Colleen Gilbert

Sequential prophylactic oral and empiric once-daily parenteral antibiotics for neutropenia and fever after high-dose chemotherapy and autologous bone marrow support.

PURPOSE We studied the effectiveness of prophylactic oral ciprofloxacin and rifampin on fever prevention in patients undergoing autologous bone marrow transplantation (ABMT) for breast cancer. Furthermore, we evaluated the toxicity and efficacy of empiric once-daily vancomycin and tobramycin for febrile neutropenia. PATIENTS AND METHODS Ninety-nine assessable women received prophylactic ciprofloxacin and rifampin after high-dose chemotherapy (HDC) for advanced or high-risk primary breast cancer supported with either bone marrow and peripheral-blood progenitor cells (PBPCs) or bone marrow purged with chemotherapy and monoclonal antibodies. Neutropenic fever was treated with empiric once-daily vancomycin and tobramycin. Patients were compared with historic controls treated with the identical HDC and bone marrow support regimen. RESULTS In patients treated with bone marrow and PBPCs, the incidence of fever during neutropenia was reduced by ciprofloxacin and rifampin from 98% to 57%. Documented infections were reduced from 42% to 13% (P < .01) and bacteremia from 18% to 0% (P < .001). In purged bone marrow recipients, the overall infection rate decreased from 74% to 17% (P < .001), and bacteremia from 29% to 7%. (P = .02). No patient developed breakthrough bacteremia or sepsis syndrome while on study. Serum creatinine level greater than 1.8 g/dL was noted in 7% of controls and 10% of study patients. Increased ototoxicity was not encountered with the higher peak concentrations of vancomycin and tobramycin. CONCLUSION The therapeutic strategy of ciprofloxacin and rifampin followed by once-daily vancomycin and tobramycin markedly reduced the incidence of infection and virtually eliminated bacteremia in both purged and nonpurged bone marrow recipients. Once-daily vancomycin and tobramycin was safe and effective and, because of the ease of use, facilitates outpatient management of ABMT patients.

Pharmacokinetic interaction between ondansetron and cyclophosphamide during high-dose chemotherapy for breast cancer

Purpose: Both ondansetron and cyclophosphamide are thought to be metabolized by hepatic microsomal processes. The purpose of this study was to evaluate the potential pharmacokinetic interactions between ondansetron and high-dose alkylating agent chemotherapy. Methods: A total of 54 breast cancer patients receiving high-dose cyclophosphamide, cisplatin and carmustine were treated prospectively in four sequential cohorts. Cohorts I and II received continuous infusions of both ondansetron and prochlorperazine, and cohorts III and IV received a continuous infusion of ondansetron alone at the same doses. All patients received lorazepam every 4 h. A group of 75 matched historical controls had received a continuous infusion of prochlorperazine with lorazepam. Pharmacokinetic monitoring of each drug used in the high-dose chemotherapy regimen was conducted. Results: Median AUCs of cyclophosphamide in patients receiving ondansetron (73.6 mg/ml · min) were lower than those of the control patients (88.3 mg/ml · min, n = 75, P = 0.0004), but the median cisplatin AUC was approximately 10% higher and no difference in the disposition of carmustine was demonstrated. Patients treated with ondansetron displayed a higher frequency of headaches than the controls. The frequency of achieving complete emetic control was greater in the ondansetron + prochlorperazine groups compared to the ondansetron alone groups and was greater in both these groups than in the prochlorperazine alone group on the first day of therapy only. Conclusion: Ondansetron altered the systemic exposure to cyclophosphamide when these agents were administered concomitantly. Ondansetron did not substantially improve overall emetic control when used alone but may improve control in combination with prochlorperazine. Future randomized studies are needed to delineate the effect of ondansetron on the disposition of the active cyclophosphamide metabolites so that clinical implications can be addressed.

Prognostic and Predictive Factors for Patients With Metastatic Breast Cancer Undergoing Aggressive Induction Therapy Followed by High-Dose Chemotherapy With Autologous Stem-Cell Support

PURPOSE We performed a retrospective review to determine predictive and prognostic factors in patients with metastatic breast cancer who received induction therapy, and, if they responded to treatment, high-dose chemotherapy. PATIENTS AND METHODS Patients with metastatic breast cancer received induction therapy with doxorubicin, fluorouracil, and methotrexate (AFM). Partial responders then received immediate high-dose chemotherapy, whereas those who achieved complete remission were randomized to immediate or delayed high-dose chemotherapy with hematopoietic stem-cell support. We performed a retrospective review of data from these patients and used Cox proportional hazards regression models for analyses. RESULTS The overall response rate for the 425 patients enrolled was 74% (95% confidence interval, 70% to 78%). Multivariate analysis of data from all 425 patients revealed that positive estrogen receptor status (P =.0041), smaller metastatic foci (</= 2 v > 2 cm) (P =. 0165), a longer disease-free interval from initial diagnosis to diagnosis of metastases (</= 2 v > 2 years) (P =.0051), and prior treatment with tamoxifen (P =.0152) were good prognostic signs for overall survival. Patients who had received prior adjuvant therapy (P =.0001) and those who developed liver metastases (P =.0001) had decreased long-term survival. In the subgroup of responders to AFM induction, multivariate analysis showed that those with visceral metastases did less well (P =.0006), as did patients who had received prior adjuvant therapy (P =.0023). However, those who had received tamoxifen therapy in the adjuvant setting did better (P =. 0143). CONCLUSION The chance for long-term remission with induction therapy with AFM and high-dose chemotherapy is increased for hormone receptor positive-patients with nonvisceral metastases who have not received prior adjuvant chemotherapy and have long disease-free intervals.

Evaluation of Symptom Distress in a Bone Marrow Transplant Outpatient Environment

OBJECTIVE: To measure patient perceptions of autologous bone marrow transplantation (ABMT)-associated symptoms in the outpatient setting, assess the efficacy of the established antiemetic protocol, evaluate patient satisfaction, and report patient medication compliance. DESIGN: A prospective, descriptive study of patients with breast cancer who were enrolled in an outpatient ABMT program. SETTING: Duke University Autologous Bone Marrow Transplantation Program. METHODS: Patient perceptions of 12 symptoms were measured by the Symptom Distress Scale (SDS) on the day of admission to the hospital, the day of discharge to the outpatient clinic, after bone marrow reinfusion, and before patient release from the clinic. The number of retching and vomiting episodes was recorded by each patient daily. Patient satisfaction was determined by a standardized personal interview conducted prior to discharge. Patient compliance was assessed by a review of patient medication documentation. RESULTS: Twenty-eight patients were enrolled over 5 months. The median SDS scores for each symptom evaluated revealed that anorexia, nausea, fatigue, insomnia, and bowel problems were the most distressing symptoms patients experienced in the outpatient ABMT program. Scores for pain, negative outlook, cough, diminished concentration, and change in appearance indicated only mild distress associated with these variables. The total number of vomiting episodes ranged from 1 to 33 total episodes per patient per outpatient stay. The percentage of patients experiencing a complete antiemetic response ranged from 24% to 48% over the 4 days after chemotherapy but steadily improved thereafter to a peak of 90% 1 week later. Patient satisfaction results showed that patients preferred being out of the hospital and reported their anxiety controlled, although most had some problems with the outpatient clinic or medications required. CONCLUSIONS: Loss of appetite, fatigue, and insomnia have been identified as symptoms that are frequently present during the course of the outpatient ABMT program. Mild, intermittent nausea persists in the outpatient setting for up to 9 days after bone marrow transplant despite continuous combination antiemetic therapy. Patient interviews confirmed the belief that patients enjoy being out of the hospital. Medication compliance is more than 90% in this structured outpatient setting.

A phase I/II study of high-dose cyclophosphamide, cisplatin, and thioTEPA followed by autologous bone marrow and granulocyte colony-stimulating factor-primed peripheral-blood progenitor cells in patients with advanced malignancies

Abstract The purpose of the present study was to determine the maximally tolerated dose of thioTEPA given with fixed high-dose cyclophosphamide (CPA) and cisplatin (cDDP) followed by autologous bone marrow (ABM) with or without granulocyte colonystimulating factor (G-CSF)-primed peripheral-blood progenitor cells (PBPCs) in patients with advanced malignancies. Patients were required to have histologically documented malignancies and adequate renal, hepatic, pulmonary, and cardiac function. CPA was given at 1,875 mg/m2 per day as a 1-h i.v. infusion for 3 consecutive days, and cDDP was given at 55 mg/m2 per day as a 24-h continuous i.v. infusion over 3 days concurrently with CPA. ThioTEPA was given once as a 1-h i.v. infusion (300–900 mg/m2) either following (the first 13 patients) or prior to CPA and cDDP. In all, 31 patients received PBPCs. A total of 46 patients were treated. There were 6 deaths among the 15 patients who did not receive PBPCs (13 received thioTEPA following CPA and cDDP). Among the other 31 patients who received PBPCs (all of whom also received thioTEPA prior to CPA and cDDP), there were 4 deaths, all involving patients with refractory ovarian carcinoma. The main toxicities were mucositis, esophagitis, hepatotoxicity, and nephrotoxicity. The median time required to achieve an absolute neutrophil count of 500 μl was 10 days (range, 9–12 days) for those who received PBPCs and 15 days (range, 15–34 days) for those who did not receive PBPCs. Altogether, 47% of the major organ toxicities (grades 3 and 4 renal, hepatic, and cardiac toxicities) occurred among the 15 patients who did not receive PBPCs, although these patients received thioTEPA at the lowest 2 dose levels. There were 3 complete responses and 22 partial responses among 35 evaluable patients (overall response rate, 71%), with the median duration of response being 3.5 months (range, 2–17 months). The maximally tolerated dose of thioTEPA was 600 mg/m2 given as a 1-h i.v. infusion on the day prior to CPA and cDDP administration. The combination of high-dose CPA, cDDP, and thioTEPA is a well-tolerated regimen when thioTEPA is given prior to CPA and cDDP and when the combination also includes PBPCs in addition to ABM. This regimen is active in a variety of malignancies.

Reduced mortality following bone marrow transplantation for breast cancer with the addition of peripheral blood progenitor cells is due to a marked reduction in veno-occlusive disease of the liver

Clinical trials involving breast cancer in the Duke University Bone Marrow Transplant Program were evaluated to assess the association between type of hematopoietic support and treatment-related morbidity/ mortality. Case histories of patients treated with high-dose chemotherapy and hematopoietic rescue on three separate protocols between 1986 and 1994 were reviewed. This included 307 patients with stage IV disease and 85 patients with high-risk (10 or more positive axillary lymph nodes) stage II or III disease. One hundred and twenty-eight of these patients were rescued with autologous bone marrow (BM) alone and 264 additionally received autologous peripheral blood progenitor cells (PBPC). The 100 day transplant-related mortality rate in those patients who received BM alone was 20.3%, with an overall mortality rate due to the high-dose chemotherapy procedure of 24.2%. The PBPC-treated group experienced a 100 day transplant-related mortality of only 6.1% and an overall transplant- related mortality of 10.2%. Sixteen of 31 deaths were attributed to veno-occlusive disease (VOD) in the group that received BM alone compared to only one VOD-related death in the PBPC group. These data demonstrate a marked improvement in transplant-related mortality which is related to the use of PBPC. This effect has been almost entirely due to a reduction in mortality from hepatic veno-occlusive disease.

High-dose combination cyclophosphamide, cisplatin, and melphalan with autologous bone marrow support - A clinical and pharmacologic study

SummaryA total of 23 patients were treated at five dose escalations with high-dose combination cyclophosphamide, cisplatin, and melphalan with autologous bone marrow support. The maximum tolerated doses of cyclophosphamide, cisplatin, and melphalan were 5,625, 180, and 80 mg/m2, respectively. The dose-limiting toxicity was cardiac toxicity. Objective tumor regression occurred in 14 of 18 evaluable cases, with a median duration of 3.5 months. Pharmacokinetic evaluation of melphalan in 20 patients revealed a dose-related increase in maximum plasma concentration (Cmax) and area under the curve (AUC). Perturbation of the melphalan plasma half-life and AUC, associated with severe toxicity, resulted when renal insufficiency occurred. The results suggest that high-dose combination cyclophosphamide, cisplatin, and melphalan produces frequent, rapid responses in breast cancer, melanoma, and sarcoma, although with significant extramedullary toxicity. The pharmacokinetics suggest that modification of the treatment schedule may result in a reduction of treatment-related toxicity.

A phase I trial of recombinant human interleukin-1β (OCT-43) following high-dose chemotherapy and autologous bone marrow transplantation

We studied the effects of escalating doses of recombinant human IL-1β in patients receiving high-dose chemotherapy and ABMT for metastatic breast cancer or malignant melanoma. Sixteen patients received IL-1β, 4 to 32 ng/kg/day administered subcutaneously for 7 days beginning 3 h after bone marrow infusion. Three patients at the highest dose level also received G-CSF following completion of IL-1β. All patients completed the 7 days of therapy. The majority of patients experienced chills and fever following one or more injections, and seven had severe pain at the injection site. There was one episode of hypotension and one episode of transient confusion at the highest dose level; other significant toxicity was not identified. Recovery of neutrophils to >0.5 × 109/l and platelet transfusion independence occurred at a median of 23 and 22 days, respectively, which was comparable to historical controls. The mean number of bone marrow colony-forming unit granulocyte–macrophage (CFU-GM) per 105 mononuclear cells on day +21 post-ABMT was more than twice that of control patients or patients receiving G-CSF or GM-CSF. A linear correlation was found between the dose of IL-1β and endogenous concentrations of several cytokines. These patients also displayed significantly higher concentrations of endogenous G-CSF compared to historical controls receiving GM-CSF. While IL-1β was moderately toxic and had no effect on recovery of peripheral blood counts after ABMT, the increased number of bone marrow CFU-GM suggests that the addition of G- or GM-CSF to a short course of IL-1β may accelerate hematologic recovery.

Effects of granulocyte‐macrophage colony stimulating factor produced in Chinese hamster ovary cells (regramostim), Escherichia coli (molgramostim) and yeast (sargramostim) on priming peripheral blood progenitor cells for use with autologous bone marrow after high‐dose chemotherapy

Abstract: Peripheral blood progenitor cells (PBPCs) were collected without prior association with chemotherapy but after the administration of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) produced in Chinese hamster ovary cells (CHO‐GM, regramostim), Escherichia coli (E. coli‐GM, molgramostim), or yeast (Yeast‐GM, sargramostim) and used in conjunction with autologous bone marrow after high‐dose chemotherapy in 69 patients with breast cancer or melanoma. The mean peripheral white blood cell (WBC) counts increased by 2.2 to 2.7‐fold after regramostim, 4.5 to 7.3‐fold after molgramostim and 4.3‐fold after sargramostim. All patients underwent three leukaphereses. The mean (& standard error) total nucleated pheresed cells per kg × 108 were 4.15 & 0.56, 15.10 & 1.77 and 7.24 & 1.00 for patients receiving regramostim, molgramostim or sargramostim respectively. The mean (& standard error) granulocyte‐macrophage colony‐forming units per kg × 104 mobilized into the PB were 8.75 & 3.63, 71.03 & 17.85, and 65.11 & 18.74 for patients receiving regramostim, molgramostim, or sargramostim respectively. The total mean (& standard error) CD34+ cells per kg × 107 collected by three leukaphereses were 3.28 & 1.62, 1.34 & 0.51 and 2.57 & 1.93, for patients receiving regramostim, molgramostim or sargramostim respectively. The use of either molgramostim‐ or sargramostim‐primed PBPCs led to complete elimination of absolute leukopenia with a WBC count under 100/mm3 in 64% and 77% of patients treated, respectively. Patients receiving molgramostim‐primed PBPCs required fewer red blood cells transfusions than patients receiving regramostim‐primed PBPCs (p = 0.0062). Our data indicate that PBPCs collected without prior association with chemotherapy but after either molgramostim or sargramostim with autologous bone marrow support and GM‐CSF shorten the hematopoietic recovery after myeloablative chemotherapy in patients with breast cancer or melanoma.

Peripheral Blood Progenitor Cell Transplantation for Breast Cancer: Pharmacoeconomic Considerations

The recent observation that mobilized peripheral blood progenitor cells (PBPCs) can be used as a source of hematopoietic support has had a major effect on the cost and morbidity associated with bone marrow transplantation in patients with breast cancer. The pharmacoeconomic impact of this new technology is especially evident when secondary costs are analyzed. We see a reduction in hospital stay, decreased use of resources such as platelet transfusions and antibiotics, and long‐term quality life‐years gained for those patients benefiting from this therapy. Experienced transplant centers have found that the direct cost of high‐dose chemotherapy using filgrastim and PBPC support is reduced as much as 50% to the patient or their insurance company. Pharmacists will play a key role in optimizing the benefits of PBPC transplantation, particularly because this therapy is moving to the outpatient arena. This article will review the pharmacoeconomic impact of PBPC transplantation primarily in terms of secondary cost measures and quality of life and discuss the limited direct cost data available and the impact of this therapy on pharmacy practice.