months after ABMT I (two late relapses at 28 and 44 months). The median PFS and OS for the whole group are 4 and 14 months, respectively. Patients with relapsed/ refractory testicular cancer benefit most from ABMT if they have platinum-sensitive disease in first relapse. Patients who do poorly despite ABMT have a mediastinal primary site, true cisplatin-refractory disease, disease progression prior to ABMT, and/or markedly elevated betaHCG at ABMT. New treatment modalities are needed for the latter group.

Roundtable discussion: Incorporating bone marrow transplantation into NCCN guidelines.

A newly formed National Comprehensive Cancer Network (NCCN) panel on bone marrow transplantation has the task of ensuring the incorporation of allogeneic and autologous transplantation into all disease guidelines where significant evidence exists to warrant their inclusion. The panel is further charged with ensuring that there is consistency among guidelines regarding the use of marrow transplantation. A preliminary review of existing NCCN guidelines found that marrow transplantation was appropriately included for the treatment of the common hematologic malignancies of adults, including acute myeloid leukemia, chronic myeloid leukemia, myelodysplasia, multiple myeloma, Hodgkin's disease, and the malignant lymphomas. Frequent refinements regarding lymphomas will be necessary, particularly in rapidly evolving areas, such as multiple myeloma and myelodysplasia, and conditions with changing definitions, such as malignant disease. The increasing volume of data supporting the use of autologous bone marrow transplantation in advanced primary and responding metastatic breast cancers needs to be reflected in the breast cancer guideline if it is to remain credible. Well-designed and well-conducted clinical trials are the most appropriate setting for all bone marrow transplantations and patient referral to these trials remains the standard of care in all settings.

NCCN Practice Guidelines for Breast Cancer.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. In many situations, the patient and physician have the responsibility to jointly explore and ultimately select the most appropriate option from among the available alternatives. With rare exception, the evaluation, treatment, and follow-up recommendations contained within these guidelines were based largely on the results of past and present clinical trials. However, there is not a single clinical situation in which the treatment of breast cancer has been optimized with respect to either maximizing cure or minimizing toxicity and disfigurement. Therefore, patient and physician participation in prospective clinical trials allows patients not only to receive state-of-the-art cancer treatment but also to contribute to the improvement of treatment of future patients.

Patterns of swallowing after supraglottic laryngectomy.

OBJECTIVE: To understand the anatomical and physiological basis for early recovery of swallowing function after supraglottic laryngectomy. STUDY DESIGN: Retrospective review. METHODS: The records of nine patients who had undergone supraglottic laryngectomy at the Stratton Veteran's Administration Hospital (Albany, NY) between 1994 and 1998 were reviewed. Videofluoroscopic swallowing studies were obtained on all patients as early as was safely possible and were reviewed by a multidisciplinary team of physicians, nurses, and speech pathologists with regard to anatomical and functional differences between successful and unsuccessful recovery of swallowing function. RESULTS: Five of nine patients resumed regular diets including thin liquids within 1 year of surgery; three patients remained dependent on enteral support. Swallowing success was most closely associated with short oropharyngeal transit time and an anterosuperior position of the larynx. Laryngeal positioning, tongue base mobility, and placement and coordination of the bolus for maximum swallowing efficiency can be improved with time and speech therapy. CONCLUSIONS: Factors that placed patients at significantly higher risk for aspiration included low laryngeal position and delayed oropharyngeal transit time. Tight lingual-laryngeal closure did not completely prevent aspiration. At the time of the initial surgical procedure it may be important to position the laryngeal remnant as far superior and anterior under the tongue base as possible.

Transplantation in patients with multiple myeloma: a multicenter comparative analysis of peripheral blood stem cell and allogeneic transplant.

We performed a multicenter comparative analysis of autologous peripheral blood stem cell transplantation (PBSCT) and allogeneic bone marrow transplantation (alloBMT) in multiple myeloma. Forty-eight consecutive patients received either PBSCT (24 patients) or alloBMT (24 patients) at one of three institutions in the study group. Preparatory regimens consisted of melphalan and total body irradiation (TBI) or melphalan alone in the PBSCT group. The alloBMT group received one of four regimens: cyclophosphamide and TBI; cyclophosphamide, VP-16 and 1,3-bis(2-chloroethyl)-1-nitrosourea (CVB); busulfan and cyclophosphamide (BU/CY) and total marrow irradiation (TMI); or melphalan and TBI. Procedure-related mortality was 12.5% for the PBSCT group and 25% for the alloBMT group. With a median follow-up for survivors in the PBSCT and alloBMT groups of 11 months (range, 4-46) and 15 months (range, 2-84 months), respectively, there was no significant difference in median overall survival (33.5 versus 38.6 months, p = 0.7637) or event-free survival (16.7 versus 31 months, p = 0.8450). There was, however, a plateau in survival at 40% in the alloBMT group. No plateau in survival was seen in the PBSCT group. Clinical relapses occurred as late as 39 months posttransplant. Patients have survived up to 28 months postrelapse.

A single session, group study of exposure and Eye Movement Desensitization and Reprocessing in treating Posttraumatic Stress Disorder among Vietnam War veterans: preliminary data.

This report summarizes data gathered thus far from an ongoing study. Two groups (total N = 12) of Vietnam War veterans diagnosed with Posttraumatic Stress Disorder (PTSD) received a single session of exposure or Eye Movement Desensitization and Reprocessing (EMDR) focusing on the veterans' most distressing war experience. Group assignment was random, treatment providers were blind to assessment data, and the pre- and posttreatment assessor was blind to treatment assignment. Both groups showed improvement on the Impact of Event Scale. EMDR treatment resulted in greater positive changes in within-session Subjective Units of Discomfort levels and on self-monitored severity of intrusive recollection. A trend toward decreased heart rate reactivity was observed in both groups. Results must be considered carefully due to the small number of subjects used in the study.

Eye movement desensitization and reprocessing: effectiveness and autonomic correlates.

Eighteen subjects distressed by memories of a specific traumatic event were randomly assigned to a single session of one of three conditions: Eye Movement Desensitization and Reprocessing (EMDR), a Time Interval Condition (TIC), or Tapping Alternate Phalanges (TAP). All subjects treated in the EMDR group showed desensitization as monitored by SUDs, which correlated with the physiological data and cessation of pronounced symptomatology. Only one subject in a control group showed desensitization. Compared to TIC and TAP, autonomic measures showed distinct changes during EMDR: (1) respiration synchronized with the rhythm of the eye movements in a shallow, regular pattern; (2) heart rate slowed significantly overall; (3) systolic blood pressure increased during early sets, invariably declined during abreactions, and decreased overall; (4) finger tip skin temperature consistently increased; and (5) the galvanic skin response consistently decreased in a clear "relaxation response". This relaxing effect of the eye movements suggests that at least one of the mechanisms operating during EMDR is desensitization by reciprocal inhibition, by pairing emotional distress with an unlearned or "compelled" relaxation response.

Pedicled temporoparietal galeal myofascial flap for orbital and cheek lining following radical maxillectomy.

Radical maxillectomy is indicated for stage III and IV antroethmoidal carcinoma. In those cases where the anterior bony wall of maxillary antrum or the anterior facial soft tissue is involved or a previous Caldwell-Luc antrostomy was performed, a generous amount of cheek soft tissue has to be resected with the surgical specimen in order to achieve tumour-free margins. In such cases survival of the cheek flap is in jeopardy. Following orbital exenteration the resultant defect requires covering to promote healing and to protect the underlying bone. Traditionally, a skin graft has been used to line the orbital defect and the cheek flap. The pedicled temporoparietal galeal myofascial flap offers well-vascularized, reliable, supple and plentiful tissue which can be used to line both the orbit and the cheek, thus covering both sites with one flap. Such a case is presented and the surgical anatomy and technique are described.

Experience in posology.

We used an organized problem-solving method to resolve posology problems in integrated curriculum. A thorough assessment of the extent of problems revealed the need for a mathematical foundation (perhaps due to decreased mathematics SAT scores) to achieve a high level of accuracy with posology in preparation for professional nursing practice. Early curriculum intervention allowed for higher learning level achievement and sufficient time for demonstration of acquired skills. The implementation of a self-learning module in conjunction with small group intervention appeared to have an impact on students' level of knowledge as well as the application of knowledge. This was evidenced by an increased mean score from pre- to post-testing on a multiple-choice examination. Ongoing evaluations will measure students' ability to actualize these concepts in their clinical practice. Perhaps now is the time to identify posology within integrated curricula and examine it as a basis for pharmacology to better prepare all students for this vital nursing responsibility.