Search

Supplemental Digital Content is available in the text., Grateful patients provide substantial philanthropic funding for health care institutions, resulting in important societal benefits. Although grateful patient fundraising (GPFR) is widespread, it raises an array of ethical issues for patients, physicians, development professionals, and institutions. These issues have not been described comprehensively, and there is insufficient guidance to inform the ethical practice of GPFR. Consequently, the authors convened a “Summit on the Ethics of Grateful Patient Fundraising,” with the goal of identifying primary ethical issues in GPFR and offering recommendations regarding how to manage them. Participants were 29 experts from across the United States who represented the perspectives of bioethics, clinical practice, development, law, patients, philanthropy, psychology, and regulatory compliance. Intensive discussions resulted in articulating ethical issues for physicians and other clinicians (discussions with patients about philanthropy; physician-initiated discussions; clinically vulnerable patients; conflicts of obligation and equity regarding physician’s time, attention, and responsiveness and the provision of special services; and transparency and respecting donor intent) as well as for development officers and institutions (transparency in the development professional–donor relationship; impact on clinical care; confidentiality and privacy; conflicts of interest; institution–patient/donor relationship; concierge services for grateful patients; scientific merit and research integrity; transparency in use of philanthropic gifts; and institutional policies and training in responsible GPFR). While these recommendations promise to mitigate some of the ethical issues associated with GPFR, important next steps include conducting research on the ethical issues in GPFR, disseminating these recommendations, developing standardized training for clinicians regarding them, and revising them as warranted.

Drug overdose has become the leading cause of injury death in the United States. More than half of those deaths involve prescription drugs, specifically opioids. A key component of addressing this national epidemic is improving prescriber practices.A review of the curricula at the four medical schools in Massachusetts revealed that, although they taught components of addiction medicine, no uniform standard existed to ensure that all students were taught prevention and management strategies for prescription drug misuse. To fill this gap, the governor and the secretary of health and human services invited the deans of the state's four medical schools to convene to develop a common educational strategy for teaching safe and effective opioid-prescribing practices. With leadership from the Department of Public Health and Massachusetts Medical Society, the deans formed the Medical Education Working Group in 2015. This group reviewed the relevant literature and current standards for treating substance use disorders and defined 10 core competencies for the prevention and management of prescription drug misuse.The medical schools have incorporated these competencies into their curricula and have committed to assessing students' competence in these areas. The members of the Medical Education Working Group have agreed to continue to work together on key next steps, including connecting these competencies to those for residents, equipping interprofessional teams to address prescription drug misuse, and developing materials in pain management and opioid misuse for practicing physicians. This first-in-the-nation partnership has yielded cross-institutional competencies that aim to address a public health emergency in real time.

Author(s): Tefferi, Ayalew; Kantarjian, Hagop; Rajkumar, S Vincent; Baker, Lawrence H; Abkowitz, Jan L; Adamson, John W; Advani, Ranjana Hira; Allison, James; Antman, Karen H; Bast, Robert C; Bennett, John M; Benz, Edward J; Berliner, Nancy; Bertino, Joseph; Bhatia, Ravi; Bhatia, Smita; Bhojwani, Deepa; Blanke, Charles D; Bloomfield, Clara D; Bosserman, Linda; Broxmeyer, Hal E; Byrd, John C; Cabanillas, Fernando; Canellos, George Peter; Chabner, Bruce A; Chanan-Khan, Asher; Cheson, Bruce; Clarkson, Bayard; Cohn, Susan L; Colon-Otero, Gerardo; Cortes, Jorge; Coutre, Steven; Cristofanilli, Massimo; Curran, Walter J; Daley, George Q; DeAngelo, Daniel J; Deeg, H Joachim; Einhorn, Lawrence H; Erba, Harry P; Esteva, Francisco J; Estey, Elihu; Fidler, Isaiah J; Foran, James; Forman, Stephen; Freireich, Emil; Fuchs, Charles; George, James N; Gertz, Morie A; Giralt, Sergio; Golomb, Harvey; Greenberg, Peter; Gutterman, Jordan; Handin, Robert I; Hellman, Samuel; Hoff, Paulo Marcelo; Hoffman, Ronald; Hong, Waun Ki; Horowitz, Mary; Hortobagyi, Gabriel N; Hudis, Clifford; Issa, Jean Pierre; Johnson, Bruce Evan; Kantoff, Philip W; Kaushansky, Kenneth; Khayat, David; Khuri, Fadlo R; Kipps, Thomas J; Kripke, Margaret; Kyle, Robert A; Larson, Richard A; Lawrence, Theodore S; Levine, Ross; Link, Michael P; Lippman, Scott M; Lonial, Sagar; Lyman, Gary H; Markman, Maurie; Mendelsohn, John; Meropol, Neal J; Messinger, Yoav; Mulvey, Therese M; O'Brien, Susan; Perez-Soler, Roman; Pollock, Raphael; Prchal, Josef

Reductions in federal support and clinical revenue jeopardize biomedical research and, in turn, clinical medicine.

Peritoneal mesothelioma is a rare cancer of the peritoneum with about 250 new cases diagnosed each year in the United States. It is the second most common site for mesothelioma development and accounts for 10-20% of all mesotheliomas diagnosed in the United States. A meeting sponsored by the NIH Office of Rare Diseases was held in Bethesda, Maryland on September 13 and 14, 2004. The objective of this meeting was to review the epidemiology, biology and current surgical and medical management of peritoneal mesothelioma. In addition, the meeting also discussed clinical and pre-clinical evaluation of novel treatments for mesothelioma as well as ongoing laboratory research to better understand this disease. This report summarizes the proceedings of the meeting as well as directions for future clinical and basic research. © 2006 Oxford University Press.

BACKGROUND The current study was conducted to assess the activity and toxicity of high-dose ifosfamide and mesna with recombinant human granulocyte–colony-stimulating factor (rhG-CSF), given in an outpatient setting, in the treatment of patients with unresectable malignant mesothelioma. METHODS Between September 1994 and September 1996, 41 patients with histologically verified, unresectable malignant mesothelioma were registered, 38 of whom were analyzable (2 were ineligible and 1 was nonanalyzable). Patients received intravenous ifosfamide at a dose of 2.8 g/m2 over 3 hours (total dose of 14 g/m2), plus mesna at a dose of 0.56 g/m2 prior to and at 4 hours and 8 hours after ifosfamide infusion daily for 5 days every 21 days. rhG-CSF at a dose of 5 μg/kg/day was administered subcutaneously on days 6–15. RESULTS Response assessment could be determined adequately in 21 patients. Two patients obtained responses; 1 was a confirmed partial response (3%; 95% confidence interval [95% CI], 0–14%) and 1 was an unconfirmed response (3%; 95% CI, 5–14%). Eleven patients had stable disease (29%), 7 patients developed disease progression (18%), 1 patient had an early death (3%), and 17 patients had inadequate assessment (45%). At the time of last follow-up, 36 of the 38 eligible patients had developed disease progression, with a median progression-free survival of 5 months (95% CI, 3–7 months) and 34 patients had died with a median survival of 7 months (95% CI, 6–9 months). Twenty-four patients (63%) and 7 patients (18%), respectively, had Grade (according to Southwestern Oncology Group Toxicity Criteria) 4 hematologic toxicities and Grade 4 nonhematological toxicities. There was one treatment-related death, the result of infection, pulmonary edema, and renal failure. CONCLUSIONS This regimen demonstrated a low overall objective response rate with substantial toxicity, and in the opinion of the authors does not warrant further investigation in the treatment of patients with unresectable malignant mesothelioma. Cancer 2003;98:331–6. © 2003 American Cancer Society. DOI 10.1002/cncr.11512

Metastatic breast cancer has been a common indication for autologous hematopoietic stem cell transplantation (HSCT). Previous reports indicate 3-year survival and progression-free survival (PFS) rates after autotransplant to be about 30 and 15%, respectively. Most deaths are from recurrent disease. One potential cause for high relapse rates is graft contamination with tumor. We describe 14 women with metastatic breast cancer transplanted between 1991 and 1998 with hematopoietic cells from identical twins. Median age was 41 y (range 34-50). Most women (12 of 14) were treated with mastectomy, and all received anthracycline-based regimens in their pretransplant course; nine women also received a taxane, seven radiotherapy and three hormonal therapy. Four women were in complete remission (one CR, three CRU) at transplant, five were in partial remission, two had stable disease and two had progressive disease. Eight women have died, one of treatment-related causes and seven of progressive breast cancer. Three-year survival was 48% (21-71%) and 3-year PFS was 21% (5-45%). Although the number of patients is small, outcomes for women transplanted with syngeneic grafts are similar to those of women receiving autologous grafts. This suggests that residual cancer in the patient is the major contributor to relapse after transplantation for breast cancer.

BACKGROUND The similarity between the mechanism of action between docetaxel and estramustine generated the hypothesis of synergistic antimicrotubule effects and cytotoxicity when the two agents are combined. In addition, it has been demonstrated that estramustine binds P-glycoprotein in vitro and, thus, may prevent the efflux of taxanes in tumors that over-express P-glycoprotein. To further evaluate the combinations clinical efficacy and safety, a trial was performed in heavily pretreated patients with metastatic breast carcinoma (MBC). METHODS Thirty-six patients with MBC were treated with estramustine 900 mg/m2 per day divided into 3 doses given on Days 1–3 and docetaxel 70 mg/m2 given by intravenous administration over 1 hour on Day 3 after the first dose of estramustine, every 21 days. Patients may have received any number of prior chemotherapy regimens for MBC. RESULTS Nine partial responses were observed in 31 assessable patients, for an objective response rate of 29% (95% confidence interval, 14–48%). The median progression free survival was 4 months (range, 1–41 months), and the median overall survival was 17 months (range, 2–45 months). Severe toxicities (Grade 3 or 4) were neutropenia, hypophosphatemia, and thrombosis. Seventy-five percent of patients experienced either an improvement or no change in quality of life. CONCLUSIONS The combination of docetaxel and estramustine produced responses in heavily pretreated women with MBC while maintaining quality of life. Cancer 2003;97:537–44. © 2003 American Cancer Society. DOI 10.1002/cncr.11082

On November 8th, 2001, faculty from Universities, government and non-profit community organizations met to determine how, separately and together, they could address disparities in survival of women with breast cancer in the diverse patient populations served by their institutions. Studies and initiatives directed at increasing access had to date met modest success. The day was divided into three sections, defining the issues, model programs, government initiatives and finally potential collaborations. By publishing these proceedings, interested readers will be aware of the ongoing programs and studies and can contact the investigators for more information. The Avon Foundation funded this symposium to bring together interested investigators to share programmatic experiences, data and innovative approaches to the problem.

Purpose: Based upon the hypothesisthat prolonged exposure to the S-Phasespecific agent topotecan would be moreefficacious in the treatment of soft tissuesarcomas than a conventional 5-day scheduleof the drug, the Southwest Oncology Groupperformed a Phase II trial of topotecanadministered as a continuous infusion inadult patients with advanced soft tissuesarcomas.

‘Now is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning’ Winston Churchill in a speech to the Canadian Senate and House of Commons, December 30, 1941 In laboratory models of cancer, dose of cytotoxic chemotherapy correlates with curative therapy, while cumulative dose is associated with longer survival for those who are not cured [1] . These observations suggests a strategy of using high doses when cure is the objective but smaller doses over a prolonged period when palliation and survival are the goal. A strategy combining repetitive cycles of higher doses of cytotoxic therapy, followed by the optimal combination of hormonal and biological agents based on the tumor’s receptors might contribute to both the highest possible cure rate and the longest survival. The development of bone marrow transplant (BMT) for leukemias, and its subsequent modification for support after high dose therapy for other malignancies, has a long, complex and emotional history in medicine. At least partly because of firmly held opinions and the way large randomized trials are funded in the United States, few American randomized trials of BMT or high dose therapy strategies have been completed. The vast majority of published randomized BMT and high dose studies are European. Interestingly, in contrast, two large American randomized trials of high dose chemotherapy for breast cancer had actually completed accrual. Accrual on a third was on target until the presentation of five very small or very early randomized trials at the American Society of Clinical Oncology meeting in May of 1999. Results from some of these trials, which were analyzed after a relatively brief follow-up, are too premature to allow definitive conclusions. Nevertheless, these data have been over and misinterpreted within the scientific and lay communities. The remaining studies included a limited number of patients, thus restricting the statistical power of the observations. The desire for quick answers impeded dispassionate analysis of the available data. The opportunity for collegial review of the data further deteriorated with another round of press coverage when the data from the South African adjuvant study were found to be unreliable. Rather than increasing commitment to accrual on randomized and appropriate pilot trials, accrual to the only large American study in existence at that time tricked to a halt. In response to press coverage, Susan Edmonds from the Fred Hutchinson Cancer Research Center observed that ‘the NYT article tends to cast shadows generally on the therapy and those providing the therapy rather than pointing out early in the article (where the public will readily see it) that there are a number of very credible research institutions conducting research directed at breast cancer, some looking at high dose chemotherapy and stem cell transplantation.’ Dr. Rodenhuis, presenting the large positive Dutch Randomized study (funded by the Dutch insurance industry) at ASCO in 2000, commented on the ‘unreasonably high expectations until 1999’ and ‘unreasonably negative [opinion-ed] since 1999’ for high dose adjuvant chemotherapy for breast cancer.

In 1872, Moritz Kaposi, a Hungarian dermatologist, described five men with aggressive “idiopathic multiple pigmented sarcomas of the skin.”1 One patient died of gastrointestinal bleeding 15 months after the initial appearance of the skin lesions, and an autopsy showed visceral lesions in the lungs and the gastrointestinal tract. Subsequently, other investigators described four clinical variants of Kaposi's sarcoma that had identical histologic features but developed in specific populations and had different sites of involvement and rates of progression (Table 1). In the light of recent discoveries regarding the viral pathogenesis of Kaposi's sarcoma, these variants most likely represent different manifestations . . .

The purpose of this study was to determine the outcome of high-dose therapy with autologous hematopoietic stem cell support (autotransplants) in men with breast cancer. We studied 13 men receiving autotransplants for breast cancer and reported to the Autologous Blood and Marrow Transplant Registry (ABMTR) by 10 centers. Six men had stage 2 breast cancer, four had stage 3, and three had metastatic breast cancer. Of twelve tumors tested, all were estrogen receptor positive. Median age at transplant was 50 years. The most common conditioning regimen was cyclophosphamide, thiotepa and carboplatin (n = 5); the remaining eight men received other alkylator-based regimens. Three men received bone marrow, eight received blood stem cells, and two received both for hematopoietic support. All patients had hematopoietic recovery. There were no unexpected regimen-related toxicities. Of 10 men receiving autotransplants as adjuvant therapy, three relapsed 3, 5 and 50 months post-transplant and died 16, 19 and 67 months post-transplant. Seven of 10 are disease-free with median follow-up of 23 months (range 6-50 months). Of three men treated for metastatic breast cancer, one had progressive disease and two recurrent disease at 6, 7 and 16 months post-transplant. In conclusion, results of autotransplants for male breast cancer appear similar to those reported for women receiving autotransplants for breast cancer.

This phase I dose-escalation study was performed to determine the tolerability of three-drug combination high-dose BCNU (B) (450 mg/m2), escalating-dose thiotepa (500–800 mg/m2) and etoposide (1200 mg/m2) in divided doses over four days in 22 adults with malignant primary brain tumors. Patients received G-CSF and hematopoeitic support with peripheral blood progenitor cells (PBPC) (n=18) or both PBPC and marrow (n=4). The maximum tolerated dose of thiotepa with acceptable toxicity was determined as 800 mg/m2. The 100-day mortality rate was 9% (2/22). Grade III/IV toxicities included mucositis (71%), diarrhea (29%), nausea/vomiting (19%), and hepatic toxicity (14%). Neurological toxicities occurred in 24% and included seizures (two patients) and encephalopathy (three patients). Encephalopathy was transient in two patients and progressive in one patient. All patients had neutropenic fever. Median time to engraftment with absolute neutrophil count (ANC) >0.5×109/l was 10 days (range 8–30 days). Platelet engraftment >20×109/l occurred after 11 days (range 9–65 days). In the eighteen patients supported solely with PBPC, there was a significant inverse correlation between CD34+ dose and days to ANC (rho=−0.78, p=0.001) and platelet engraftment (rho=−0.76, p=0.002). Overall, 11% of evaluable patients (2/18) had a complete response to BTE. Median time to tumor progression (TTP) was 9 months, with an overall median survival of 17 months. BCNU (450 mg/m2), thiotepa (800 mg/m2) and etoposide (1200 mg/m2) in divided doses over four days is a tolerable combination HDC regimen, the efficacy of which warrants further investigation in adults with optimally resected chemoresponsive brain tumors.

PURPOSE Young Ashkenazi Jewish women or those from high-risk families who test positive for BRCA1 or BRCA2 mutant genes have a significant risk of developing breast or ovarian cancer by the age of 70 years. Many question whether they should have prophylactic surgical procedures, ie, bilateral mastectomy and/or oophorectomy. METHODS A Markov model was developed to determine the survival, quality of life, and cost-effectiveness of prophylactic surgical procedures. The probabilities of developing breast and ovarian cancer were based on literature review among women with the BRCA1 or BRCA2 gene and mortality rates were determined from Surveillance, Epidemiology, and End Results (SEER) data for 1973 to 1992. The costs for hospital and ambulatory care were estimated from Health Care Financing Administration (HCFA) payments in 1995, supplemented by managed care and fee-for-service data. Utility measures for quality-adjusted life-years (QALYs) were explicitly determined using the time-trade off method. Estimated risks for breast and ovarian cancer after prophylactic surgeries were obtained from the literature. RESULTS For a 30-year-old woman, according to her cancer risks, prophylactic oophorectomy improved survival by 0.4 to 2.6 years; mastectomy, by 2.8 to 3.4 years; and mastectomy and oophorectomy, by 3.3 to 6.0 years over surveillance. The QALYs saved were 0.5 for oophorectomy and 1.9 for the combined procedures in the high-risk model. Prophylactic surgeries were cost-effective compared with surveillance for years of life saved, but not for QALYs. CONCLUSION Among women who test positive for a BRCA1 or BRCA2 gene mutation, prophylactic surgery at a young age substantially improves survival, but unless genetic risk of cancer is high, provides no benefit for quality of life. Prophylactic surgery is cost-effective for years of life saved compared with other medical interventions that are deemed cost-effective.

PURPOSE Normal bone marrow cells have little or no expression of the MDR p-glycoprotein product and, therefore, are particularly susceptible to killing by MDR-sensitive drugs, such as vinca alkaloids, anthracyclines, podophyllins, and paclitaxel and its congeners. Here we report the results of a phase I clinical trial that tested the safety and efficacy of transfer of the human multiple drug resistance (MDR1, MDR) gene into hematopoietic stem cells and progenitors in bone marrow as a means of providing resistance of these cells to the toxic effects of cancer chemotherapy. PATIENTS AND METHODS Up to one third of the harvested cells of patients who were undergoing autologous bone marrow transplantation as part of a high-dose chemotherapy treatment for advanced cancer were transduced with an MDR cDNA-containing retrovirus; these transduced cells were reinfused together with unmanipulated cells after chemotherapy. RESULTS High-level MDR transduction of erythroid burst-forming unit (BFU-E) and colony-forming unit-granulocyte macrophage (CFU-GM) derived from transduced CD34+ cells was shown posttransduction and prereinfusion. However, only two of the five patients showed evidence of MDR transduction of their marrow at a low level at 10 weeks and 3 weeks, respectively, posttransplantation. The cytokine-stimulated transduced cells may be out-competed in repopulation by unmanipulated normal cells that are reinfused concomitantly. The MDR retroviral supernatant that was used was shown to be free of replication-competent retrovirus (RCR) before use, and all tests of patients' samples posttransplantation were negative for RCR. In addition, no adverse events with respect to marrow engraftment or other problems related to marrow transplantation were encountered. CONCLUSION These results indicate the feasibility and safety of bone marrow gene therapy with a potentially therapeutic gene, the MDR gene.

BACKGROUND Malignant mesothelioma is a disease that is refractory to chemotherapy. Therefore, the objective of this multi-institutional, cooperative group Phase II trial was to determine the efficacy of dihydro-5-azacytidine (DHAC), a pyrimidine analogue, in the treatment of malignant mesothelioma. METHODS Forty-one patients with histologically confirmed malignant mesothelioma received 120-hour continuous infusions of DHAC (1,500 mg/m2/day every 21 days) until maximal response, intolerable toxicity, or disease progression. RESULTS One patient had a complete response, two had objective partial responses, and four had regression of evaluable disease. The overall response rate was 17%. The one complete responder remains without disease progression at 6 years. Chest pain and nausea were the most common toxicities. Supraventricular tachycardia and pericardial effusion occurred in 20% and 15% of patients, respectively. In most patients, gastrointestinal effects were manageable. There was no significant hematologic toxicity. CONCLUSIONS In malignant mesothelioma, a disease that is refractory to chemotherapy, dihydro-5-azacytidine has definite antitumor activity. Its modest hematologic toxicity profile favors its use in combination with other agents. Caution regarding cardiac arrhythmias and pericardial effusion is necessary. Cancer 1997; 79:2237-42. © 1997 American Cancer Society.

PURPOSE To identify trends in high-dose therapy with autologous hematopoietic stem-cell support (autotransplants) for breast cancer (1989 to 1995). PATIENTS AND METHODS Analysis of patients who received autotransplants and were reported to the Autologous Blood and Marrow Transplant Registry. Between January 1, 1989 and June 30, 1995, 19,291 autotransplants were reviewed; 5,886 were for breast cancer. Main outcomes were progression-free survival (PFS) and survival. RESULTS Between 1989 and 1995, autotransplants for breast cancer increased sixfold. After 1992, breast cancer was the most common indication for autotransplant. Significant trends included increasing use for locally advanced rather than metastatic disease (P < .00001) and use of blood-derived rather than marrow-derived stem cells (P < .00001). One-hundred-day mortality decreased from 22% to 5% (P < .0001). Three-year PFS probabilities were 65% (95% confidence intervals [Cls], 59 to 71) for stage 2 disease, and 60% (95% Cl, 53 to 67) for stage 3 disease. In metastatic breast cancer, 3-year probabilities of PFS were 7% (95% Cl, 4 to 10) for women with no response to conventional dose chemotherapy; 13% (95% Cl, 9 to 17) for those with partial response; and 32% (95% Cl, 27 to 37) for those with complete response. Eleven percent of women with stage 2/3 disease and less than 1% of those with stage 4 disease participated in national cooperative group randomized trials. CONCLUSION Autotransplants increasingly are used to treat breast cancer. One-hundred-day mortality has decreased substantially. Three-year survival is better in women with earlier stage disease and in those who respond to pretransplant chemotherapy.

The use of CFU-GM and CD34+ cell enumeration for assessing harvest quality and factors affecting peripheral blood progenitor cell (PBPC) harvest and engraftment were investigated in 45 women with high-risk and metastatic breast cancer scheduled for dose-intensive cyclophosphamide, thiotepa, and carboplatin (CTCb). PBPC were mobilized with standard breast cancer regimens or cyclophosphamide (1.5 g/m2) and 5 micrograms/kg/day G-CSF and used together with G-CSF for hematopoietic support post-CTCb. There was a significant correlation between peripheral blood CD34+ cells/microliter and harvest CD34+/kg (r = 0.73, p0.0001) and between harvest CFU-GM and CD34+ cells/kg (r = 0.5, p0.0001). CFU-GM clonogenic assays were of no clinical use beyond that of CD34+ cell enumeration, with the latter allowing for real-time decisions regarding harvesting. Multiple stepwise regression identified the number of prior chemotherapy cycles as the only significant clinical predictor of CD34+ cell yield. For 34 patients proceeding to CTCb with PBPC support, multiple stepwise regression identified as the best predictors for engraftment CFU-GM and CD34+ cells/kg for neutrophils and CFU-GM, CD34+ cells/kg, and the number of prior cycles of chemotherapy for platelets, respectively. A threshold dose of 1 x 10(6) CD34+ cells/kg, obtained in 87% of these heavily pretreated breast cancer patients, was adequate to ensure engraftment within 15 days. There was no significant difference in length of hospital stay or blood product use between patients receiving 1-2.5 x 10(6) CD34+ cells/kg and greater than 2.5 x 10(6) CD34+ cells/kg, although median time to engraftment of neutrophils (9 days versus 8 days, p = 0.007) and platelets (12 days versus 9 days, p = 0.006) was significantly longer. The established threshold ofor = 1 x 10(6) CD34+ cells/kg will allow for more confident consideration of using aliquots of this threshold dose for hematopoietic support in sequential high-dose regimens inclusive of CTCb.

Telomeres, or chromosome ends, are essential in maintaining chromosomal integrity. Telomeres consist of a short hexameric sequence, 3'-TTAGGG-5', repeated in tandem arrays added to chromosomes by the ribonucleoprotein enzyme telomerase. In this study, we assessed whether penclomedine, a novel synthetic pyridine compound presently being evaluated in clinical trials for its anticancer activity, influences telomere fusions (chromosome end-to-end associations) and telomerase activity in cells in culture. We found that penclomedine reduced the mitotic index, induced chromosome end associations in all phases of the cell cycle, and rapidly induced chromatin blebbing in a concentration-dependent manner in both cervical carcinoma (HeLa) cells and in normal human fibroblasts (AG1522). However, the effectiveness of the drug was much more pronounced in HeLa cells. In addition, there was a drug-mediated, concentration-dependent decline in telomerase activity noted in the HeLa cells that correlated with a decrease in mitotic index and an increase in telomere fusions. Interestingly, when the mitotic index, chromatin blebbing, and telomere fusions were compared between the telomerase positive (HeLa) and negative (AG1522) cell types, penclomedine affected chromatin stability to a greater extent in those cells with detectable telomerase activity. In addition, telomerase positive colorectal carcinoma cells with abrogated p53 (RC-10.3 cells) were more sensitive to penclomedine than were telomerase positive cells with wild-type p53 (RKO cells). These studies suggest that penclomedine may have a therapeutic advantage in killing tumor cells that are positive for telomerase activity and defective in p53 function.

High-dose chemotherapy is increasingly utilized for the treatment of metastatic and high-risk breast cancer. Autologous Blood and Marrow Transplant Registry data reveal that a single high-dose cycle of chemotherapy with stem cell support can produce high complete response rates, with 10% to 20% of patients disease-free at 5 years. For patients with locally advanced disease, pooled results estimate 63% without relapse at 3 years for stage II and III disease and 42% for inflammatory breast cancer. New strategies to improve on these results include the incorporation of newly identified active drugs into established regimens and the use of multiple high-dose cycles. Multicycle chemotherapy produces complete response rates ranging from 35% to 93% depending on the regimen. Additional strategies include the use of monoclonal antibodies, immunotherapy, and gene therapy for post-transplant consolidation. The strongest predictor of long-term disease-free survival in virtually all studies is a complete response prior to or following high-dose chemotherapy. Randomized studies are now in the process of being completed in Europe and the United States with reporting scheduled over the next several years.

Study objective Treatment of malignant mesothelioma (MM) at an early stage results in increased survival. Cytologic examination of pleural effusions is one of the first diagnostic techniques attempted in these patients. The objective of this study was to define the role of cytologic examination of pleural fluid in facilitating early diagnosis. Design The medical records and cytologic slides of patients with pleural MM were reviewed. Setting: Medical records were reviewed from two institutions: a large general hospital and a cancer hospital. Patients Twenty-nine patients ranging in age from 32 to 81 years (mean, 59 years) met the study criteria. Interventions All patients had at least one cytologic pleural fluid examination. Measurements and results The median time from initial symptoms to the diagnosis of MM was 8 weeks for all patients. For patients with a positive or suspicious cytologic result, the median was 4 weeks, and in those with a negative cytologic result, it was 12 weeks. The overall sensitivity of cytologic examination for the diagnosis of MM was 32%. Cytogenetic analysis of pleural fluid had a sensitivity of 56%, and was positive in 1 case in which results of cytologic examination were negative. Patients in whom the time from presentation to diagnosis was greater than 1 year all had negative cytologic results followed by long periods without further workup, despite a history of exposure to asbestos. Conclusions A positive or suspicious cytologic result was associated with a decreased median time to diagnosis. Unfortunately, the sensitivity of cytologic examination for a diagnosis of MM was only 32%. Until better diagnostic techniques are developed, we recommend immediate pleural biopsy in patients in whom MM is suspected and cytologic evaluation of pleural fluid gives negative results.

PURPOSE With a median observation time of 50 months from transplant, 13 (22%) of 62 women with metastatic breast cancer treated with high-dose chemotherapy at the Dana-Farber Cancer Institute (DFCI)/Beth Israel Hospital (BIH) remain progression-free. This study determined factors prognostic for prolonged progression-free survival (PFS). METHODS From June 1988 to January 1992, women who responded to standard chemotherapy received high-dose cyclophosphamide, thiotepa, and carboplatin with autotransplantation. Data encompassing initial breast cancer diagnosis, metastatic presentation, and response to induction treatment were examined for correlations with improved PFS. RESULTS The 5-year PFS rate for the entire group is estimated to be 21% (95% confidence interval [CI], 10% to 32%). For those patients who attained a complete response (CR) to induction therapy, the 5-year PFS rate is estimated to be 31% (95% CI, 0% to 63%). In univariate analyses, a single metastatic site, CR to induction therapy, prolonged interval from primary diagnosis to first metastases, estrogen receptor (ER)-negative tumors, and older age (> or = 40 years) were associated with prolonged PFS. In multivariate analyses, single metastatic site (P = .002) and attainment of a CR to induction chemotherapy (P = .04) were the most significant predictors for PFS, with a strong trend observed for an interval from primary diagnosis to onset of metastatic disease of 24+ months (P = .066). CONCLUSION We and others have shown that 10% to 25% of women with metastatic breast cancer are progression-free after high-dose chemotherapy with autotransplantation. Those with chemosensitive disease, minimal tumor bulk, and a prolonged disease-free interval appear to benefit most. Emphasis should continue to focus on the development of more effective cytotoxic regimens and biologic approaches to increase the percentage of patients who may benefit from this approach.

PURPOSE To compare the efficacy and safety of ciprofloxacin (CIP) and trimethoprim/sulfamethoxazole (TMS) for the prevention of bacterial infections in patients who received bone marrow transplantation (BMT) for the treatment of solid and hematopoietic neoplasms. PATIENTS AND METHODS Adult inpatients about to undergo BMT for lymphoma, leukemia, or solid tumors were enrolled onto a prospective, randomized, double-blinded, controlled trial that compared CIP (750 mg orally twice per day) with TMS (160 mg trimethoprim and 800 mg sulfamethoxazole orally twice per day). Subjects were stratified before randomization according to tumor and BMT type. Prophylaxis was begun within 96 hours of initiation of the BMT preparative regimen and continued until the onset of fever, signs or symptoms of infection, serious adverse effects, or recovery of the absolute granulocyte count (AGC) to > or = to 400/microL. RESULTS Seventy-five CIP recipients and 71 TMS recipients were assessable for efficacy. No difference was noted between the two groups in occurrence of fever during neutropenia, time to onset of first fever, or overall infection rates. Ten bacteremias occurred in CIP recipients versus six in TMS recipients (P = .43). Ten episodes of Clostridium difficile enterocolitis occurred in TMS recipients versus no episodes in CIP recipients (P = .001). Four infections caused by gram-negative bacilli, including one bacteremia, occurred in TMS recipients versus none in CIP recipients (P = .06). No differences were noted in the incidence of rash or organ toxicity. TMS recipients had longer durations of granulocytopenia at AGC levels < or = to 500/microL and < or = to 100/microL than did CIP recipients (P = .08 for both comparisons). Mean peak and trough serum levels of CIP decreased significantly between weeks 1 and 2 of prophylaxis. CONCLUSION CIP and TMS were equally safe and effective in the prevention of bacterial infections in BMT patients when the overall infection rate was used as the principal end point. TMS prophylaxis was associated with a higher incidence of C difficile enterocolitis and infections caused by gram-negative bacilli, as well as a trend toward prolongation of granulocytopenia.

PURPOSE Folic acid antagonists are reported to have activity against mesothelioma. The Cancer and Leukemia Group B (CALGB) undertook this phase II study of the new antifolate, trimetrexate (TMTX), to evaluate its response rate and toxicity in chemotherapy-naive patients with malignant mesothelioma. PATIENTS AND METHODS Fifty-two patients were accrued to this protocol. Because of concerns about TMTX toxicity in patients with malignant effusions and/or hypoalbuminemia, the first 17 patients were treated at a dose of 6 mg/m2 daily for 5 days every 21 days. Because minimal toxicity was observed, the subsequent 35 patients were treated at a dose of 10 mg/m2. RESULTS Two of 17 patients (12%) in the 6-mg/m2 treatment group had a partial response (PR) and four of 34 eligible patients (12%) in the 10-mg/m2 treatment group had a PR or regression (R) of assessable disease. No patient achieved a complete response (CR). Median survival durations were 5.0 and 8.9 months in the 6- and 10-mg/m2 treatment groups, respectively, while the 2-year survival rates were identical at 18%. At the 10-mg/m2 dose, toxicity was tolerable, with one toxic death from sepsis and a 12% rate of grade 4 thrombocytopenia and granulocytopenia. CONCLUSION In this large trial, TMTX showed minor activity in the treatment of malignant mesothelioma. Myelosuppression was mild and dose-related. Future studies of higher doses of TMTX should be considered.

Sarcomas originate from bone or soft tissue. The most common bone sarcomas are osteosarcomas, Ewing sarcomas, and chondrosarcomas. Soft tissue sarcomas develop in fibrous tissue, fat, muscle, blood vessels, and nerves. Historically, soft tissue sarcomas of the trunk and extremities were reported separately from those of visceral organs (e.g., gastrointestinal and gynecologic sarcomas). This chapter discusses the classification, epidemiology, diagnosis, staging, and treatment of sarcomas of bone and cartilage, and classic soft tissue sarcomas. Management of Kaposi sarcoma, gastrointestinal stromal tumors (GISTs), mesothelioma, and rhabdomyosarcoma is also described. Figures include images of patients with osteosarcoma, liposarcoma, uterine leiomyosarcoma, GIST, and osteosarcoma in a patient with Paget disease of bone. Tables list epidemiologic features of sarcomas, a summary of sarcomas by histology, familial syndromes associated with increased risk of sarcoma, survival rates in sarcoma patients, staging of soft tissue sarcomas, and results of a meta-analysis of doxorubicin-based adjuvant chemotherapy for localized resectable soft tissue sarcoma. This chapter contains 126 references.

Sarcomas originate from bone or soft tissue. The most common bone sarcomas are osteosarcomas, Ewing sarcomas, and chondrosarcomas. Soft tissue sarcomas develop in fibrous tissue, fat, muscle, blood vessels, and nerves. Historically, soft tissue sarcomas of the trunk and extremities were reported separately from those of visceral organs (e.g., gastrointestinal and gynecologic sarcomas). This chapter discusses the classification, epidemiology, diagnosis, staging, and treatment of sarcomas of bone and cartilage, and classic soft tissue sarcomas. Management of Kaposi sarcoma, gastrointestinal stromal tumors (GISTs), mesothelioma, and rhabdomyosarcoma is also described. Figures include images of patients with osteosarcoma, liposarcoma, uterine leiomyosarcoma, GIST, and osteosarcoma in a patient with Paget disease of bone. Tables list epidemiologic features of sarcomas, a summary of sarcomas by histology, familial syndromes associated with increased risk of sarcoma, survival rates in sarcoma patients, staging of soft tissue sarcomas, and results of a meta-analysis of doxorubicin-based adjuvant chemotherapy for localized resectable soft tissue sarcoma. This chapter contains 126 references.

Escalating costs of health care delivery and the current constraints imposed by the federal budget deficit seriously threaten to compromise patient care and innovative biomedical research. Recent third-party refusal to cover some patients treated in protocols has had considerable impact on trial research. In addition, reimbursement for conventional care sometimes has been refused if delivered as part of a study (e.g., MOPP therapy versus ABVD therapy) or for an indication that is not specifically cited on the Food and Drug Administration label. Who should cover the patient care costs of patients participating in clinical trials? One approach would have patients cover these costs themselves. A second approach is the reinstitution of patient care costs into research grants. A third possibility is that the pharmaceutical industry support patient care costs of clinical research. Historically, hospital expenses of patients participating in studies have been paid by health insurance policies. In the absence of a clinical trial, many patients would be treated with Food and Drug Administration-approved therapies despite a lack of substantial benefit. Such marginal treatments are compensated by third-party payers routinely. The current system is arbitrary and expensive, compromises research and development, and equates new treatment with no treatment. By refusing to reimburse the patient care costs of investigational therapy, third-party carriers are, in fact, making medical decisions. There is a growing and legitimate concern that the pace of clinical research will be impeded significantly at a time when many exciting developments will be ready for clinical trials. The molecular steps in carcinogenesis are being documented rapidly for common malignancies, such as colon cancer. Immunologic, biologic, and hormonal approaches, and emerging technologies, such as marrow transplant or antibody toxin conjugates, already are being studied in the clinic. Health policy legislation and decisions by the insurance industry have a direct impact on physicians, facilitating, or often impeding, the care physicians are able to provide. Who makes health policy decisions? Increasingly, these decisions are being made not by physicians, but by public health experts, economists, and, more recently, large industries grappling with the cost of providing insurance coverage (and its effects on competitive pricing in a world market). Therefore, physicians need to position themselves to influence the development of medical policy, particularly as it relates to the prevention, diagnosis, and treatment of patients with cancer.

PURPOSE We studied a multimodality approach using extrapleural pneumonectomy, chemotherapy, and radiotherapy in patients with malignant pleural mesothelioma. PATIENTS AND METHODS From 1980 to 1992, 52 selected patients, underwent treatment. Median age was 53 years (range, 33 to 69). Initial patient evaluation was performed by a multimodality team. Pathologic diagnosis was reviewed and confirmed before therapy. Patients with no medical contraindication and potentially resectable mesothelioma on computed tomography (CT) (magnetic resonance imaging [MRI] when it became available) received extrapleural pneumonectomy, cyclophosphamide, doxorubicin, and cisplatin (CAP) chemotherapy, and radiotherapy. RESULTS Perioperative morbidity and mortality rates were 17% and 5.8%, respectively. The overall median survival duration is 16 months (range, 1 month to 8 years). The 32 patients with epithelial histologic variant had 1-, 2-, and 3-year survival rates of 77%, 50%, and 42%, respectively. Patients with mixed and sarcomatous cell disease had 1- and 2-year survival rates of 45% and 7.5%; no patient lived longer than 25 months (P < .01). At resection, positive regional mediastinal lymph nodes were found in 13. Positive lymph nodes were associated with poorer survival than were negative nodes (P < .01). Patients with epithelial variant and negative mediastinal lymph nodes had a survival rate of 45% at 5 years. CONCLUSION Multimodality therapy including extrapleural pneumonectomy has acceptable morbidity and mortality for selected patients. Prolonged survival occurred in patients with epithelial histologic variant and negative mediastinal lymph nodes. These data provide a rationale for a revised staging system for malignant pleural mesothelioma; furthermore, they permit stratification of patients into groups likely to benefit from aggressive multimodality treatment.

To determine the benefit of aggressive surgical therapy, we studied 77 consecutive patients presenting to our sarcoma registry with pulmonary metastases. Detailed follow-up was available on all patients; the median follow-up of the 13 long-term survivors was 72 months from the date of diagnosis of the primary tumor. Survival of these 77 patients with metastatic disease was independent of the size, location, and histology of the primary tumor. Once metastases developed, survival of patients with pulmonary metastases was not influenced by the extent of surgical resection of the primary tumor or by the use of radiation therapy. Pulmonary metastases were initially treated with thoracotomy and metastasectomy in 34 patients. The median survival after thoracotomy was 26 months. Seven patients were alive more than 4 years after their diagnosis. Pulmonary metastases were treated with chemotherapy alone in 43 patients. Although the survival was shorter (median survival 14 months) in patients treated with chemotherapy, an objective response to chemotherapy was obtained in 13 (30%) patients. Four of these patients were alive 4 years after their diagnosis. These data demonstrate that both thoracotomy and chemotherapy are associated with long-term survival of patients with sarcoma metastatic to the lung. © 1993 Wiley-Liss, Inc.

Asbestos exposure constitutes the primary cause of pleural and peritoneal mesothelioma in humans. Risk relates to the duration and intensity of exposure. Thus, those exposed at younger ages are at higher lifetime risk. Families of asbestos workers exposed to asbestos on hair and clothing as well as to asbestos items brought home from the workplace are also at risk, as are employees working in the same vicinity as asbestos workers. The public health significance of exposure from asbestos in public and private buildings remains controversial. Malignant mesothelioma is difficult to diagnose and carries a poor prognosis. Chemotherapy with single or multiple agents has thus far been disappointing, but doxorubicin and cisplatin or mitomycin and cisplatin are probably most active with response rates in measurable disease of 25%. Palliative radiotherapy is also problematic since differences between tumor cytotoxicity and pulmonary tolerance are small and radiation pneumonitis may significantly impair quality of life.

High dose chemotherapy with autologous bone marrow support (ABMT) can achieve prolonged relapse-free survival in relapsed lymphomas, leukemias, and certain solid tumors. The principal morbidity and mortality relate to the infectious complications that occur during the 3-4 week aplasia until the marrow autograft recovers. Progenitor cells can be mobilized into the peripheral blood compartment by hematopoietic growth factors, used alone or after chemotherapy. We describe four trials using cytokine-mobilized peripheral blood progenitor cells (PBPC). In the first trial, PBPC collected after GM-CSF administration were used to augment marrow. Reconstitution of trilineage marrow function occurred promptly, resulting in short hospital stays and fewer platelet transfusions. In a second study, GM-CSF/chemotherapy-mobilized PBPC were used as the sole hematopoietic support during high dose chemotherapy. Granulocyte and platelet reconstitution was rapid. Time to hematopoietic recovery, transfusion requirements, and duration of hospital stay were all significantly improved for the patients receiving PBPC compared with similar patients receiving marrow alone. While most patients experienced prompt hematopoietic recovery they showed sluggish platelet engraftment. The next two trials built on the observation that a few PBPC alone could support both granulocyte and platelet recovery and were designed to test the feasibility of sequential high-dose therapies. In one trial, PBPC given with and without marrow made it possible to deliver two sequential cycles of high-dose therapy. The second trial utilized PBPC plus cytokines to deliver four cycles of dose-intensive chemotherapy at doses that could not be given with cytokine support alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone marrow transplantation (BMT) is being increasingly used in a wide variety of diseases. During the period of re-engraftment the patient is particularly susceptible to a number of opportunistic infections which can radically affect acute morbidity and mortality. Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has been shown to mobilise haemopoietic progenitor cells for use after high-dose therapy, to enhance myeloid engraftment and stimulate mature monocytes/macrophages and neutrophils. Evidence is emerging that GM-CSF may be useful in BMT. A review of clinical trials in patients receiving BMT has revealed that the administration of rhGM-CSF significantly reduces the duration to re-engraftment, number of antibiotic treatment days, and the period of hospitalisation. Thus, rhGM-CSF appears to be a useful adjunct to BMT.

The overall median survival of women with advanced or high-risk primary breast cancer has not changed with conventional chemotherapy. Regimens employing high-dose chemotherapy with autologous stem cell support (ABMT) have been developed with the hope of optimizing tumor response and increasing survival. Early phase I studies in women with advanced refractory disease achieved high response rates of short duration. Second generation studies combined an induction phase followed by one high-dose intensification at time of maximum tumor response. The Dana-Farber Cancer Institute/Beth Israel Hospitals have developed the high-dose intensification regimen of cyclophosphamide, thiotepa, and carboplatin (CTCb) for use in women with metastatic and high-risk stage IIIB/inflammatory breast cancer. To date, approximately 19% of women with metastatic disease remain progression free using this approach, with median length of follow-up approaching 40 months. Although the median duration of follow-up for the stage IIIB women is much shorter (approximately 12 months), greater than 90% of these women are thus far disease free. With the advent of hematologic support, such as blood stem cells and colony-stimulating factors, the morbidity, mortality, and costs associated with this treatment have been substantially reduced, allowing for two or more cycles of high-dose intensification to be employed, to exploit the potential of dose-intensity to optimize response.

torical series, suggesting either patient selection or an effect of the “intermediate”-dose CBP. Importantly, fewer relapses have occurred in the high-dose arm, but survival in the two arms is similar, presumably because of the early toxic mortality of 7.4%. The Scandinavian trial compared three cycles of induction FEC followed by one high-dose cycle of CTCb with nine cycles of moderately high dose “tailored” FEC. (That is, the doses in mg/m 2 of FEC were tailored to individual tolerance up to 600 of 5-fluorouracil, 120 of epirubicin, and 1800 of cyclophosphamide per cycle.) The cumulative doses for tailored therapy that were actually delivered substantially exceeded those for the CTCb arm. Therefore, this study assesses the role of one high-dose cycle compared with nine cycles of chemotherapy intensified to individual tolerance with a higher cumulative chemotherapy dose. The study probably includes some patients with metastatic disease, since patients with involved marrow and abnormal bone scans were included (5).

PURPOSE The study was designed to determine the duration of complete response (CR) for patients with unresectable or metastatic breast cancer treated with high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) while responding to conventional-dose therapy. METHODS Eligibility criteria included histologically documented metastatic or unresectable breast cancer, at least a partial response (PR) to conventional-dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m3, and physiologic age between 18 and 55 years. Patients with inadequate renal, hepatic, pulmonary, and/or cardiac function or tumor involvement of marrow or CNS were excluded. Cyclophosphamide 6,000 mg/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 were given by continuous infusion over 4 days. After recovery, sites of prior bulk disease were to be radiated or resected if feasible. RESULTS Of 29 registered patients, one died of toxicity (3%; hemorrhage). CRs and PRs continued a median of 16 and 5 months after transplant, respectively (26 and 9 months from initiation of chemotherapy for metastatic disease). Of 10 patients transplanted in CR, four have not progressed at 17 to 31 months after transplantation (25 to 43 months after beginning standard-dose therapy). One of four patients with uptake on bone scan as their only sites of residual disease before transplant and one of three who converted from PR to CR with transplant have not progressed at 27 and 29 months, respectively, after transplant. CONCLUSIONS CTCb is an intensification regimen with a low mortality that delivers a significantly increased dose of agents with known activity at conventional doses in breast cancer. Although the duration of PR is short as expected, CRs appear to be durable.

High-dose chemotherapy with autologous bone marrow support (ABMS) achieves prolonged relapse-free survival in relapsed lymphomas and leukemias and has provided durable complete responses in certain solid tumors. The principal morbidity and mortality result from the infectious and bleeding complications during the 3–4 week aplasia until the bone marrow autograft can recover. Hematopoietic growth factors, alone or used after chemotherapy, increase the number of circulating progenitor cells in the peripheral blood compartment. In one trial, 12 patients with solid tumors were treated with high-dose chemotherapy and supported with both bone marrow and peripheral blood progenitor cells (PBPC) collected after GM-CSF administration. Reconstitution of bone marrow function occurred quickly (ANC >500/µl by day 17; platelet-transfusion independence by day 16), resulting in short hospital stays (median, 28 days). In a second study, 12 patients with metastatic breast cancer responding to induction chemotherapy (doxorubicin, 5-fluorouracil, and methotrexate) were given GM-CSF during induction to collect PBPCs during leukocyte recovery. These PBPCs were used as the sole hematopoietic support during high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin. Granulocyte and platelet reconstitution were extremely rapid (median, 14 and 12 days, respectively). When compared with 29 patients undergoing the same intensification therapy using ABMT as sole support, time to hematopoietic recovery, transfusion requirements, and duration of hospital stay were all significantly improved for the patients receiving PBPC. PBPC with or without marrow may enhance the safety, tolerance, and cost of high-dose therapy. Moreover, PBPC may render multiple course combination, high-dose therapy feasible.

Sarcomas arise primarily from mesenchymal structures at any site in the body, even within visceral stroma and neurovascular bundles. Sarcomas have been associated with prior radiation therapy, toxic exposures, and genetic conditions and soft tissue sarcomas have been distinguished from bone sarcomas. For localized soft tissue sarcoma, tumor grade is the most important prognostic variable. Low-grade tumors are generally cured by wide surgical excision, but there is a significant rate of both local recurrence and development of distant metastasis in high-grade lesions. The treatment of soft tissue sarcoma histologic subtypes is generally similar grade-for-grade, with the exception of rhabomyosarcoma, Kaposi's sarcoma, and mesothelioma. Tumor location strongly influences resectability. Radiation therapy has been used successfully in conjunction with conservative surgery to improve local control rates for soft tissue sarcomas, particularly in extremity lesions. Currently, adjuvant chemotherapy remains unproven for most adult soft tissue sarcomas, but is established in the treatment of rhabdomyosarcomas, osteosarcomas, and Ewing's sarcomas.

In this phase I study, 16 adult cancer patients were treated with concurrent 4-day continuous infusions of ifosfamide at 12 g/m2 and escalating doses of carboplatin (400-1600 mg/m2) to determine the major non-haematological dose-limiting toxicity of the combination. Mesna was given by continuous infusion over 5 days for uroprotection (total dose per course = 15 g/m2). Autologous bone marrow support, which was mandated for subsequent dose levels once granulocytes remained below 500/microliters for more than 14 days in at least 2 patients entered at a given dose level, was used at dose levels above 400 mg/m2 carboplatin. Renal toxicity became dose-limiting at the maximum tolerated dose level of 1600 mg/m2 carboplatin. Temporary creatinine elevations above 2 mg/dl (median peak 2.6 mg/dl) were observed in 3 and irreversible renal toxicity occurred in 1 (peak creatinine 6.9 mg/dl, chronic creatinine 5-6 mg/dl) of the 5 patients entered at this dose level. Severe confusion and lethargy associated with rising creatinine developed in 2 patients. Two complete and four partial responses were documented in 14 heavily pretreated evaluable patients. The complete responses continue at 14+ and 20+ months in a patient with germ cell carcinoma and Ewing's sarcoma, respectively. Carboplatin appears to contribute to the renal toxicity of ifosfamide. Nevertheless, the combination of carboplatin and ifosfamide at 80% and 75% of the single-agent maximal tolerated doses respectively produced acceptable non-haematological toxicity. Further studies in the treatment of sarcoma, germ cell, ovarian and lung carcinomas with this combination are warranted.

Twenty-six oncology patients, 25 of whom received bone marrow transplants, were enrolled in a prospective, randomized, double-blinded, placebo-controlled trial assessing the efficacy of ciprofloxacin, 750 mg p.o. b.i.d., for preventing bacterial infections during prolonged neutropenia. Treatment was begun within 48 hr of initiation of chemotherapy and continued until the absolute granulocyte count recovered to greater than or equal to 500/microliters, or until the onset of fever (greater than or equal to 38.3 degrees C). Seven evaluable subjects received ciprofloxacin, and 11 received placebo. Risk factors for infection were comparable in both groups. Fever occurred in all study subjects, but onset was delayed in ciprofloxacin recipients (median = 6 days after the fall of the absolute granulocyte count to less than or equal to 500/microliters vs. 3 days for placebo recipients, P = 0.01). No clinically or microbiologically documented infections occurred in ciprofloxacin recipients vs. 10 infections in placebo recipients (5 bacteremias, 4 skin/soft tissue infections, 1 urinary tract infection, P = 0.0003). Ciprofloxacin recipients required fewer days of therapeutic antimicrobials (median: 28 antibiotic-days vs. 49, P0.02). The bioavailability of ciprofloxacin appeared comparable to that found in previously published studies of normal volunteers and patients not receiving chemotherapy. Adverse effects and colonization by ciprofloxacin-resistant microorganisms were monitored, but the sample sizes were too small to permit meaningful conclusions about these safety parameters. Ciprofloxacin appears to be effective for preventing bacterial infections in neutropenic patients. Additional trials are needed to establish the optimal dose of ciprofloxacin and to compare its safety and efficacy with those of currently used prophylactic regimens.