Association of High-Dose Cyclophosphamide, Cisplatin, And

Home , Carmustine, Cisplatin, Pulmonary toxicity

698 Vol. 8, 698–705, March 2002 Clinical Cancer Research

Association of High-dose Cyclophosphamide, Cisplatin, and Carmustine Pharmacokinetics with Survival, Toxicity, and Dosing Weight in Patients with Primary Breast Cancer1

William P. Petros,2,3 Gloria Broadwater, sition was not found to be different in those developing -Kaplan-Meier anal .(0.96 ؍ P ;25 ؍ Donald Berry,4 Roy B. Jones,5 pulmonary toxicity (n James J. Vredenburgh, Colleen J. Gilbert, ysis (median follow-up of 5.9 years) demonstrated that patients with lower cyclophosphamide AUC (faster parent John P. Gibbs, O. Michael Colvin, and drug clearance to potentially cytotoxic compounds) survived 6 .(0.031 ؍ William P. Peters longer (P Bone Marrow Transplant Program, Duke University Medical Center, Inter-individual differences in the pharmacokinetic dis- Durham, North Carolina 27710 position of high-dose chemotherapy may explain variability in both response and toxicity. Prospective strategies, which attempt to individualize AUC, should be evaluated in this ABSTRACT setting. This report investigates relationships between the pharmacokinetics and pharmacodynamics of high-dose alkylators used for the treatment of primary breast cancer. INTRODUCTION Eighty-five women with primary breast cancer involv- Utilization of high-dose chemotherapy with hematopoietic ing >10 lymph nodes received four cycles of standard-dose stem cell support has resulted in improvement in the treatment chemotherapy followed by a high-dose regimen consisting of malignancies such as some lymphomas and leukemias (1–3). -of: cyclophosphamide (1875 mg/m2 once daily ؋ 3), cisplatin However, inter-patient variability in the pharmacokinetic dispo (165 mg/m2 given over 72 h), carmustine (600 mg/m2), and sition of the agents used in the high-dose regimens may result in stem cell transplantation. Dosages were attenuated in pa- observable differences in outcome (4). Such variability is of tients whose body weight exceeded their calculated ideal particular concern in the transplant setting because the chemo- weight by >20%. Pharmacokinetics of the high-dose che- therapy ablative regimens use doses 4–10 times those tolerated motherapeutic agents were evaluated in each patient by without hematopoietic support and have a higher frequency of collection and analysis of serial blood samples. life-threatening toxicity (5). In addition, preclinical data from Area under the concentration time curve (AUC) for cell culture experiments suggest that the concentrations cyclophosphamide and carmustine was highly variable achieved with high-dose alkylator regimens lie in a steep portion (>10-fold inter-patient range) with coefficients of varia- of the dose-response curve (6–8). Despite these concerns, rel- tion > 50%, in contrast to cisplatin exposures (2-fold range; atively few studies of high dose chemotherapy pharmacokinet- coefficient of variation 12%). The dosing method for over- ics are found in published literature. weight patients resulted in significantly lower systemic ex- We have reported previously the clinical results of a Phase -The parent cyclophospha- II study using high-dose alkylators and autologous hematopoi .(0.035 ؍ posure to cisplatin (P mide clearance on the 1st day of administration was etic stem cell support in 85 women with high-risk, primary significantly higher in patients who experienced acute car- breast cancer (9). The Kaplan-Meier curves for overall survival whereas carmustine dispo- appeared very stable by the 6-year median follow-up time for ,(0.011 ؍ P ;5 ؍ diac toxicity (n these patients. Thus, we felt that this would be a reasonable time to analyze the association between the systemic chemotherapy exposure achieved by a patient and her likelihood for survival. We also describe other relationships between toxicity, individ- Received 5/1/01; revised 12/20/01; accepted 12/13/01. The costs of publication of this article were defrayed in part by the ual dose calculations, and pharmacokinetics of the high-dose payment of page charges. This article must therefore be hereby marked alkylators used in these patients. advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported in part by NIH Grant PO1CA47441. PATIENTS AND METHODS 2 To whom requests for reprints should be addressed, at Mary Babb Treatment Plan and Assessment. All 85 patients who Randolph Cancer Center, West Virginia University, P. O. Box 9300, were treated at Duke University Medical Center on the Phase II Morgantown, WV 26506. Phone: (304) 293-0495; Fax: (304) 293-4667; E-mail: [email protected]. protocol mentioned above also consented to have pharmacoki- 3 Present address: West Virginia University Health Sciences Center, netic blood draws obtained during the high-dose chemotherapy Morgantown, WV 26506. regimen. Demographic and clinical information regarding the 4 Present address: University of Texas, M. D. Anderson Cancer Center, patients is presented in Table 1. The high-dose regimen con- Houston, TX 77030. 2 5 sisted of 3 days of cyclophosphamide (1875 mg/m i.v. given Present address: University of Colorado Health Sciences Center, Den- 2 ver, CO 80262. over 60 min each day) and cisplatin (165 mg/m as a 72-h 6 Present address: Karmanos Cancer Institute, Detroit, MI 48201. continuous i.v. infusion concurrent with cyclophosphamide),

Table 1 Patient demographics and clinical data for this study after the start of the infusion on each day of cyclophosphamide The actual body weight was used to calculate the adjusted body administration. Approximately 5 ml of blood were collected into surface area except in situations where the actual weight was Ͼ120% of heparinized tubes for each time point using a lumen separate the ideal weight. In the latter cases, an “adjusted” body weight was used from the point of infusion. Plasma was obtained by refrigerated by averaging the body surface area obtained from the ideal weight and the actual weight. The “adjusted (dosing) body surface area” shown in centrifugation at 900 G for 10 min. Samples were stored at this table is a median value used for prescribing the high-dose chemo- Ϫ20¡C for 24Ð48 h and then analyzed. therapy. Standards and quality control samples were prepared from Characteristic n or Median value neat chemical (Sigma Chemical Co., St. Louis, MO) and diluted with single donor plasma to yield concentrations ranging Յ100 Number of evaluable patients 85 Age 38 yrs ␮l/ml. The extraction of cyclophosphamide from plasma sam- Race (Caucasian/African-American/Hispanic) 80/4/1 ples was initiated by adding 1 ml of a 25 ␮g/ml ifosfamide Actual body surface area 1.73 m2 (Bristol-Myers Squibb, Princeton, NJ) internal standard solution 2 Adjusted (dosing) body surface area 1.72 m to 1 ml of plasma. The mixture was then loaded onto a Supel- Number of patients Ͼ20% ideal weight 25 Antiemetics during chemotherapy clean LC-Si solid phase extraction column (Supelco, Bellefonte, Prochlorperazine 58 PA) and eluted with 1 ml of acetonitrile. All solvents used in the Metoclopramide 27 assays reported here were HPLC7 grade. The eluants were Transplant-related toxicities blown dry with nitrogen and re-eluted in 300 ␮l of methanol. Cardiac 7 (8%) Samples were analyzed by modification of a method pub- Renal 18 (21%) Pulmonary 26 (31%) lished previously (11). Briefly, 25 ␮l of the eluates were in- Hepatic 10 (12%) jected onto an HPLC system consisting of a 3.9 ϫ 150-mm ␮ Waters NovaPak C18 analytic column (4 m of particle size; Millipore, Milford, MA). The mobile phase (15% acetonitrile: 85% monobasic sodium phosphate) was delivered isocratically followed by carmustine (600 mg/m2 i.v. given over 2 h) on the at a rate of 1.3 ml/min. The Waters Associates HPLC system 4th day. The details of such and associated clinical results have (Milford, MA) consisted of a Model 510 pump, a refrigerated been described previously (9). The dose of chemotherapy for an WISP Model 710B autosampler, and a Model 490 programma- individual patient was calculated from the actual body weight, ble multiwavelength detector set at 200 nm. The system was unless the actual weight was Ͼ120% of the ideal weight. In the interfaced to a personal computer using Maxima 820 software. latter cases, an “adjusted” body weight was used by averaging The lower limit of cyclophosphamide quantitation for this assay the BSA obtained from the ideal weight and the actual weight. was 1 ␮g/ml inter-assay, and intra-assay variabilities were 7 and Ideal body weight was determined from NY Life Insurance 5%, respectively. actuarial tables, which use height and body frame size, as Determination of Cisplatin Concentrations. Blood determined by wrist circumference. Concurrent antiemetic ther- samples were collected in heparinized tubes every 24 h during apy included continuous i.v. infusion of either prochlorperazine the cisplatin continuous infusion. The samples were centrifuged or metoclopramide, with the addition of lorazepam. All patients at 900 G for 10 min at 4¡C, and the plasma was stored at Ϫ70¡C were placed on central cardiac monitors throughout the 4 days for later analysis. of chemotherapy, and electrocardiograms were performed be- Standards and quality control samples were prepared from fore each daily administration of chemotherapy. Physical exam- platinum atomic absorption standard solution (Sigma Chemical ination, complete blood count with differential, and a chemistry Co.). A stock solution was prepared in 0.9% saline. Fresh, single panel for serum creatinine, blood urea nitrogen, glucose, potas- donor plasma (American Red Cross, Durham, NC) was used to sium, chloride, sodium, bicarbonate, magnesium, and phospho- make the final dilutions for plasma standards of 200-1500 rus were performed daily. Liver function tests were done before ng/ml. Plasma samples and standards were diluted 1:3.5 with chemotherapy and every 4 days thereafter. Patient weight, fluid 0.25% Triton ϫ 100 (Sigma Chemical Co.) before injection. intake and output, and vital signs were recorded daily. Patient samples, controls, and standards were analyzed for plat- Patients were divided into groups based on the occurrence inum content by a modification of our previously published of transplant-related toxicities using the following criteria. Pul- graphite-furnace atomic absorption spectrophotometry assay us- monary toxicity was defined by the sudden onset of progressive ing automated sample delivery (models 2380, HGA 400, and exertional dyspnea accompanied by a reduced diffusing capacity AS40; Perkin-Elmer, Norwalk, CT; Ref. 12). Aliquots (25 ml) for carbon monoxide on pulmonary function testing, as de- were dispensed into a pyrolytically coated graphite tube, and the scribed previously (9). Acute cardiac toxicity was identified by platinum was detected at a wavelength of 265.9 nm using a slit symptomatic chest pain and electrocardiogram evidence of ST width of 0.7 mm. The furnace program consisted of three drying depression. Nephrotoxicity was defined by serum creatinine steps followed by a 1100¡C char and a 2700¡C atomization. The values Ͼ 1.4 mg/dl (Cancer and Leukemia Group B grade 1). data were collected and analyzed using a Perkin-Elmer Nelson Patients were identified as experiencing hepatic toxicity if they integrator. The lower limit of platinum quantitation for this met the criteria for veno-occlusive disease, as defined by Mc- Donald et al. (10). Determination of Cyclophosphamide Concentrations. Samples were drawn at 0 h (preinfusion), 1⁄2 h (mid-infusion), 7 The abbreviations used are: HPLC, high-performance liquid chroma- 1 h (end of infusion), and at 11⁄2, 2, 3, 5, 7, 9, 12, 17, and 21 h tography; AUC, area under the concentration time curve.

Fig. 1 Cyclophosphamide, cisplatin, and carmustine plasma concentration data for a patient who displayed AUC values closest to the median for each drug. All concentrations are expressed in units of ␮g/ml.

assay was 200 ng/ml. Samples with concentrations appearing to estimations were performed by curve-stripping techniques exceed the standard curve were diluted in donor plasma and (RSTRIP V.4.03; MicroMath, Salt Lake City, UT). Subsequent reanalyzed. Inter-assay and intra-assay variabilities were 3.7 and evaluations of individual data sets were conducted by weighted 4.2%, respectively. nonlinear least-squares regression using a one- or two-compart- Determination of Carmustine Concentrations. Sam- ment model each with zero-order input and a first-order elimi- ples were collected at 0 (preinfusion), 60, 120 (end of infusion), nation process for carmustine and cyclophosphamide, respec- 130, 140, 150, 165, 180, and 210 min after the start of the tively (PCNONLIN V.4.2; ClinTrials, Apex, NC). AUC data infusion into 10 ml of heparinized tubes containing 3 ml of a 25 were derived from the pharmacokinetic parameter estimates. ␮g/ml 5,5 diphenylhydantoin (the internal standard; Sigma The AUC for each dose of cyclophosphamide was estimated Chemical Co.) solution in ethyl acetate. Precisely 3 ml of whole independently; thus, the “total AUC” values reported here re- blood were added to each tube at the designated sample time flect the addition of all three AUCs for each patient. followed by inversion and refrigeration. The cellular compo- Pharmacokinetic/pharmacodynamic correlations were con- nents were separated by refrigerated centrifugation at 900 G for ducted on segregated data sets using the Kruskal-Wallis test. 10 min within 24Ð48 h of sample collection and a 1-ml aliquot Ten patients experiencing high-dose, chemotherapy-related of the supernatant was transferred to a glass tube. mortality were intended to be excluded from the pharmacoki- Standards ranging Յ10 ␮g/ml and quality control samples netics: survival analyses because high systemic exposure could were prepared by the addition of diluted pharmaceutical-grade theoretically send the curve in the opposite directions in the case carmustine (Bristol-Myers Squibb Company) to whole blood of toxic death versus extended disease-free survival. Pharmaco- (American Red Cross) using sampling tubes as described above. kinetic-survival assessments were conducted by segregation of The ethyl acetate supernatants from samples and standards were patients based on the median systemic exposure to each high- concentrated with nitrogen and reconstituted subsequently with dose alkylator via Kaplan-Meier plots and the Log-rank test 300 ␮l of methanol. (13). Carmustine concentrations were determined by modification of a method published previously (5). Briefly, 25-␮l aliquots of the eluates were injected onto an HPLC system con- RESULTS sisting of a 25 cm ϫ 4.6-mm Supelcosil LC-18-DB column Examples of high-dose chemotherapy disposition in a pa- (5-␮m particle size; Supelco). The mobile phase (55% metha- tient closest to the median level of systemic exposure for all nol:45% purified water) was delivered isocratically at a rate of three drugs are displayed in Fig. 1. Parent levels of cyclophos- 1.6 ml/min. The Waters Associates HPLC system consisted of a phamide declined within a patient on each repeat dose, consist- Model 510 pump, a refrigerated Model 712 WISP autosampler, ent with autoinduction of its metabolism. Plasma platinum con- and a Lambda Max Model 481 LC Spectrophotometer set at a centrations increased over the course of the 72-h cisplatin wavelength of 237 nm. The system was interfaced using Max- infusion. This is most likely an accumulation of activated plat- ima 820 software. The lower limit of carmustine quantitation for inum species bound to plasma proteins and small sulfhydryl this assay was 0.5 ␮g/ml inter-assay, and intra-assay variability molecules. Wide inter-patient variability in the systemic clear- was 4 and 10%, respectively. ances of both carmustine and parent cyclophosphamide was Pharmacokinetic Modeling and Statistics. Selection of observed, compared with a relatively tight range of variation in the appropriate pharmacokinetic models and initial parameter cisplatin disposition (Table 2).

Table 2 Median (percentage of coefficient of variation) high-dose vival, as shown in Fig. 3. Those with parent drug AUC values, chemotherapy pharmacokinetic parameters in all 85 patients which were below the median, had a higher chance of survival. Drug Systemic exposurea Systemic clearanceb We believe these data indicate that the parent drug is being Cyclophosphamide converted to the activated 4-hydroxycyclophosphamide metab- Dose 1 32.1 (67) 58.3 (39) olite quicker and/or more efficiently in these individuals. Sim- Dose 2 19.7 (66) 95.2 (51) ilar relationships were not found when patients were segregated Dose 3 17.8 (54) 105.5 (50) by either the carmustine or cisplatin exposures. Total AUC 69.6 (59) NAc Dose 3/dose 1 0.50 (31) 2.00 (36) Cisplatin (ng/ml) 24-h Concentration 864 (26) NA DISCUSSION 48-h Concentration 1738 (16) Perhaps the first published clinical example of a clear 72-h Concentration 2301 (12) association between inter-patient differences in chemotherapy Carmustine 599 (145) 1002 (49) pharmacokinetic disposition and anticancer response was pro- a AUC data are presented for cyclophosphamide and carmustine in vided by Evans et al. (14). Their data demonstrated a correlation units of mg/ml ϫ min and ␮g/ml ϫ min, respectively. b Units for this parameter are ml/min/m2. between the systemic exposure to repetitive high doses of meth- c NA, not applicable. otrexate and disease-free survival in children with acute lymphocytic leukemia. Inter-patient variability in drug disposition should be most evident and important when the majority of malignant cells are Cyclophosphamide systemic clearance increased by a me- thought to be chemotherapy sensitive, and there is a good dian of 2-fold within patients over the 3 days of drug adminis- chance for a prolonged overall disease-free survival in the tration (Table 2). This effect was rapid and relatively consistent, population. We felt that such was the case in the treatment of occurring in all but 1 patient. There was some evidence for an high-risk primary breast cancer with adjuvant high-dose chem- association between a patient’s cyclophosphamide AUC or otherapy and, thus, undertook this study to primarily focus on clearance on the first dose compared with the last dose, as investigation of associations between alkylating agent systemic shown in Fig. 2. exposure and outcome. Table 3 displays the systemic chemotherapy exposures A prolonged overall disease-free survival, while obviously found in those patients whose weight was Ͼ120% of their ideal desirable, makes a correlation of variations in systemic chemo- weight and, thus, were given attenuated doses (as described in therapy exposure with efficacy rather difficult because of the “Patients and Methods”) compared with the others on this study duration of follow-up necessary before conducting these inves- who weighed Ͻ120% of their ideal weight. The data suggest tigations. We chose to first evaluate pharmacokinetic-efficacy that this approach to dose attenuation is under-treating the obese correlates at the 6-year median follow-up time because the individuals in the case of cisplatin and also possibly cyclophos- relapse rate had stabilized by then. These investigations revealed phamide. Simulation of the systemic platinum exposure, which a correlation between parent cyclophosphamide AUC (but not would have been achieved if the obese patients were dosed on that of carmustine or cisplatin) and overall survival (Fig. 3). their actual weight, negates the statistical difference in these Randomized studies that used single doses of cyclophos- groups (assuming there is a linear relationship between the dose phamide per cycle of standard chemotherapy have demonstrated and systemic exposure). It is difficult to make conclusions for conflicting results as to the relationship between dose and effi- the cyclophosphamide and carmustine data because of the wide cacy (15, 16). Comparison of these data with those obtained on degree of inter-patient variability in the clearance of these two the current study is difficult because of the multiple dose nature agents and, thus, lack of power of such comparisons. of the high-dose regimen and, thus, the potential for auto- Associations between transplant regimen-related toxicities induction of metabolic activation, as discussed below. Perhaps and the systemic exposure of the chemotherapy agent(s) sus- more importantly, combination of cyclophosphamide with glu- pected to be implicated in such are shown in Table 4. Patients tathione-depleting alkylators, such as cisplatin and carmustine, with acute cardiac toxicity (occurring, by definition, on the last may exaggerate its clinical effects in the high-dose setting. The day of high-dose chemotherapy) displayed substantially faster concentration of glutathione in tumor cells has been shown to parent cyclophosphamide systemic clearance values during the correlate with the degree of resistance to cyclophosphamide 1st day of drug administration. No other relationships were metabolites (17). found to be statistically different in patients exhibiting toxicity. Cyclophosphamide requires metabolic activation via con- Fourteen patients treated on this protocol have relapsed version to a 4-hydroxylated species for clinical activity. We with breast cancer after high-dose therapy by the 6-year median believe our data demonstrate that faster rates of conversion (i.e., follow-up time. Alkylator systemic exposures for the 10 patients lower parent drug levels) result in increased exposure to the who died of regimen-induced toxicity were not substantially intermediate metabolite, 4-OH cyclophosphamide, and this ul- different for cyclophosphamide or cisplatin; however, there was timately provides more intracellular exposure to the active phos- a trend toward higher carmustine levels. Nevertheless, we cen- phoramide mustard species. This mode of reasoning is consist- sored these individuals out of the efficacy analysis, as was our ent with data published by other investigators who, by using original intention. Evaluation of the remaining 75 patients based similar doses and without concurrent influence of metabolic on the median chemotherapy exposures yielded a significant inhibitors, such as thiotepa, were able to correlate the exposure relationship between cyclophosphamide AUC and overall sur- of parent drug to that of the 4-OH metabolite (18, 19). It is

Fig. 2 Association of cyclophosphamide AUC (mg/ml ϫ min) during the first dose with that obtained after the third dose. The correlation coefficient for the linear regression line (as shown) was 0.65 (P Ͻ .001), whereas the precision and bias were 21 and Ϫ18 mg/ml ϫ min, respectively.

Table 3 Median systemic exposure to chemotherapy in patients who were Ͼ120% of their ideal body weight (“obese”) compared with others, indicating the potential influence of the formula used to calculate chemotherapy doses Variable Obese Nonobese P Number of patients 25 60 Total cyclophosphamide AUC (mg/ml ϫ min) 63.9 73.4 0.055 Cisplatin 72-h concentration (ng/ml) 2240 2349 0.035 Carmustine AUC (␮g/ml ϫ min) 642 579 0.824

Table 4 Associations between chemotherapy median pharmacokinetic parameters and post-transplant organ toxicitiesa Nontoxic Toxic Toxicity Pharmacokinetic parameter patients patients P Cardiac Total cyclophosphamide AUC 76.3 55.6 0.094 Cyclophosphamide dose 1 clearance 49.0 79.9 0.011 Renal 24-h Cisplatin concentration (ng/ml) 857 936 0.229 72-h Cisplatin concentration (ng/ml) 2295 2374 0.431 Pulmonary Carmustine AUC 599 595 0.963 Hepatic Total cyclophosphamide AUC 70.1 63.4 0.645 Carmustine AUC 599 482 0.927 a AUC data are presented for cyclophosphamide and carmustine in units of mg/ml ϫ min and ␮g/ml ϫ min, respectively.

important to realize that doses slightly higher than those used in will experience acute cardiac toxicity during the stress of car- our study (or when cyclophosphamide is given with metabolic mustine administration (Table 4). More recently developed an- inhibitors) may not display such a relationship because of sat- alytic methods allow for clinical measurement of the active uration of metabolic pathways (19). 4-OH metabolite of cyclophosphamide (22). Future studies Ayash et al. (20) also investigated the relationship between should compare the utility of parent versus metabolite exposures parent cyclophosphamide disposition, toxicity, and efficacy in as predictors of patient effects. 19 women with metastatic breast cancer who were receiving The potential for cyclophosphamide to induce its own high-dose cyclophosphamide, thiotepa, and carboplatin. Patients metabolism has been described previously (23Ð25); however, who experienced cardiac toxicity displayed a significantly faster the degree of change we have seen in parent drug clearance over parent cyclophosphamide clearance (low AUC) and had a lon- the 3-day course indicates a potential for very high active ger duration of response, consistent with our data. Similar metabolite formation on the final infusion. An intriguing com- associations between nonhematological toxicity and cyclophos- parison may be found between these data and those found with phamide AUC were found by investigators at the University of the more widely used high-dose cyclophosphamide-thiotepa Colorado using the same cyclophosphamide/cisplatin/carmus- regimen. The latter calls for the administration of a similar total tine regimen studied here (21). Importantly, our study shows dose of cyclophosphamide to the cyclophosphamide/cisplatin/ that the parent cyclophosphamide clearance on the first of the carmustine regimen; however, it is given over 96 h as a contin- three doses may allow for early identification of patients who uous infusion concurrent with thio-tepa (26). The ratio of the

A direct association between systemic exposure to carmustine and post-transplant pulmonary toxicity was demonstrated by investigators at the University of Colorado Bone Marrow Tranplant Program (28). We have not found this correlation in the patients treated on this trial (Table 4) or in another series, which we published recently (29). Patients who had very high systemic exposures to carmustine on the latter trial did have a higher frequency of pulmonary toxicity; however, there was no difference in the median exposures when subjects were segregated based on toxicity. Reasons for the discrepancy between Duke and Colorado analyses may be related to slight differences in the infusion duration between the centers and/or differences in the definition/identification of pulmonary toxicity. Previous evaluations of cisplatin pharmacokinetics by our group during the cylcophosphamide/cisplatin/carmustine regimen and by others have demonstrated associations between systemic platinum exposure and subsequent nephrotoxicity (30Ð 33). The 21% of patients in the current trial with post-transplant nephrotoxicity displayed a slightly higher median systemic platinum exposure; however, this difference was not statistically significant, perhaps attributable to the low frequency of toxicity. The pharmacokinetic disposition of various drugs, including some antineoplastics, has been evaluated in obese patients (34Ð36). These studies imply that the systemic clearance of highly extracted drugs may be enhanced, whereas data are also available, which describe reduced clearance for other agents (37). Most institutional dosing policies for “obese” individuals have not been derived from actual pharmacokinetic or toxicity studies, and it is doubtful that one policy will provide accurate dosing for every drug. Retrospective evaluation of clinical studies, in which the doses of combination chemotherapy (including cyclophosphamide) were determined based on actual patient weight, has not demonstrated increased toxicity (38, 39). Such associations may not hold true in the situation of high-dose Fig. 3 Disease-free survival (A) and overall survival (B) of 75 patients chemotherapy where the therapeutic index and drug disposition who survived Ն30 days post-transplant. Data were segregated for characteristics can be dramatically different (5). Kaplan-Meier analysis based on the median systemic exposure (AUC) Similar to many other bone marrow transplant programs, to parent cyclophosphamide. OOO, patients with AUC above the median; ⅐⅐⅐⅐, patients with AUC below the median. The X-axis values for we have a systematic approach to attenuation of chemotherapy years to the events were calculated from the initiation of the standard doses in patients who are “significantly” above their ideal chemotherapy. weight. Utilization of such a strategy was justified in the earlier days of transplantation because of the relatively high frequency of treatment-related toxicity. Contemporary changes in post- transplant ancillary therapies, particularly the use of colony- parent drug systemic exposure on the last versus 1st day of drug stimulating factor-primed peripheral blood progenitor cells, administration yields average values of 0.5 for the carmustine- have been associated with a surprising reduction in toxicity (40). based regimen compared with 0.7 for the thio-tepa-based regi- Thus, the concern for potentially overdosing obese patients if men. This apparent difference may be suggestive of either their total body weight is used in the calculation of doses may thio-tepa’s inhibitory effect on cyclophosphamide oxidation or not be as worrisome today. Regardless of this, we feel that the less likely, attributable to the continuous infusion schedule of data presented here do not support such dose attenuation. Given administration. We are planning to further characterize any the associations we found with drug levels and response, this differences between the regimens evaluating disposition of the practice may even reduce efficacy. It is important to realize that 4-hydroxycyclophosphamide species in patients receiving the no patients on this study were morbidly obese, i.e., greater than carmustine-based regimen by the use of an assay method, which two to three times their ideal weight. It may make sense to converts the metabolite to a stable entity at the bedside, as has arbitrarily attenuate doses in such individuals, but there is little been conducted previously with patients treated with the thio- actual data to support this practice. Fortunately, such obese tepa-based regimen (22). Relatively minor changes in the se- patients are exceedingly rare in our population; thus, collabora- quence of short infusions of cyclophosphamide and thio-tepa tions between major centers and cooperative groups treating have been shown to have dramatic effects on cyclophospha- high numbers of patients should look at this issue prospectively. mide’s metabolic profile (27). Evans et al. (41) have published subsequently the fol-

low-up trial to their study described in the first paragraph of this transplantation: diagnosis, incidence, and predisposing factors. Hepatol- “Discussion.” Their randomized trial demonstrated that the ogy, 4: 116Ð122, 1984. group of patients whose chemotherapy doses were individual- 11. Burton, L. C., and James, C. A. Rapid method for the determination ized to achieve a target systemic exposure had a significantly of ifosfamide and cyclophosphamide in plasma by high-performance liquid chromatography with solid-phase extraction. J. Chromatogr., 431: better outcome compared with a group dosed based on body 450Ð454, 1988. surface area alone (41). The data presented in our study also 12. Petros, W. P., Chaney, S. G., Smith, D. C., Fangmeier, J., Sakata, suggest that individualization of a patient’s systemic ablative M., Brown, T. D., and Trump, D. L. Pharmacokinetic and biotransfor- regimen exposure should optimize therapy. However, formal mation studies of ormaplatin in conjunction with a phase I clinical trial. prospective approaches will be needed to confirm the benefit of Cancer Chemother. Pharmacol., 33: 347Ð354, 1994. such a strategy and assess its impact on both the short- and 13. Kaplan, E. L., and Meier, P. Nonparametric estimation from incom- long-term chemotherapy-related toxicities (42, 43). plete observations. J. Am. Stat. Assoc., 53: 457Ð481, 1958. 14. Evans, W. E., Crom, W. R., Abromowitch, M., Dodge, R., Look, ACKNOWLEDGMENTS A. T., Bowman, W. P., George, S. L., and Pui, C. H. Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. We thank all of the patients who participated in this trial, as well as Identification of a relationship between concentration and effect. the clinicians and nurses who cared for them. N. Engl. J. Med., 314: 471Ð477, 1986. 15. Fisher, B., Anderson, S., Wickerham, D. 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