Impact of source of sulfur on ruminal hydrogen sulfide and logic for the ruminal available sulfur for reduction concept.

Effects of organic and inorganic sources of S on intake, intake pattern, ruminal pH, VFA profile, and ruminal H2S gas concentration ([H2S]) were evaluated, which lead to development of a procedure to measure ruminal S availability for reduction [ruminal available S (RAS)] as well as compare with an estimated number [adjusted ruminal protein S (ARPS)]. Ruminally cannulated crossbred beef steers (n = 5; BW = 548 ± 46 kg) were assigned to 1 of 5 diets in a 5×5 Latin square design and fed ad libitum in five 21-d periods. Steers were fed a dry-rolled corn diet (CON), inorganic S source (ammonium sulfate; INORG), organic S source (corn gluten meal) fed at 9.8 (ORG-L) or 23% of diet DM (ORG-H), or wet distillers grains with solubles (WDGS) fed at 50% of diet DM. For the laboratory procedure, individual ingredients were incubated with ruminal fluid from heifers fed 60% corn-based diets (n = 2) and McDougall's buffer. Bottles were cooled in ice, centrifuged, and decanted, and the precipitate was analyzed for S. Steers fed INORG tended (P = 0.12) to consume 12% less DM. Total S intake was greater (P < 0.01) for steers fed WDGS (60 g/d) followed by ORG-H, and the lowest S intake was observed for CON (22 g/d). Intakes of ARPS and RAS were greater (P < 0.01) for steers fed WDGS followed by INORG, ORG-H, ORG-L, and CON diets. Steers fed WDGS and INORG diets spent 13% more time eating (P < 0.01) compared with other treatments. There was an interaction (P = 0.05) between treatment and time for ruminal [H2S]. Similar [H2S] were observed for steers fed INORG and WDGS diets (P = 0.28), which were greater (P ≤ 0.05) than other treatments. Greater ruminal [H2S] at 8 h compared with 13 h postfeeding was observed for steers fed ORG-H, ORG-L, and CON diets (P ≤ 0.04). Nearly 65% of ruminal [H2S] variation was explained (linear; P < 0.01) by RAS intake, ARPS explained 58% (linear; P < 0.01), S intake explained 29% (quadratic; P < 0.01), average ruminal pH explained 12% (linear; P < 0.01), and area below ruminal pH 5.6 explained 16% (linear, P < 0.01) of the variation. A 6% decrease in acetate (P = 0.01), 20% increase in propionate molar proportions (P = 0.02), and a lower acetate:proprionate ratio (P = 0.02) were observed for steers fed INORG compared with CON diet. The RAS concept is important for predicting ruminal [H2S] rather than just total S in the diet. Coefficients of RAS for individual ingredients can be predicted using in vitro procedures. Ruminal [H2S] may also modulate intake pattern.

Effect of corn bran and steep inclusion in finishing diets on diet digestibility, cattle performance, and nutrient mass balance.

One metabolism trial and 2 finishing trials were conducted to evaluate the effects of adding corn bran and steep liquor (steep) in replacement of dry-rolled corn (DRC) on diet digestibility, cattle performance, and nutrient mass balance in open feedlot pens. The metabolism trial (Exp. 1) used 8 ruminally cannulated heifers in a 4 × 4 Latin square design and the 2 finishing trials used 128 steer calves fed for 167 d (Exp. 2) and 256 yearling steers fed for 126 d (Exp. 3). Dietary treatments for all trials included a DRC-based control (CON), 30% corn bran (30/0), 30% corn bran plus 15% steep (30/15), and 45% corn bran plus 15% steep (45/15), in which by-products replaced DRC and molasses in the diet (DM basis). Diets were not isonitrogenous or isoenergetic. In the metabolism trial, feeding the by-product diets produced greater rumen pH (5.95) than CON (5.76; P < 0.01). Total tract DM and OM digestibility were greater for heifers fed CON than the by-product diets (P < 0.01). Dry matter and NDF ruminal disappearance (%/h) of corn bran were numerically less for cattle fed the CON diet than the by-product diets (2.36 vs. 2.84 and 0.72 vs. 1.66, respectively). In the performance trials, steers fed the by-product diets consumed more DM (P = 0.06) and G:F was either similar for all diets in Exp. 2 (P = 0.56) or less for cattle fed 30/0 than the other diets in Exp. 3 (P = 0.05). Percent N loss was reduced in Exp. 2 by including corn bran in diets compared with CON (P < 0.01). However, in Exp. 3, no differences in percent N loss were detected among treatments (P = 0.16), but more N was removed in the manure from pens where steers were fed by-products (P = 0.01). Although steep did not improve diet digestibility, it was beneficial in maintaining cattle performance in the feedlot studies. Feeding corn bran in combination with steep increased manure N removed and N in compost, but decreased percent N lost during the winter months only.

Ruminally undegradable protein content and digestibility for forages using the mobile bag in situ technique.

Four experiments were conducted to evaluate RUP content and digestibility for smooth bromegrass, subirrigated meadow, upland native range, and warm-season grasses. Samples were collected from esophageally cannulated cows or ruminally cannulated steers. Forages were ruminally incubated in in situ bags for durations of time based on 75% of total mean retention time, which was based on IVDMD and rate of passage calculations. One-half of the bags were duodenally incubated and excreted in the feces, and NDIN was analyzed on all bags for RUP calculations. Crude protein was numerically greater early in the growing cycle for grasses compared with later as grasses matured (P ≤ 0.32). The RUP was 13.3%, 13.3%, and 19.7% of CP for smooth bromegrass, subirrigated meadow, and upland native range, respectively. These values tended to be lower early in the growth cycle and increased (linear P ≤ 0.13) as forages matured for warm-season grasses and subirrigated meadows. Because both CP and RUP content change throughout the growing season, expressing RUP as a percentage of DM gives more consistent averages compared with RUP as a percentage of CP. Coefficient of variation values for RUP as a percentage of DM averaged 0.21 over all 4 experiments compared with 0.26 for RUP as a percentage of CP. Average RUP as a percentage of DM was 2.03%, 1.53%, and 1.94% for smooth bromegrass, subirrigated meadow, and upland native range, respectively. Total tract indigestible protein (TTIDP) linearly increased with maturity for subirrigated meadow samples (P < 0.01). A quadratic response (P ≤ 0.06) for TTIDP was observed in smooth bromegrass and warm-season grass samples. Digestibility of RUP varied considerably, ranging from 25% to 60%. Subirrigated meadow, native range, and smooth bromegrass samples tended to have linear decreases (P ≤ 0.11) in RUP digestibility throughout the growing season. The amount of digested RUP was fairly consistent across experiments and averages for smooth bromegrass, subirrigated meadow, and upland native range were 0.92%, 0.64%, and 0.49% of DM, respectively. Warm-season grasses in Exp. 2 had greater RUP (4.31% of DM) and amount of RUP digested (2.26% of DM), possibly because of cattle selecting for leadplant that contains more CP than the grasses. Forages can vary in CP, RUP, TTIDP, and RUP digestibility depending on the forage type, year, and time within year, but RUP digestibility is likely less than what previous sources have reported.

Effect of feeding combinations of wet distillers grains and wet corn gluten feed to feedlot cattle.

Three experiments were conducted to evaluate the use of combinations of wet corn gluten feed (WCGF) and wet distillers grain plus solubles (WDGS) in dry-rolled and high-moisture corn-based finishing diets for beef cattle. In Exp. 1, 250 steers (BW = 343 +/- 13.5 kg) were fed 5 treatments consisting of a corn-based, control diet with 0% coproducts, and diets including 30% WCGF, 30% WDGS, 15% WCGF plus 15% WDGS, or 30% WCGF plus 30% WDGS. No associative effects resulted from feeding 15% WCGF plus 15% WDGS; DMI, ADG, and G:F were intermediate between steers fed WCGF or WDGS at 30% of diet DM. Feeding coproducts in combinations at 30 and 60% of diet DM increased ADG, G:F, and final BW (P < 0.05) compared with the corn-based diet. In Exp. 2, 280 yearling steers (BW = 370 +/- 0.45 kg) were used to evaluate feeding 0, 25, 50, or 75% coproducts as a combination of 50% WCGF:50% WDGS (DM basis). Additional diets were fed containing decreased alfalfa hay at 5, 2.5, and 0% (DM basis) as coproduct blend inclusions increased at 25, 50, and 75% (DM basis), respectively. No interactions were observed between alfalfa hay and coproduct blend levels, and no effects on ADG or G:F (P > 0.21) were observed due to alfalfa hay. Intake, ADG, and G:F responded quadratically (P < 0.05) across coproduct levels, with the greatest ADG and G:F at 25 and 50% blend, and similar ADG and G:F for the 0 and 75% blend levels. In Exp. 3, 504 steers (BW = 376 +/- 16 kg) were fed to evaluate 0, 10, 15, 20, 25, and 30% (DM basis) WDGS in diets containing 30% WCGF (DM basis) as well as a control diet with no coproducts. The inclusion of 30% WCGF in the diets increased DMI, ADG, and G:F (P < 0.05) when compared with control. Response to inclusion level of WDGS tended to be quadratic for DMI (P = 0.12), quadratic for ADG (P = 0.05), and no effect for G:F (P = 0.96). Greatest ADG was achieved with 15 to 20% WDGS inclusion in diets containing 30% WCGF. The use of combinations of WCGF and WDGS in finishing diets resulted in similar or improved steer performance compared with corn, suggesting replacement of corn with coproduct combinations up to 75% diet DM is possible if a roughage source is fed.

Effect of corn processing method and corn wet distillers grains plus solubles inclusion level in finishing steers.

Two experiments were conducted to determine the effect of corn processing method and corn wet distillers grains plus solubles (WDGS) level on steer performance and metabolism. In Exp. 1, 480 crossbred steer calves (314 +/- 18 kg of BW) were used in a finishing experiment with a randomized complete block design and a 3 x 4 treatment structure. Diets were based on dry-rolled (DRC), high-moisture (HMC), or steam-flaked corn (SFC) with increasing levels of WDGS (0, 15, 27.5, or 40%; DM basis). A corn processing x WDGS level interaction (P < 0.01) was observed for ADG and G:F. Average daily gain and G:F increased linearly (P < 0.01) in steers fed DRC; ADG increased quadratically (P = 0.04) and G:F increased linearly (P = 0.02) in steers fed HMC; and ADG decreased quadratically (P = 0.02) with no change in G:F (P = 0.52) in steers fed SFC as WDGS increased. In Exp. 2, 7 ruminally fistulated steers (440 +/- 41 kg of BW) were used in a 6-period crossover design with 3 x 2 factorial treatment structure. Diets were the same as those fed in Exp. 1, except they contained only 2 levels of WDGS (0 or 40% of diet DM). Total tract starch digestibility was greater (P < 0.01) for steers fed SFC than for steers fed DRC or HMC. Minimum ruminal pH was less (P < 0.01) for steers fed SFC than for steers fed HMC or DRC. Variance of ruminal pH was different among all 3 processing methods with DRC < HMC < SFC (P < 0.10). In situ 22-h DM digestibility of DRC and HMC and starch digestibility of DRC were greater (P < 0.10) in steers fed DRC compared with steers fed HMC or SFC. Steers fed 0% WDGS had less (P < or = 0.02) intake of DM, OM, NDF, and ether extract compared with steers fed 40% WDGS. Total tract digestibility of DM and OM was greater (P < or = 0.08) and digestibility of ether extract tended (P = 0.11) to be less for steers fed 0% WDGS compared with steers fed 40% WDGS. Maximum ruminal pH and pH variance were greater (P < or = 0.08) in steers fed 0% WDGS. A corn processing x WDGS level interaction (P = 0.09) was observed for ruminal acetate to propionate ratio (A:P). Within diets containing 0% WDGS, A:P in steers fed SFC was less (P < or = 0.08). In diets containing 40% WDGS, A:P was similar between processing methods and not different from the SFC with 0% WDGS. The corn processing x WDGS level interaction observed in the finishing experiment may be due to the decreased ruminal A:P in DRC and HMC diets with 40% WDGS.

Economic evaluation of filgrastim, sargramostim, and sequential sargramostim and filgrastim after myelosuppressive chemotherapy.

Filgrastim alone and sequential sargramostim and filgrastim have been shown to be more effective than sargramostim alone in the mobilization of CD34(+) cells after myelosuppressive chemotherapy (MC). We sought to compare costs and resource use associated with these regimens. Data were collected prospectively alongside a multicenter, randomized trial of filgrastim, sargramostim, and sequential sargramostim and filgrastim. Direct medical costs were calculated for inpatient and outpatient visits and procedures, including administration of growth factors and MC. We followed 156 patients for 30 days or until initiation of high-dose chemotherapy. The main outcome measures were resource use and costs of inpatient and outpatient visits, platelet and red blood cell transfusions, antibiotic use, and apheresis procedures. Hospital admissions, red blood cell transfusions, and use of i.v. antibiotics were significantly more common in the sargramostim group than in the other treatment arms. In univariate and multivariable analyses, total costs were higher for patients receiving sargramostim alone than for patients in the other groups. Mean costs in multivariable analysis for the filgrastim and sequential sargramostim and filgrastim arms were not significantly different. Filgrastim alone and sequential sargramostim and filgrastim are less costly than sargramostim alone after MC, as well as therapeutically more beneficial.

Autologous stem cell transplantation for non-Hodgkin's lymphoma: comparison of radiation-based and chemotherapy-only preparative regimens.

The aim of this study was to compare toxicity and efficacy of total body irradiation (TBI), cyclophosphamide (CY) and etoposide (E) (TBI/CY/E) vs busulfan, melphalan and thiotepa (Bu/Mel/T) in patients receiving autologous stem cell infusion (ASCI) for malignant lymphoma (NHL). Between September 1990 and July 1998, 351 patients with NHL were treated with TBI/CY/E (n = 221) or Bu/Mel/T (n = 130) followed by ASCI. Patients in first, or second remission, first responding or untreated relapse were defined as having less advanced disease before transplantation. The median follow-up was 5 years (range 1-9) and 3.5 years (1-6) for patients receiving TBI/CY/E and Bu/Mel/T, respectively. The cumulative probabilities of survival, event-free survival (EFS) and relapse at 5 years were 44%, 32%, 49% following TBI/CY/E and 42%, 34% and 42% following Bu/Mel/T. The probability of EFS at 5 years for patients who had prior dose-limiting radiation (n = 59) was 32% after Bu/Mel/T therapy. Transplant-related mortality was 16% for TBI/CY/E and 21% for Bu/Mel/T. In univariate and multivariate analyses, more advanced disease status was associated with poor outcome (TBI/CY/E: RR 0.70, CI 0.50 to 0.97 P = 0.04; Bu/Mel/T: RR 0.61, CI 0.39 to 0.97 P = 0.03). No significant differences in toxicities and outcomes were observed between these two regimens despite the inclusion of patients who had received dose-limiting irradiation in the Bu/Mel/T regimen.

Mobilization of peripheral blood stem cells following myelosuppressive chemotherapy: a randomized comparison of filgrastim, sargramostim, or sequential sargramostim and filgrastim.

Myelosuppressive chemotherapy is frequently used for mobilization of autologous CD34(+) progenitor cells into the peripheral blood for subsequent collection and support of high-dose chemotherapy. The administration of myelosuppressive chemotherapy is typically followed by a myeloid growth factor and is associated with variable CD34 cell yields and morbidity. The two most commonly used myeloid growth factors for facilitation of CD34 cell harvests are granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We performed a randomized phase III clinical trial comparing G-CSF, GM-CSF, and sequential administration of GM-CSF and G-CSF following administration of myelosuppressive chemotherapy. We evaluated CD34 yields, morbidity, and cost-effectiveness of the three cytokine schedules. One hundred and fifty-six patients with multiple myeloma, breast cancer, or lymphoma received cyclophosphamide with either paclitaxel or etoposide and were randomized to receive G-CSF 6 microg/kg/day s.c., GM-CSF 250 microg/m(2)/day s.c., or GM-CSF for 6 days followed by G-CSF until completion of the stem cell harvest. Compared with patients who received GM-CSF, patients who received G-CSF had faster recovery of absolute neutrophil count to 0.5 x 10(9) per liter (median of 11 vs14 days, P = 0.0001) with fewer patients requiring red blood cell transfusions (P= 0.008); fewer patients with fever (18% vs 52%, P = 0.001); fewer hospital admissions (20% vs 42%, P = 0.13); and less intravenous antibiotic therapy (24% vs 59%, P = 0.001). Patients who received G-CSF also yielded more CD34 cells (median 7.1 vs 2.0 x 10(6) kg per apheresis, P = 0.0001) and a higher percentage achieved 2.5 x 10(6) CD34 cells per kilogram (94% vs 78%, P = 0.21) and 5 x 10(6) CD34 cells per kilogram (88% vs 53%, P = 0.01) or more CD34 cells per kilogram with fewer aphereses (median 2 vs 3, P = 0.002) and fewer days of growth factor treatment (median 12 vs 14, P = 0.0001). There were no significant differences in outcomes between groups receiving G-CSF alone and the sequential regimen. After high-dose chemotherapy, patients who had peripheral blood stem cells mobilized with G-CSF or the sequential regimen received higher numbers of CD34 cells and had faster platelet recovery with fewer patients requiring platelet transfusions than patients receiving peripheral blood stem cells mobilized by GM-CSF. In summary, G-CSF alone is superior to GM-CSF alone for the mobilization of CD34(+) cells and reduction of toxicities following myelosuppressive chemotherapy. An economic analysis evaluating the cost-effectiveness of these three effective schedules is ongoing at the time of this writing.

Randomized trial of filgrastim, sargramostim, or sequential sargramostim and filgrastim after myelosuppressive chemotherapy for the harvesting of peripheral-blood stem cells.

PURPOSE: The purpose of this study was to compare the effects of filgrastim, sargramostim, or sequential sargramostim and filgrastim on CD34(+) cell yields and morbidity after myelosuppressive mobilization chemotherapy (MC). PATIENTS AND METHODS: One hundred fifty-six patients were randomized to receive filgrastim (n = 51), sargramostim (n = 52), or sargramostim for 5 days followed by filgrastim (n = 53) after MC with either cyclophosphamide and etoposide (n = 75) or paclitaxel and cyclophosphamide (n = 81). RESULTS: Compared with those who received sargramostim, patients who received filgrastim had faster recovery of an absolute neutrophil count of 0.5 x 10(9)/L or greater (a median of 11 v 14 days; P =. 0001), with fewer patients requiring RBC transfusions (P =.008), fewer patients with fever (18% v 52%; P = 0.001), fewer hospital admissions (20% v 42%; P =.013), and less intravenous antibiotic therapy (24% v 69%; P =.001). Patients who received filgrastim yielded more CD34(+) cells (median, 7.1 v 2.0 x 10(6)/kg/apheresis; P =.0001), and a higher fraction achieved 2.5 x 10(6) (94% v 78%; P =.021) and 5 x 10(6) (88% v 53%; P =.001) or more CD34(+) cells/kg with fewer aphereses (median, 2 v 3; P =.002) and fewer days of growth-factor treatment (median, 12 v 14; P =.0001). There were no major differences in outcomes between the filgrastim alone and the sequential regimens. After high-dose chemotherapy, patients who had peripheral-blood stem cells (PBSCs) mobilized with filgrastim or the sequential regimen received higher numbers of CD34(+) cells and had faster platelet recovery (P =.015), with fewer patients (P =.014) receiving fewer platelet transfusions (P =.001) than patients receiving sargramostim-mobilized PBSCs. CONCLUSION: It was concluded that filgrastim alone or sequential sargramostim and filgrastim were superior to sargramostim alone for the mobilization of CD34(+) cells and reduction of toxicities after MC.

Peripheral blood stem cell mobilization for high-dose chemotherapy.

Several studies have clearly documented a more rapid hematopoietic recovery with growth factor-mobilized PBSC than with bone marrow. Time to engraftment for neutrophils and platelets average 8-12 days in contrast to 2-4 weeks after bone marrow. This rapid hematopoietic recovery with PBSC has decreased the duration of hospitalization, transfusion requirements, and costs. Although growth factors alone may mobilize enough PBSC for high-dose chemotherapy, administration of growth factor after submyeloablative chemotherapy increases the yield of CD34+ cells. Based on the current data, CD34+ cell content of PBSC appears to be the single most powerful predictor of hematopoietic recovery. Infusion of > or =5 x 10(6) CD34+ cells/kg is associated with a rapid engraftment of neutrophils and platelets, although successful engraftment has also been reported with infusion of 2.5-5 x 10(6) CD34+ cells/kg. Age, prior radiotherapy, marrow involvement, and prior chemotherapy regimens are important factors influencing the yield of stem cells. Therefore, using these pa-rameters, we may identify the patients who will fail to mobilize sufficient numbers of PBSC before collection and use new strategies for stem cell mobilization. Because of the ease of collection and rapid engraftment after myeloablative therapy, PBSC have replaced bone marrow for autologous transplantation and may supplant bone marrow for allogeneic transplantation in the near future.

Mobilization of peripheral blood stem cells with docetaxel and cyclophosphamide (CY) in patients with metastatic breast cancer: a randomized trial of 3 vs 4 g/m2 of CY.

The purpose of this study was to develop a regimen of docetaxel, cyclophosphamide (CY) and filgrastim for mobilization of peripheral blood stem cells (PBSC) in patients with metastatic breast cancer (n = 66). A phase I trial of CY 2, 3 or 4 g/m2 with docetaxel 100 mg/m2, in consecutive cohorts of four patients each, did not reveal any dose-limiting toxicities and subsequent patients were randomized to receive 3 or 4 g/m2 of CY. The median yield of CD34+ cells from all patients was 11.06x10(6)/kg (range, 0.03-84.77) from a median of two aphereses (range, 1-7); 6.52x10(6) CD34+ cells/kg/apheresis (range, 0.01-52.07). Target CD34+ cell doses > or =2.5 and > or =5.0x10(6)/kg were achieved in 89% and 79%, respectively. There were no statistically significant differences in CD34+ cell yields or target CD34+ cell doses achieved following 3 or 4 g/m2 of CY. Patients with only one prior chemotherapy regimen yielded a median of 12.82x10(6) CD34+ cells/kg/apheresis compared to 5.85 for those receiving > or =2 regimens (P = 0.03). It was concluded that the combination of docetaxel, 100 mg/m2, CY 3 g/m2 without mesna could be administered with acceptable toxicity with collection of adequate quantities of PBSC from the majority of patients.

Adjuvant dose-intense chemotherapy with peripheral blood stem cell support in stage II-III breast cancer with five to nine involved axillary lymph nodes.

The purpose of this study is to determine outcomes for patients with high-risk nonmetastatic breast cancer undergoing high-dose chemotherapy with peripheral blood stem cell support. Forty-three patients with stage II-III disease, five to nine positive axillary lymph nodes, and a median age of 44 years (range, 27-60 years) were enrolled in a study that included: 1) standard dose doxorubicin, 5-fluorouracil, and methotrexate adjuvant therapy; 2) cyclophosphamide, etoposide, filgrastim, and peripheral blood stem cell harvest; and 3) high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) followed by peripheral blood stem cell infusion. All 43 patients received doxorubicin, 5-fluorouracil, and methotrexate, 42 (98%) received etoposide, and 41 (95%) received CTCb. Thirty-two patients (74%) are alive, 28 (65%) without relapse at a median of 55 months (range, 41-87 months). Two died (5%) of treatment-related causes, (subclavian catheter complication after etoposide and late radiation pneumonitis), and nine other deaths (21%) were associated with recurrent breast cancer. The probabilities of overall and event-free survival at 4 years were 0.77 and 0.67, respectively, compared with 0.82 and 0.69, respectively, for 72 similar patients with 10 or more positive axillary nodes receiving the same sequence of therapy. Thus, patients with five to nine positive axillary lymph nodes have a similar risk of failure after high-dose chemotherapy and peripheral blood stem cell support as patients with 10 or more positive axillary lymph nodes.

Single-agent paclitaxel in patients with metastatic breast cancer receiving high-dose chemotherapy with peripheral blood stem cell support.

The purpose of this trial was to determine the effects of paclitaxel in patients with newly diagnosed metastatic breast cancer scheduled to receive high-dose chemotherapy with peripheral blood stem cell support. Eighty-four patients received anthracycline-based induction and two doses of paclitaxel at 170 mg/m2 (n = 52) or 250 mg/m2 (n = 32). Eighty-two (98%) received cyclophosphamide and etoposide (n = 50) or paclitaxel and cyclophosphamide (n = 32) with granulocyte colony-stimulating factor for mobilization of peripheral blood stem cells, and 79 (94%) received cyclophosphamide, thiotepa, and carboplatin with peripheral blood stem cell support. One patient (1%) died of infection and 56 (67%) died of progressive disease. For patients with measurable disease, the complete response rate was 21% after induction and 29% after paclitaxel (p = 0.54). Results were compared with those of 125 patients who received the same sequence of therapy without paclitaxel. The complete response rate after high-dose chemotherapy was 54% for patients receiving paclitaxel and 62% for those not receiving paclitaxel (p = 0.60). The probabilities of overall survival and event-free survival at 3 years for patients receiving paclitaxel were 46% and 24%, respectively, compared with 54% and 22%, respectively, for patients not receiving paclitaxel (p = 0.62). Further trials evaluating this dose and schedule of paclitaxel in patients with metastatic breast cancer receiving high-dose chemotherapy are not warranted.

High-dose busulfan, melphalan and thiotepa followed by autologous peripheral blood stem cell (PBSC) rescue in patients with advanced stage III/IV ovarian cancer.

The purpose of this study was to evaluate the efficacy of high-dose chemotherapy (HDC) with busulfan, melphalan and thiotepa (BUMELTT) followed by autologous PBSC infusion in treating patients with advanced ovarian cancer. Thirty-one patients, 18 with stage III/IIIc and 13 with stage IV ovarian cancer, were treated with BU (12 mg/kg), MEL (100 mg/m2) and TT (500 mg/m2) and autologous PBSC rescue. Fifteen patients were in clinical complete remission (CR) at treatment; 11 had platinum-sensitive disease. Sixteen patients were not in CR; two had platinum-sensitive disease. The probabilities of overall survival (OS), event-free survival (EFS) and relapse (R) for all patients at 18 months were 0.57, 0.30 and 0.63; for patients in CR, the rates were 0.87, 0.44 and 0.49 and for patients not in CR, 0.38, 0.13 and 0.81. Two patients (6.5%) died of treatment-related causes. Among the 13 patients with platinum-sensitive disease, all are still alive, with seven having relapsed 129-1021 days after PBSC infusion. OS, EFS and R were 1.00, 0.52 and 0.48. Of the 18 patients with platinum-resistant disease, four remain alive (two in remission). Six patients did not respond and eight relapsed from days 104-429. The OS, EFS and R were 0.33, 0.11 and 0.78. We conclude that BUMELTT is well tolerated in patients with advanced ovarian cancer and results are equivalent to other published HDC regimens.

A randomized trial of once vs twice daily administration of intravenous granisetron with dexamethosone in patients receiving high-dose cyclophosphamide, thiotepa and carboplatin.

The purpose of this study was to determine the optimal schedule of i.v. granisetron and dexamethosone for control of nausea and emesis in patients receiving high-dose chemotherapy (HDC). Seventy patients with breast cancer received high-dose cyclophosphamide, thiotepa and carboplatin (CTCb) for 3 consecutive days. All 70 received dexamethasone 12 mg i.v. and granisetron 1 mg i.v. prior to infusion of CTCb and were randomized to receive placebo (n = 37) or an additional identical dose of granisetron (n = 33) 12 h later. Beginning on day 2 of chemotherapy administration, 55 patients evaluable later self-administered a cocktail of diphenhydramine (benadryl), lorazepam (ativan) and dexamethasone (BAD). Fourteen of 37 patients (38%) receiving granisetron once a day and 15/33 (44%) receiving it twice a day had a complete response during the first 24 h following the first doses of chemotherapy (P = 0.52). In the 55 evaluable patients receiving BAD, 18 of 29 (62%) in the once daily group and 14/26 (54%) in the twice daily group required additional medications (P = 0.54). The median time to first emetic episode was 20 h (range 6.6-79.5) for patients receiving once a day and 21.4 hours (range 5.8-105.3) for patients receiving twice a day granisetron (P = 0.48). Five patients in the once daily and seven patients in the twice daily group had complete control of nausea and emesis throughout the study period (P = 0.37). It was concluded that there were no statistically significant differences in nausea and emetic control between dexamethasone with once daily or twice daily i.v. granisetron administration in patients receiving high-dose CTCb.

Sequential treatment including high-dose chemotherapy with peripheral blood stem cell support in patients with high-risk stage II-III breast cancer: outpatient administration in community cancer centers.

The authors determined outcomes for patients with localized high-risk breast cancer undergoing sequential outpatient treatment with conventional-dose adjuvant therapy, chemotherapy, and growth factor mobilization of peripheral blood stem cells (PBSC) and high-dose chemotherapy (HDC) with PBSC support in community cancer centers. Ninety-six patients with stage II-IIIB noninflammatory breast cancer with 10 or more positive lymph nodes and a median age of 46 years (range, 22-60 years) were treated with: 1) doxorubicin, 5-fluorouracil, and methotrexate (AFM), four courses at 2-week intervals; 2) cyclophosphamide (4 g/m2) and etoposide (600 mg/m2) (CE), followed by filgrastim (6 microg/kg per day) and PBSC harvest; and 3) cyclophosphamide (6 g/m2), thiotepa (500 mg/m2), and carboplatin (800 mg/m2) (CTCb), followed by PBSC infusion. All 96 patients received AFM, 95 (99%) received CE, and 95 (99%) received CTCb with a median hospital stay of 12 days (5-34 days) for all phases of treatment. Sixty-nine patients (72%) are alive, 55 (57%) without relapse at a median follow-up of 53 months (range, 37-77 months). One patient (1%) died of acute myeloid leukemia and all other deaths were associated with recurrent breast cancer. The probabilities of event-free survival (EFS) at 4 years for patients with or without locally advanced disease were 0.37 and 0.69, respectively (p = 0.004), and 0.71 and 0.48 for patients who were estrogen/progesterone receptor (ER/PR) positive or ER/PR negative, respectively (p = 0.016). In multivariate analyses, locally advanced disease (relative risk, 2.3; p = 0.021) and ER/PR-negative hormone receptor status (relative risk, 2.2; p = 0.014) were the only adverse risk factors for EFS identified. Patients with zero, one, or two of these adverse risk factors had 4-year EFS of 0.80, 0.56, and 0.33, respectively. The sequential administration of AFM, CE, and CTCb followed by PBSC in an outpatient community setting was well tolerated in patients with high-risk stage II-III breast cancer. More intensive or more novel treatment strategies will be required to decrease relapses in patients who have ER/PR-negative tumors and/or have locally advanced disease.

Intravenous immunoglobulin and the risk of hepatic veno-occlusive disease after bone marrow transplantation.

Recent reports using historical controls or registry cohorts suggest, respectively, either an increase in the mortality or a decrease in the incidence of hepatic veno-occlusive disease (VOD) with the administration of intravenous immunoglobulin (i.v.Ig) after bone marrow transplantation. These divergent results prompted us to conduct a retrospective analysis of two randomized clinical trials conducted at our center to determine the effect of i.v.Ig infusions on the development and severity of VOD. Patients were randomized to receive (n=318) or not to receive (n=315) i.v.Ig prophylaxis after human leukocyte antigen-identical sibling (n=414), mismatched or unrelated (n=178), or autologous or syngeneic (n=41) marrow transplantation. To determine the relationship of i.v.Ig to the development and severity of VOD, a single observer reviewed data displays created for each patient for grading VOD without knowledge of patient i.v.Ig use. In this analysis, VOD was defined as hyperbilirubinemia > or =2.0 mg/dL before day 20 and abrupt weight gain > or =2% before day 14 posttransplant in the absence of other causes of liver disease. Hepatic VOD developed in 235 (37%) of the 633 randomized patients. No evidence for VOD was found in 230 (36%) patients. The remaining 168 (27%) patients were classified as having liver disease of uncertain etiology. Hepatic VOD was judged to be severe in 63 (10%) and mild or moderate in 172 (27%) patients. The number of patients developing any VOD or severe VOD was similar between those randomized to i.v.Ig prophylaxis and untreated controls (115 vs. 120 and 32 vs. 31, respectively). Logistic regression models identified several covariates as significant (p < 0.01) factors associated with the development of severe VOD. Increased risk occurred with elevated pretransplant serum aspartate aminotransferase (odds ratio [OR] = 2.64) and earlier year of transplant (OR = 3.73); decreased risk occurred with autologous or twin donors (OR = 0.09) and acute myeloid leukemia (OR = 0.39). The development of any VOD was associated with an elevated pretransplant alkaline phosphatase (OR = 4.1), pretransplant use of vancomycin (OR = 1.6) or amphotericin (OR = 3.0), posttransplant use of cyclosporine (OR = 2.5), older patient age (OR = 1.03), and obesity (OR = 0.78). We concluded from the controlled trials of 633 patients that the administration of i.v.Ig did not influence the development or severity of VOD after bone marrow transplantation.