melphalan and Body-Weight

The action of some anti-tumour drugs on normal organ and body growth was studied in rats. The obtained results point to some correlation between the spectrum of the anti-tumour activity of the drugs and the spectrum of their organotoxicity. In some cases, the inhibition of normal growth was also influenced by the loss of appetite and the decrease of food utilization caused by the drugs.

Topics: Animals; Antineoplastic Agents; Body Weight; Chlorambucil; Melphalan; Nitrogen Mustard Compounds; Organ Size; Rats; Thiotepa; Uracil Mustard

Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability.. A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated.. Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16-23 kg; 0.95 mg/kg for >23-34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3-17.2 years (median 5.6 years).. No difference in AUC values was observed between weight strata (mean +/- SD 1248 +/- 205 micromol.min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900-1500 micromol.min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.

Topics: Adolescent; Age Factors; Antineoplastic Agents, Alkylating; Area Under Curve; Body Weight; Busulfan; Child; Child, Preschool; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Monitoring; Female; Hematologic Diseases; Humans; Infant; Infusions, Intravenous; Male; Melphalan; Models, Biological; Neoplasms; Prospective Studies; Stem Cell Transplantation

Carboplatin dosage is calculated by using the estimated glomerular filtration rate (GFR) to achieve a target plasma area under the plasma concentration-time curve (AUC). The aims of the present study were to investigate factors that influence the pharmacokinetics of carboplatin in children with high-risk neuroblastoma, and whether target exposures for carboplatin were achieved using current treatment protocols.. Data on children receiving high-dose carboplatin, etoposide and melphalan for neuroblastoma were obtained from two study sites [European International Society for Paediatric Oncology (SIOP) Neuroblastoma study, Children's Hospital at Westmead; n = 51]. A population pharmacokinetic model was built for carboplatin to evaluate various dosing formulas. The pharmacokinetics of etoposide and melphalan was also investigated. The final model was used to simulate whether target carboplatin AUC (16.4 mg ml. Allometric weight was the only significant, independent covariate for the pharmacokinetic parameters of carboplatin, etoposide and melphalan. The paediatric Newell formula and modified Calvert formula were suitable for achieving the target AUC of carboplatin for children with a GFR <100 ml min. GFR did not appear to influence the pharmacokinetics of carboplatin after adjusting pharmacokinetic parameters for weight. This model-based approach validates the use of weight-based dosing as an appropriate alternative for carboplatin in children with either mild renal impairment or normal renal function.

Topics: Age Factors; Antineoplastic Agents; Area Under Curve; Body Weight; Carboplatin; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Dosage Calculations; Etoposide; Female; Glomerular Filtration Rate; Humans; Infant; Kidney; Male; Melphalan; Models, Biological; Neuroblastoma

Limited guidance exists for dosing melphalan for autologous stem cell transplantation (ASCT) in the obese patient population, because the current literature reports conflicting clinical outcomes between obese and nonobese patients. In 2014, the American Society for Blood and Marrow Transplantation published conditioning chemotherapy dosing guidelines for obese patients and recommended dosing of melphalan using actual body weight (ABW) in the body surface area calculation. The practice at Barnes-Jewish Hospital has consistently been to dose melphalan using adjusted body weight (AdBW), with a 20% correction when a patient weighs ≥120% of his or her ideal body weight (IBW). The purpose of this study was to compare outcomes of melphalan ASCT in patients with multiple myeloma between obese (≥120% IBW) and nonobese (<120% IBW) populations. This retrospective, single-center study included adult patients with multiple myeloma undergoing first ASCT with melphalan conditioning between January 2009 and December 2012. Patient demographic data, transplantation characteristics, and clinical outcomes were collected. The primary outcome was 3-year event-free survival (EFS). Secondary outcomes included response at 100 days post-transplantation, 3-year overall survival, treatment-related mortality (TRM), time to neutrophil engraftment, and hospital length of stay (LOS). To ensure that melphalan dosage adjustment in the obese population did not impact efficacy, the primary outcome was assessed using a noninferiority design, with a predetermined noninferiority margin of 7%. Assuming a 70% 3-year EFS in the nonobese population, a noninferiority margin of 7%, a power of 80%, and an α value of .05, an analysis of 280 patients was required. A total of 270 patients, including 171 (63%) obese patients and 99 (37%) nonobese patients, met our inclusion criteria. Baseline characteristics were well matched between the 2 cohorts, including high-risk cytogenetics, disease severity at diagnosis, and use of maintenance therapy, with the only detectable differences related to weight itself. The 3-year EFS was 41% for the total cohort, with fewer events occurring in the obese cohort compared with the nonobese cohort (51% versus 40%; P = .0025). The 95% lower confidence limit established noninferiority. High-risk cytogenetics, disease severity at diagnosis, and therapy response pre- and post-ASCT were all associated with significantly shorter EFS. No between-group differences in TRM, time to

Topics: Aged; Autografts; Body Weight; Disease-Free Survival; Female; Humans; Length of Stay; Male; Melphalan; Middle Aged; Multiple Myeloma; Obesity; Retrospective Studies; Stem Cell Transplantation; Survival Rate

Isolated limb perfusion combined with melphalan is an accepted treatment for obtaining locoregional control in advanced melanoma of the extremities and other malignant neoplasias restricted to the limb. This study aims to examine the factors associated with toxicity caused by the regional method. We considered the technical aspects of severe complications associated with the procedure in an attempt to diminish the patient morbidity that occurs during the learning curve.. We conducted a retrospective analysis of the records of patients who underwent perfusion at the AC Camargo Hospital in São Paulo, Brazil between January 2000 and January 2009. The Wieberdink scale was applied to classify local toxicity and its relation to clinical and laboratory variables.. Fifty-eight perfusions were performed in 55 patients. Most patients (86.2%) presented a toxicity level between I and III. Grade V toxicity was seen in five cases (8.6%), four of which occurred in the first 2 years. Creatine phosphokinase, an important predictive factor for toxicity, had an average value of 231.8 for toxicity grades I-III and 1286.2 for toxicity grades IV-V (p = 0.001). There was a relationship between the melphalan dose and toxicity, which was 77 mg (25 to 130 mg) for toxicity grades I-II and 93.5 mg (45 to 120 mg) for toxicity grades IV-V (p = 0.0204).. It is possible to prevent the toxicity associated with melphalan by adjusting the dose according to the patient's body weight (especially for women and obese patients) and the creatine phosphokinase values in the postoperative period.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Chemotherapy, Cancer, Regional Perfusion; Creatine Kinase; Drug Dosage Calculations; Female; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Retrospective Studies; Risk Factors; Skin Neoplasms; Statistics, Nonparametric; Young Adult

Isolated limb infusion (ILI), introduced in 1992, is a technique used to deliver regional chemotherapy to treat advanced melanoma confined to a limb. Adjusting melphalan dose according to ideal body weight (IBW) has been proposed as a method of decreasing limb toxicity without compromising outcome. The current study analyzed this proposed dose adjustment.. We reviewed 99 consecutive patients with lower extremity melanomas treated by ILI at our institution between May 1998 and February 2009. Toxicity and outcomes were tested for correlation with differences between administered dose and calculated adjusted dose, both in mg and mg/L, and with differences between actual limb volume and calculated adjusted limb volume.. The median actual body weight was 71 kg, whereas the calculated median IBW was 57 kg (p < .001). Median administered melphalan dose was 7.7 mg/L. The median calculated adjusted dose was 6.5 mg/L (range 3.2-9.3 mg/L, p < .001). None of the three aforementioned parameters correlated with either Wieberdink toxicity grade or outcome. BMI did not correlate with toxicity either. Interestingly, a higher total melphalan dose did not only correlate with higher toxicity, but also with a lower response rate.. Adjusting the melphalan dose for IBW does not appear to reduce toxicity following ILI for melanoma. The effect on outcome remains uncertain. More research is needed to optimize melphalan concentrations in individual patients during ILI to limit toxicity without compromising the response.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Body Mass Index; Body Weight; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Organ Size; Retrospective Studies; Skin Neoplasms; Treatment Outcome

Melphalan is an important cytotoxic drug. The empirical practice of body surface area-based (BSA) dosing (mg/m2) of melphalan has been critically analyzed in several observations. BSA-based dosing leads to significant variability in doses administered per kilogram of body weight (mg/kg), contributes to increased oral toxicity and probably does not have any significant effect on treatment results within equally BSA (mg/m2) dosed melphalan regimens.

Topics: Animals; Antineoplastic Agents, Alkylating; Body Weight; Humans; Melphalan; Neoplasms; Stem Cell Transplantation

CD34+ cell dose calculations are usually based on actual body weight (ABW). We have shown that ideal body weight (IBW) may provide a better basis for this in a small population of patients with hematologic malignancies. This was studied further in 514 myeloma autografts. The CD34+ cell doses (10(6)/kg) by IBW and ABW were 1.37-39.36 (median 6.03) and 1.15-29.67 (median 4.84), respectively. IBW-based cell doses correlated slightly better with engraftment than ABW-based doses (higher r(2)): 0.5 x 10(9)/l neutrophils 0.83 versus 0.82, 1.0 x 10(9)/l neutrophils 0.78 versus 0.77, 20 x 10(9)/l platelets 0.54 versus 0.53 and 50 x 10(9)/l platelets 0.57 versus 0.55. When outliers (hematologic recovery in <8 or >16 days) were excluded, the findings were similar: 0.5 x 10(9)/l neutrophils 0.85 versus 0.84, 1.0 x 10(9)/l neutrophils 0.85 versus 0.84, 20 x 10(9)/l platelets 0.86 versus 0.85 and 50 x 10(9)/l platelets 0.85 versus 0.84. CD34+ cell doses based on IBW as well as ABW significantly affected engraftment when analyzed separately as continuous variables. However, when analyzed together, only the dose based on IBW retained significance. We conclude that calculation of CD34+ cell numbers for autotransplantation should be based on IBW.

Topics: Adult; Aged; Antigens, CD34; Biomarkers; Body Mass Index; Body Weight; Combined Modality Therapy; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Retrospective Studies; Transplantation, Autologous

This study aims to determine what effect correcting melphalan dosing for ideal body weight (IBW) has on toxicity and response in isolated limb infusion (ILI) in patients with advanced extremity melanoma.. This was an open observational study examining whether correcting the melphalan dose for IBW will influence response and toxicity in patients undergoing ILI for advanced extremity melanoma in 41 patients undergoing 42 procedures (13 without correction for IBW; and 29 with correction for IBW). Melphalan pharmacokinetics, limb toxicity, serologic toxicity, and response at 3 months were compared.. The corrected group had a lower estimated limb volume (V (esti)) to melphalan volume at steady state (V (ss)) (P < .0001) ratio as well as lower incidence of grade > or =3 regional toxicity, serologic toxicity, and compartment syndrome (P = .0249, P = .027, P = .02). There was a positive correlation of V (esti)/V (ss) to toxicity (P = .0127, r = .382). No significant difference in response (P = .3609) between the groups was found, although there was a trend of association between V (esti)/V (ss) and response (P = .051, r = .3383).. Correcting for IBW in ILI lowers toxicity without significantly altering response rates.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Body Weight; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms

High-dose chemotherapy and haematopoietic stem cell (HSC) transplantation is considered standard therapy in patients with chemosensitive relapsed diffuse large B cell lymphoma (DLBCL). BCNU (carmustine), etoposide, cytarabine and melphalan (BEAM) is a widely used standard DLBCL conditioning regimen. The practice of basing chemotherapy doses on body surface area (BSA) is empirical and the best biometric parameter to dose chemotherapy is unknown. Weight-based dosing has been suggested to better predict toxicity of the conditioning regimen. We correlated the dose/weight ratio with toxicity and overall outcome in a uniform cohort of 80 consecutive patients receiving HSC transplant for relapsed DLBCL at Mayo Clinic, Rochester, MN following BSA-dosed BEAM conditioning chemotherapy. Melphalan dose was used as surrogate for the entire regimen. Median age at the time of transplant was 62 (26-77) years; 65% were males. The median melphalan dose was 3.2 mg/kg (range 2.2-4.5). Patients who received >3.6 mg/kg of melphalan were more likely to have grade 3 or 4 mucositis (44.4% vs. 9.8%, P = 0.001) and prolonged hospitalization (median 13 vs. 7 d; P = 0.04). Dose/weight ratio did not correlate with cumulative incidence of relapse (P = 0.3) or survival (P = 0.8). Transplant physicians should consider limiting the dose of BEAM to the equivalent of 3.6 mg/kg of melphalan.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Carmustine; Chi-Square Distribution; Cohort Studies; Cytarabine; Drug Administration Schedule; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Length of Stay; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Middle Aged; Mucositis; Recurrence; Risk; Statistics, Nonparametric; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

The therapeutic efficacy of prophalan-L, the L-proline prodrug of melphalan that demonstrated prolidase-dependent bioactivation to melphalan, was examined in vivo in a mouse melanoma model. Prophalan-L exhibited 2- to 2.5-fold higher hydrolytic and cytotoxic activity than prophalan-D, the D-analog, in B16-F10 murine melanoma cells in vitro. Prophalan-L cytotoxicity in B16-F10 cells was lower (GI50=221 microM) than that of melphalan (GI50=173 microM). The tumor growth profiles in C57BL/6J mice injected with B16-F10 cells and treated with melphalan (5.5 microg/g i.p.) and equimolar concentrations of the prodrugs demonstrated significant difference between the control (buffered saline) and melphalan or prophalan-L but no significant difference between control and prophalan-D or between melphalan and prophalan-L. Prophalan-L was significantly less toxic than melphalan, while no significant difference was observed in toxicity, measured as percent weight loss, between the prodrugs and saline control. Tumor reduction efficacy at high doses (12 microg/g i.p.) was similar for melphalan and prophalan-L; however, fatal toxicity was associated with melphalan while prophalan-L exhibited significantly lower systemic toxicity. An excellent correlation between GI50 and tumor reduction efficacy was observed for the tested drugs (r2=0.95). Prophalan-L thus demonstrates higher therapeutic index than melphalan in the murine melanoma model.

Topics: Animals; Antineoplastic Agents, Alkylating; Body Weight; Calorimetry; Cell Proliferation; Chromatography, High Pressure Liquid; Female; Hydrolysis; Indicators and Reagents; Melanoma, Experimental; Melphalan; Mice; Mice, Inbred C57BL; Prodrugs; Proline; Spectrophotometry, Ultraviolet; Stereoisomerism; Survival Analysis

We developed a nutritional pathway for autologous stem cell transplantation (SCT) to be applied in our transplantation unit. We performed autologous SCT for 37 patients with malignant lymphoma and multiple myeloma during from April 2003 to July 2005. For 10 of them who underwent SCT since 2005,we intervened with nutritional support using our original nutritional pathway,to monitor the clinical course of SCT from the aspect of dietetics with a dietician making assessments of the individual nutrition status. From comparing the 2 groups with (n=27) or without (n=10) the nutritional pathway, oral intake at day 14 was significantly increased from 1,038 kcal to 1,440 kcal,and at discharge developed from 1,167 kcal to 1,446 kcal without statistical significance. Patients whose body weight decreased more than 5% were reduced from 52%(14/27) to 10%(1/10),and 3 days reduction of the CVC insertion period was observed after the intervention. Although the long-term clinical outcome was not fully evaluated, the efficacy of nutritional pathway for autologous SCT was suggested.

Topics: Antineoplastic Agents, Alkylating; Body Weight; Carboplatin; Critical Pathways; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Male; Melphalan; Multiple Myeloma; Parenteral Nutrition, Total; Transplantation Conditioning; Transplantation, Autologous

To analyse the pharmacokinetics of melphalan in 52 children (0.3-18 years) and determine whether any clinical factors affect the pharmacokinetic parameters Additionally, to examine whether a test melphalan dose can predict the pharmacokinetics of a full dose, when there are 5 intervening days of carboplatin therapy.. Melphalan concentrations were measured in 14 blood samples collected from each child following doses ranging from 30 to 180 mg m(-2). The pharmacokinetics were analysed with Kinetica 4.0.. Children who did not have carboplatin (n = 27) had median melphalan clearance (CL) of 15.5 l h(-1) m(-2) (interquartile range: 12.4-19.9 l h(-1) m(-2)) and steady state volume of distribution (Vss) of 14.9 l m(-2) (interquartile range: 12.7-18.3 l m(-2)). Children who had carboplatin (n = 25) had 34% lower median CL (10.2 l h(-1) m(-2)) and 18% lower median Vss (12.2 l m(-2)) (P < 0.001). Melphalan elimination was impaired in a separate group of three children given concomitant carboplatin and etoposide. Stepwise multiple linear regression indicated that weight, carboplatin, glomerular filtration rate (GFR) and total body irradiation (TBI) significantly affected CL, while weight and carboplatin influenced Vss. A test dose (10 mg m(-2)) tended to underpredict the area-under-the-concentration-vs.-time-curve for a full (180 mg m(-2)) dose in 19 individuals given carboplatin.. In children, melphalan CL is influenced by weight, carboplatin, TBI and GFR. Vss is influenced by weight and carboplatin.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Area Under Curve; Body Weight; Bone Marrow Transplantation; Carboplatin; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Interactions; Glomerular Filtration Rate; Humans; Infant; Kidney Diseases; Melphalan; Neoplasms; Time Factors; Whole-Body Irradiation

Although infants with stage 4 neuroblastoma (NB) usually have a good prognosis, metastatic relapses after 1 year of age and amplification of the N-myc oncogene are established poor prognostic factors. In order to improve the survival of patients with such high-risk factors, we performed consolidation with a busulfan (600 mg/m2)-melphalan (140 mg/m2)-containing regimen followed by autologous stem cell transplantation (SCT). From 1986 to 1998, 12 patients were treated according to this strategy. Their median age at diagnosis was 9 months (1-11). Consolidation was performed after a metastatic relapse in five children, because of persistent bone metastases in one and as first-line consolidation in six patients whose tumor exhibited N-myc amplification. The 5-year EFS rate is 64. 5% (36-85%) with a median follow-up of 92 months (20-126). One toxicity-related death occurred in a very heavily pretreated patient. Hepatic veno-occlusive disease was the major side-effect that occurred in nine of 12 children. This busulfan-melphalan combination appears to dramatically improve the prognosis of these high-risk infants with metastatic NB. Given its high toxicity, indications for this consolidation must be restricted to high-risk infants and a lower dose of busulfan (480 mg/m2) is recommended in children weighing less than 10 kg. Bone Marrow Transplantation (2000) 25, 937-942.

Topics: Antineoplastic Combined Chemotherapy Protocols; Body Weight; Brain Neoplasms; Busulfan; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Melphalan; Neuroblastoma; Prognosis; Survival Analysis; Transplantation, Autologous

Some new alkylating agents which bind to the minor groove of DNA and have sequence-specific patterns of alkylation have shown anti-neoplastic activity in pre-clinical systems. Two of them, carzelesin and tallimustine, are now in phase II. Considering the severe dose-limiting bone marrow toxicity of both these drugs in clinical use, it was of interest to investigate the mechanism of their myelotoxicity in a detailed pre-clinical study and compare it with a conventional alkylating agent, such as melphalan. The origin and progression of the myelotoxicity of carzelesin, tallimustine and melphalan were investigated comparatively in mice, combining data on bone marrow and peripheral blood cellularity with data on the proliferative activity of bone marrow cells, obtained by in vivo administration of bromodeoxyuridine. Significant differences were found between the hematopoietic response to the 3 drugs, though all caused severe leukopenia. Carzelesin induced a short-term increase in myeloid proliferative activity, which prevented the high leukocytopenia on day 3 observed with the other drugs. However, when this effect was exhausted, a second nadir was seen in peripheral blood, with a new wave of cell proliferation of all lineages in the bone marrow. Reconstruction of the lymphoid lineage was slow for all 3 drugs but particularly difficult with high-dose tallimustine. In general, the hematopoietic system response to tallimustine was dampened, with no overshoots, suggesting either lasting effects or extensive cytotoxicity from the early to late precursors of all lineages.

Topics: Animals; Antineoplastic Agents, Alkylating; Benzofurans; Body Weight; Bone Marrow Cells; Cell Cycle; Cell Division; Distamycins; Duocarmycins; Flow Cytometry; Indoles; Leukocyte Count; Male; Melphalan; Mice; Mice, Inbred Strains; Neutropenia; Nitrogen Mustard Compounds; Survival Rate; Thrombocytopenia

Our previous study revealed the appropriate conditions for the plaque- forming cell (PFC) assay in rats. Using this assay in the present study, dose-response relationships of cytotoxicity, PFC response and histology in the spleen were evaluated in rats receiving alkylating agents. Rats were given a single intravenous administration of cyclophosphamide (CY) at a dose of 3, 10 or 30 mg/kg. Spleen weights and cellularity were decreased in the rats treated with 30 mg/kg. Suppressed PFC response wes observed in the rats receiving 10 mg/kg or more. In the rats treated with CY at 1, 3 or 10 mg/kg for 7 days, spleen weights and cellularity and PFC response were reduced at doses of 3 mg/kg or more. Treatment with the other alkylating agents, however, had a different consequence. Namely, in the rats treated with nitromin once or for 7 days, spleen weights and cellularity were decreased at a dose lower than that causing a reduction in the PFC response. In the rats treated with melphalan or chlorambucil, the weights and cellularity of the spleen tended to be decreased at a dose lower than that suppressing the PFC response. Histologically, in the case of CY, the marginal zone was narrow with cellular depletion in the rates receiving 3 mg/kg, whereas little change was seen in the periarteriolar lymphoid sheath (PALS). At a dose of 10 mg/kg, the marginal zone was markedly atrophied and slight atrophy of the PALS was seen. On the other hand, in the rats treated with nitromin, a dose-related decrease in the size of the spleen was seen without changes in the tissue architecture. Melphalan caused atrophy of both the marginal zone and the PALS at a dose suppressing PFC response. Regarding the red pulp, the extramedullary hematopoiesis disappeared with melphalan and nitromin, but not with CY. These results indicate that the decreases in weights and cellularity and histological changes in the spleen caused by the alkylating agents are detectable at the dose suppressing PFC response except for CY, which has a marked immunosuppressive action. Furthermore, the observed histological findings in the spleen were characteristic of each alkylating agent.

Topics: Animals; Antineoplastic Agents, Alkylating; Body Weight; Cell Count; Cell Survival; Chlorambucil; Cyclophosphamide; Dose-Response Relationship, Drug; Hemolytic Plaque Technique; Immune System; Injections, Intravenous; Male; Mechlorethamine; Melphalan; Organ Size; Rats; Rats, Inbred F344; Sensitivity and Specificity; Spleen

The three dosimetric schedules currently used in isolated limb perfusion with melphalan for malignant melanoma of the lower limb were compared in a series of 51 patients. The doses prescribed by each of the three methods (based on total body weight (TBW), limb tissue volume (LTV) and total blood volume in the perfusion circuit (TBV)) were calculated for all patients and were then compared using Wilcoxon's signed-rank test. This revealed that the method based on TBV consistently prescribed much lower doses of drug than either of the other two methods. Pharmacokinetic profiles of melphalan obtained by HPLC analysis of blood samples during the procedure also showed that the method did not reliably predict the concentration of melphalan achieved in the perfused limb. The dosimetric schedule based on LTV prescribed slightly higher doses than that based on TBW. However, the technique is more difficult to practise due to the problems of measuring the limb volume by immersion. We conclude that the dosimetric schedule based on TBW is the most appropriate by virtue of its simplicity, the high doses of melphalan which it prescribes, and the well-controlled toxicity which it produces.

Topics: Antineoplastic Agents, Alkylating; Blood Volume; Body Weight; Chemotherapy, Cancer, Regional Perfusion; Drug Administration Schedule; Humans; Leg; Melanoma; Melphalan; Skin Neoplasms

We report the data of CD34+ cell immunoselection from peripheral blood after G-CSF-alone mobilization (10 micrograms/kg/d s.c.) in nine children with neuroblastoma (median age 4-5 years (2-8), median body weight 16 kg (10-20). Leukaphereses were carried out on a Cobe Spectra separator and two consecutive harvests (4 blood volumes processed) were used for immunoselection on a Ceprate column. The yield of CD34+ cells in the purified fraction was 50% (23-80), with a median number of 2.8 x 10(6) CD34+ cells/kg (1-9.4). All patients were reinfused with selected CD34+ cells after busulfan 600 mg/m2 +melphalan 180 mg/m2 and achieved successful haemopoietic recovery.

Topics: Antigens, CD34; Body Weight; Busulfan; Child; Child, Preschool; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Leukapheresis; Melphalan; Neuroblastoma

Regional chemotherapy allows further exploitation of the steep dose response curve of most chemotherapeutic agents, while systemic toxicity remains tolerable. We investigated the difference in maximally tolerated dose, pharmacokinetics and antitumour effect comparing administration of melphalan as a bolus in isolated liver perfusion (ILP) or via hepatic artery infusion (HAI). For these in vivo studies an experimental model for liver metastases in male WAG/Ola rats is obtained by subcapsular inoculation of CC531 rat colon carcinoma cells. In this system, ILP allowed administration of a two times higher dose than HAI (12 mg kg-1 vs 6 mg kg-1). In both treatment modalities systemic toxicity (leukopenia) was dose limiting. No hepatic toxicity was observed. Bolus administration of the maximally tolerated doses of melphalan in HAI (6 mg kg-1) and ILP (12 mg kg-1) resulted in four times higher concentrations in both liver and tumour tissue of the ILP treated rats. However, the ratio of mean drug concentration in liver vs tumour tissue appeared to be 1.5 times that found for HAI. In the range of the in tumour tissue measured melphalan concentrations the CC531 cells showed a steep dose response relationship in vitro. Whereas HAI resulted in significant tumour growth delay, complete remissions were observed in 90% of the rats treated with ILP. This study shows that with 12 mg kg-1 melphalan in ILP highly effective drug concentrations are achieved in CC531 tumour tissue; although the melphalan concentration in liver tissue shows an even higher increase than in tumour tissue, hepatic toxicity is negligible in this dose range.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Chemical Analysis; Body Weight; Cell Division; Dose-Response Relationship, Drug; Hepatic Artery; Leukocyte Count; Liver Neoplasms; Male; Melphalan; Perfusion; Rats

Topics: Antineoplastic Agents; Body Weight; Chromatography, High Pressure Liquid; Extremities; Humans; Infusion Pumps; Melphalan; Neoplasms; Regional Blood Flow

The present study was performed on rats, mainly to examine the so-called priming effect on megakaryocytopoiesis. One group of animals received 2 or 4 mg thio-TEPA or 200 mg cytosine arabinoside/kg body weight (the pretreatment) 2.5 days or 8 days prior to a dose of 10 mg thio-TEPA/kg body weight (the challenge dose). Another group received a pretreatment dose of 1 mg melphalan/kg body weight 2.5 days prior to a challenge dose of 3 mg melphalan/kg body weight. The number of bone marrow megakaryocytes, blood platelet production, mean platelet volume, blood platelet counts, leucocyte and granulocyte counts were examined on days 2, 4, 7, 10, 13, 16 and 20 after the challenge dose. The gut mucosa (number of mucosal crypts in terminal jejunum) and survival were studied in animals receiving pretreatment 2.5 days prior to a challenge dose of about LD100 for thio-TEPA and melphalan. No systematic differences were observed whether the animals received pretreatment prior to the challenge dose or not. Thus, no priming effect was observed.

Topics: Animals; Body Weight; Cytarabine; Hematopoiesis; Intestinal Mucosa; Male; Megakaryocytes; Melphalan; Rats; Rats, Inbred Lew; Species Specificity; Thiotepa; Time Factors

Since the extent of host toxicity of cytostatics is considerably affected by dosing time, a chronopharmacologic approach was undertaken for optimizing the therapeutic index of the alkylating agent, peptichemio (PTC). In 4 studies involving a total of 463 male B6D2F1 mice, a highly statistically significant circadian rhythm characterized murine tolerance for PTC (8 or 10 mg/kg/day i.v. X 3 days). Six circadian stages were explored (3, 7, 11, 15, 19 and 23 Hours After Light Onset--HALO). Day-40 survival rate varied between 20% (PTC at 3 HALO) and 55% (PTC at 15 HALO) (chi 2 = 16.7; P less than 0.01). In each study, body weight loss was maximal in mice injected with PTC at 3 HALO and minimal in those treated at 15 HALO (P less than 0.01). In a further study involving 96 male B6D2F1 mice, the toxicity of PTC on several target tissues (bone marrow, spleen, small bowel, colon, liver, kidney and lungs) was investigated by histology and leukocyte count as a function of drug dosing time. A circadian rhythm in the susceptibility of the bone marrow, the spleen and the intestinal tract was demonstrated. Optimal murine tolerance for PTC resulted from dosing it at 15 HALO, e.g. in the first half of the activity span.

Topics: Animals; Body Weight; Bone Marrow; Circadian Rhythm; Intestines; Leukocyte Count; Male; Melphalan; Mice; Mortality; Peptichemio

Current methods for cytostatic dosimetry in isolation perfusion of the limbs are based on either limb tissue volume (LTV) or body weight. None of them take into account the actual blood volume intra- and extracorporal, including even the blood leakage if any, in which the pharmacokinetics take place. The present study describes a method which allows the assessment of the actual exchangeable blood volume. The latter is calculated by a formula based on three hematocrit measurements. Thirty-one cases entered the study. Exchangeable limb blood volume representing the limb vascular bed was found to average 340 +/- 148 (SD) ml for upper limb perfusion and 768 +/- 279 and 621 +/- 454 ml for iliac and femoropopliteal perfusion, respectively. There was a good correlation between exchangeable limb blood volume and limb tissue volume (LTV, r = 0.7), a poor one with body weight (r = 0.3), and no correlation at all with body surface. Melphalan dosage was calculated per ml of blood and applied at 20 to 40 micrograms/ml. Comparison between calculated dose and concentration measured by high performance liquid chromatography showed a high correlation (r = 0.963). Since there was a correlation between exchangeable limb blood volume and LTV, it was possible to derive a conversion for melphalan dosage where 13 mg/liter corresponds to 20 micrograms/ml in upper limb perfusion and 10 mg/liter corresponds to 40 micrograms/ml in lower limb perfusion. Comparison between calculated melphalan dosage based on our method and the LTV method showed a large dispersion of values in the latter (12 to 18% coefficient of variation) while the dispersion given by the body weight-based method increased 2-fold (16 to 31% coefficient of variation). It is concluded that the present dosimetry method is the most suitable up to the present for accurate prediction of cytostatic concentration in isolation perfusion.

Topics: Blood Volume; Body Weight; Extracorporeal Circulation; Extremities; Humans; Melanoma; Melphalan; Metabolic Clearance Rate; Perfusion

The aim of this study was to investigate whether the newly synthesized bisphosphonic acid-linked N-Lost derivative BAD retains bone-seeking and cytostatic properties. The paper describes experiments on mutagenicity in vitro and on toxicity in vivo. BAD is characterized by very low mutagenic activity toward histidine auxotrophic Salmonella typhimurium strains. Cytotoxic effects were tested in rat osteosarcoma and in Walker carcinosarcoma 256B. The LD50 of i.v. injected BAD was 146 mg/kg. Acute toxicity is probably caused by calcium complexing of the bisphosphonate part of the molecule. Labeling experiments showed moderate accumulation in bone and osteosarcoma, as well as in lung metastases. BAD effected high tumor growth inhibition in osteosarcoma and Walker carcinosarcoma-bearing rats and marked prolongation of survival; histologic and radiographic examination revealed rapid calcification of osteosarcoma and lung metastases. BAD-pretreatment produced protective effects against osteolysis induced by intratibially implanted Walker carcinosarcoma ascites cells. The cytostatic efficacy of equitoxic doses of BAD in rat osteosarcoma is comparable to that of dacarbazine and in Walker carcinosarcoma to that of melphalan.

Topics: Animals; Antineoplastic Agents; Body Temperature; Body Weight; Bone and Bones; Bone Development; Bromine; Calcium; Carcinoma 256, Walker; Diphosphonates; Dose-Response Relationship, Drug; Female; Kidney; Male; Melphalan; Mice; Mice, Inbred Strains; Mutagens; Nitrogen Mustard Compounds; Osteosarcoma; Pamidronate; Radioisotopes; Rats; Rats, Inbred Strains; Salmonella typhimurium; Sex Factors; Tissue Distribution

Weight gain during adjuvant chemotherapy has been reported by several authors. Because increased body weight at diagnosis is associated with an increased risk of disease recurrence, we have assessed the prevalence of weight gain in a series of patients receiving adjuvant treatment, as well as the association of weight gain with type of treatment and risk of recurrence. We first assembled an inception cohort of 237 patients who had all undergone pretreatment evaluation and treatment at one institution, and had already been followed for at least 12 months. Body weight at the start and completion of treatment was recorded, as was type of treatment and status at last followup. Ninety-six percent of patients gained weight during treatment and none lost weight (mean increase 4.3 kg). Weight gain was strongly associated with treatment, and was least in patients receiving single agent chemotherapy, greatest in patients treated with ovarian ablation and prednisone, and intermediate in those receiving combination chemotherapy. There was no association between weight gain and disease recurrence.

Topics: Adult; Aged; Body Weight; Breast Neoplasms; Cyclophosphamide; Female; Fluorouracil; Humans; Melphalan; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Prednisone; Prognosis; Risk

The effects of melphalan were studied in rats fed raw soya flour and injected with azaserine in order to determine the suitability of this experimental model for testing drugs potentially useful for the treatment of pancreatic cancer. While melphalan did not prevent or delay the development of pancreatic cancer in these rats, the drug significantly lessened the number and size of the premalignant proliferative lesions in the pancreas. It seems that the model is useful both for testing potentially useful therapeutic agents and for analysing some of the processes involved in the development of pancreatic cancer.

Topics: Animals; Azaserine; Body Weight; Disease Models, Animal; Male; Melphalan; Nucleic Acids; Organ Size; Pancreas; Pancreatic Neoplasms; Proteins; Rats; Rats, Inbred Strains

Topics: Amino Acids, Sulfur; Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Body Weight; Diet; Drug Resistance; Glutathione; Glutathione Disulfide; Leukemia L1210; Melphalan; Mice

Topics: Aged; Body Height; Body Weight; Diagnostic Errors; gamma-Globulins; Humans; Kyphosis; Male; Melphalan; Multiple Myeloma; Proteinuria

The optimal single dosage of melphalan in isolation perfusion of the limbs for malignant melanoma was assessed. For this purpose a method to determine the volume of the isolated region in the individual patient and a grading system for the reaction of the normal tissues were introduced. A strictly standardized pharmacosurgical routine was developed that permitted an analysis of the correlation between dosage and the grade of toxic reaction in 90 perfusions. The optimal dosage of a cytostatic drug was considered to be the highest amount tolerated at an acceptable risk. Melphalan at 10 mg/l perfused tissue was determined as the likely optimum. This dose provoked remarkably little variation in toxicity, all reactions falling within a safe range. No exception to the applicability of this dosage was encountered.

Topics: Arm; Body Weight; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Drug Administration Schedule; Extremities; Humans; Leg; Melanoma; Melphalan

In mice with a transplantable mammary carcinoma, treatment with the prostaglandin-synthesis inhibitors flurbiprofen or indomethacin produced various beneficial effects. Survival time after excision of the transplanted tumour was increase, particularly when the drugs were given with the chemotherapeutic agents methrotrexate and melphalan, and there were more disease-free survivors. The combined treatment with flurbiprofen also gave less tumour recurrence at the excision site. Flurbiprofen did not seem to alter the bioavailability of the chemotherapeutic agents.

Topics: Adenocarcinoma; Animals; Biological Availability; Body Weight; Drug Therapy, Combination; Female; Flurbiprofen; Indomethacin; Male; Mammary Neoplasms, Experimental; Melphalan; Methotrexate; Mice; Neoplasm Recurrence, Local; Propionates; Prostaglandin Antagonists

Topics: Blood Sedimentation; Body Weight; Cyclophosphamide; Humans; Immunoglobulin kappa-Chains; Male; Melphalan; Middle Aged; Multiple Myeloma

Topics: Antibody Formation; Antineoplastic Agents; Body Weight; Cyclophosphamide; Cystadenocarcinoma; Endometriosis; Erythrocyte Count; Female; Humans; Leukocyte Count; Melphalan; Mesonephroma; Middle Aged; Ovarian Neoplasms; Time Factors

Topics: Animals; Autoradiography; Body Weight; Depression, Chemical; DNA, Neoplasm; In Vitro Techniques; Melphalan; Mice; Rats; Sarcoma; Sarcoma 180; Thymidine; Tritium

Topics: Adrenal Glands; Animals; Antineoplastic Agents; Body Weight; Drug Synergism; Leukocytes; Liver; Melphalan; Neoplasms, Experimental; Organ Size; Pituitary Gland; Polysaccharides, Bacterial; Rats; Sarcoma, Experimental; Serratia marcescens; Spleen; Thiotepa

Topics: Adrenal Glands; Antineoplastic Agents; Body Weight; Bone and Bones; Brain; Chlorambucil; Diaphragm; Esophagus; Gastrointestinal Tract; Growth; Heart; Humans; Kidney; Liver; Lung; Male; Mechlorethamine; Melphalan; Pharmacology; Prostate; Rats; Research; Spleen; Testis; Thiotepa; Thymus Gland; Urinary Bladder