L.A. Williams

High-dose chemotherapy for high-risk primary breast cancer: an on-site review of the Bezwoda study

BACKGROUND The efficacy of high-dose chemotherapy with progenitor-cell rescue for women with breast cancer is a controversial issue. Although historically controlled trials have suggested a survival advantage for high-dose chemotherapy, several randomised studies have yet to confirm this advantage. Two studies, however, by Bezwoda, of patients with high-risk and metastatic disease, seemed to show a significant survival advantage for high-dose compared with conventional-dose chemotherapy for metastatic and high-risk primary breast cancer. METHODS To corroborate the study results before starting a large international confirmatory study, a US team did an on-site review of records for patients in the high-risk study. Limited numbers of records were made available for review, all of which were for patients who received the high-dose-chemotherapy regimen. FINDINGS There was much disparity between the reviewed records and the data presented at two international meetings. In addition, the reviewers saw no signed informed consent, and the institutional review committee had no record of approval for the investigational therapy. After the site visit, Bezwoda admitted scientific misconduct by using a different control chemotherapy regimen from that described in presented data. INTERPRETATION The Bezwoda study should not be used as the basis for further trials to test the efficacy of the cyclophosphamide, mitoxantrone, etoposide regimen for high-dose chemotherapy in women with high-risk primary breast cancer. This review validates the essential nature of on-site audits, especially in single-institution studies.

Serum interleukin-6 predicts the development of multiple symptoms at nadir of allogeneic hematopoietic stem cell transplantation.

During the time of lowest white blood cell count (nadir) of allogeneic hematopoietic stem cell transplantation (allo‐HSCT), cancer patients suffer from tremendous symptom burden related to therapy that requires intensive patient care. However, the mechanism underlying the development of multiple symptoms has not been established.

A clinical phase I/II study of recombinant human interleukin-1 receptor in glucocorticoid-resistant graft-versus-host disease

Graft-versus-host disease (GVHD) is the major complication of allogeneic bone marrow transplantation. GVHD is accompanied by the release of inflammatory cytokines, including interleukin (IL)-1, and previous work has demonstrated that IL-1 participates in the pathogenesis of GVHD. The recombinant human IL-1 receptor (rhuIL-1R) is the soluble form of the type I IL-1 receptor that can bind to IL-1 and prevent cellular activation. We report a phase I/II trial utilizing the rhuIL-1R in the treatment of allogeneic bone narrow transplant patients not improving with glucocorticoid therapy. RhuIL-R was given at four dose levels for 21 days to 14 patients with progressive or persistent acute GVHD. The study drug had no clinical or persistent hematopoiesis and the treatment was tolerated by patients without toxicity at all dose levels. Eight of 14 patients (57%) had an improvement of GVHD after rhuIL-1R therapy. Improvement in GVHD was noted at each dose level, although a dose-response effect for rhuIL-1R treatment was not observed. This work supports the concept that IL-1 plays a role in the inflammation associated with acute GVHD. A controlled study of the rhuIL-1R for treatment of prophylaxis of GVHD is warranted.

Measuring acute GVHD related symptom burdens and inflammatory cytokines during the first 100 days after allogeneic hematopoietic stem cell transplantation

206 Measuring acute GVHD related symptom burdens and inflammatory cytokines during the first 100 days after allogeneic hematopoietic stem cell transplantation X. Wang, S. Giralt, L. Williams, Q. Shi, G. Mobley, J. Reuben, B. Lee, C. Cleeland MD Anderson Cancer Center, Symptom Research, 1515 Holcombe Blvd., Unit 1450, Houston, TX 77030, United States of America Aims: Acute graft versus host disease (aGVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). Although aGVHD-associated cytokine elevations in animal models and specific clinical manifestations of aGVHD are well recognized, many aGVHD-relevant non-specific sickness symptoms and their biological correlates in humans have not been studied. Methods: We explored dynamic changes in inflammatory cytokines and symptoms in the first 100 days of allo-HSCT in 30 patients with acute myelogenous leukemia or myelodysplastic syndrome. Multiple symptoms were measured repeatedly by the M.D. Anderson Symptom Inventory, while serum concentrations of inflammatory cytokines (IL-1RA, IL-1?, IL-6, IL-8, IL-10, IL-12p40p70, sTNF-R1) were repeatedly measured by Luminex. Mixed-effects modeling was used to analyze longitudinal data. Results: majority of patients (26/30) developed aGVHD (median: day +36 post-HSCT), and were treated with systemic steroids. Symptom burden was significantly higher in patients with aGVHD than in the non-aGVHD group (p < .05). sTNF-RI (p = .036), IL-1RA (p < .0001), and IL-12p40p70 (p = .02) showed significant elevations from nadir (lowest blood account) to aGVHD diagnosis. sTNF-R1 was the only examined cytokine significantly associated with symptom severity before and after aGVHD diagnosis. Symptom and cytokine outcomes around diagnosis of aGVHD were not related to degree of aGVHD. Conclusion: The study evidenced that serum sTNF-R1 release triggered by allo-HSCT is associated with increases in symptom burden around the time of aGVHD development. doi:10.1016/j.bbi.2010.07.015 Abstract # 207 Nuclear factor interleukin 6 is a new delayed early cell activation marker in the rat brain during the time course of LPS-induced systemic inflammation J. Damm , R. Gerstberger , J. Roth , G.N. Luheshi , C.D. Rummel a,b a Justus-Liebig University Giessen, Department of Veterinary Physiology, Giessen, Germany b Douglas Mental Health University Institute, McGill University, Mon-