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Phase I Trial and Pharmacokinetics of Gemcitabine in Children With Advanced Solid Tumors

From the Mayo Clinic, Rochester, MN; Children's Hospital Medical Center, Seattle, WA; Children's Oncology Group Operations Center, Arcadia; University of Southern California Keck School of Medicine, Los Angeles, CA; Children's National Medical Center, Washington, DC; and Vanderbilt Children's Hospital, Nashville, TN

Address reprint requests to John Holcenberg, MD, Children's Hospital Medical Center, 4800 Sand Point Way NE, Seattle, WA 98105; e-mail: john.holcenberg{at}seattlechildrens.org or jholce{at}yahoo.com

	ABSTRACT

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PURPOSE: To determine the maximum tolerated dose, toxicity, and pharmacokinetics of gemcitabine in children with refractory solid tumors.

PATIENTS AND METHODS: Gemcitabine was given as a 30-minute infusion for 2 or 3 consecutive weeks every 4 weeks, to 42 patients aged 1 to 21 years. Doses of 1,000, 1,200 and 1,500 mg/m² were administered for 3 weeks. Subsequently, gemcitabine was given for only 2 consecutive weeks at 1,500, 1,800, and 2,100 mg/m². Plasma concentrations of gemcitabine and its metabolite, 2'2'-difluorodeoxyuridine, were measured in 28 patients.

RESULTS: Forty patients who received 132 courses of gemcitabine were assessable for toxicity. The maximum tolerated dose of gemcitabine given weekly for 3 weeks was 1,200 mg/m². Dose-limiting toxicity was not seen in one-third of children treated at any doses given for 2 weeks. The major toxicity was myelosuppression in three of five patients at 1,500 mg/m² for 3 weeks, and one of seven patients at 1,800 mg/m² for 2 weeks. Other serious adverse events were somnolence, fever and hypotension, and rash in three patients. Gemcitabine plasma concentration–time data were fit to a one- (n = 5) or two-compartment (n = 23) open model. Mean gemcitabine clearance and half-life values were 2,140 mL/min/m² and 13.7 minutes, respectively. One patient with pancreatic cancer had a partial response. Seven patients had stable disease for 2 to 17 months.

CONCLUSION: Gemcitabine given by 30-minute infusion for 2 or 3 consecutive weeks every 4 weeks was tolerated well by children at doses of 2,100 mg/m² and 1,200 mg/m², respectively.

	INTRODUCTION

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Gemcitabine (2',2'-difluorodeoxycytosine) is one of the unique agents developed by G. Grindey at Lilly Company by use of experimental tumor screens in animals.1 Gemcitabine is a cytosine analog with a modification in the 2 position of the sugar ring. Preclinical studies have shown that gemcitabine has a broader spectrum of antitumor activity than cytarabine against a panel of murine tumors. Gemcitabine also exhibited a different schedule dependency, whereby intermittent rather than daily administration produced superior cytotoxicity. Activity has been seen in xenografts of human lung, breast, head and neck, colon, and ovarian cancers. Schedule dependency has also been seen in efficacy and maximum tolerated dose (MTD) in some of these models.2

Initial adult phase I trials established a weekly-for-3-weeks schedule and an MTD of 790 mg/m² due to dose-limiting thrombocytopenia in heavily pretreated patients. It was shown subsequently that doses as high as 1,500 mg/m² are tolerated in less heavily treated adult patients. At higher doses, major toxicities have been neutropenia, reversible hepatic transaminase elevations, proteinuria, nausea and vomiting, mild flulike syndrome, and mild skin rash. Objective responses have been seen in adult patients with breast, cervical, pancreatic, colon, and non–small-cell lung cancers.2,3 Gemcitabine has been approved for pancreatic cancer and non–small-cell lung cancer.

The promising adult trials prompted this pediatric trial that initially tested weekly does for 3 consecutive weeks. Adult studies have shown that a weekly-for-2-weeks schedule repeated every 21 days is easier to administer and can be combined with other anticancer drugs with less thrombocytopenia.4 This schedule also allows easier combination with a colony-stimulating factor.5 Consequently, after an MTD was established for 3-week dosage, the protocol was amended to evaluate a 2-week schedule.

	PATIENTS AND METHODS

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Eligibility Criteria
Patients were enrolled between August 1996 and September 2001. Patients were between 1 and 21 years old at enrollment, had disease refractory to conventional therapy, and had a life expectancy of at least 2 months.

Patients with bone marrow metastases were not eligible. Patients were not eligible if they had been treated with more than three chemotherapy regimens or had received a stem-cell transplant. Patients were required to be off cytokines for at least 2 weeks before the start of the study. All patients had a central venous access device. Institutional review board approval and signed informed consent according to the Declaration of Helsinki were required before entry.

Patients were to have adequate bone marrow function, defined as neutrophil count 1,000/µL, platelet count 100,000/µL independent of transfusion, and hemoglobin 10 g/dL. Patients had to have normal organ function defined as serum creatinine of 1.5x normal, or creatinine clearance or radioisotope glomerular filtration rate 70 mL/min/1.73 m²; total bilirubin less than 1.5x normal; and AST less than 2.5x the upper limit of normal. Patients with brain tumors were to have CNS toxicity of no greater than grade 2, or no recent changes in neurologic function.

Dose-Limiting Toxicity
Dose-limiting toxicity (DLT) was defined as (1) any grade 4 hematologic toxicity that did not resolve within 7 days; (2) any grade 4 nonhematologic toxicity; or (3) any grade 3 nonhematologic toxicity (except grade 3 nausea, vomiting, or liver function test abnormality) that did not return at most to grade 2 within 7 days of its detection. Only DLTs that occurred during the first course of therapy were considered in the dose escalation procedure.

Patients were enrolled in cohorts of three. If none of the first three had DLT, the dose was escalated for the next cohort. If one of three patients in the first cohort had DLT, three more patients were enrolled at that dose level. If none of the next cohort had DLT, the dose was escalated one level for three more patients.

If two or more patients had DLT, the dose was considered not tolerated and was reduced one level. Enrollment of patients in cohorts of three was continued until the maximum dose was identified at which at least five of six patients did not have DLT. This dose was considered the MTD.

Dosage and Drug Administration
The study was initiated with gemcitabine given weekly as a 30-minute infusion for 3 weeks followed by 1 week without drug administration. In September 1999, the study was amended to give gemcitabine weekly for 2 weeks followed by 2 weeks without drug administration. The escalation for the 3-week schedule was started at 1,000 mg/m²/dose. Escalation for the 2-week schedule was started at 1,500 mg/m²/dose, which was one level higher than the MTD for the 3-week schedule. The maximum dose to be examined was 2,100 mg/m²/dose because we planned to combine this agent with other myelosuppressive drugs to investigate new combinations.

Pretreatment and Follow-Up Studies
Patient history, physical examination, and urinalysis were conducted, and CBC, creatinine, bilirubin, and AST levels were measured before the start of therapy and before each subsequent course. CBC, creatinine, bilirubin, and AST measurements, and urinalysis were performed weekly. Patients with measurable disease had baseline radiographic evaluations and scans performed every 1 to 2 courses to evaluate response. Pharmacokinetic samples were collected during the first course of therapy.

Response Assessment
Patients were assessable for response if they had at least one lesion that was measurable in two perpendicular dimensions with an imaging technique, and if they had received at least two doses of therapy. Imaging was repeated before each course to estimate response duration. The criteria used to assess response were (1) complete response (CR)—complete disappearance of all known disease for at least 4 weeks; (2) partial response (PR)—a reduction of at least 50% in the sum of the products of the two largest perpendicular diameters of all measurable lesions for at least 4 weeks; (3) stable disease (SD)—decrease in tumor size of less than 50%, or increase of no more than 24% in the sum of the products of the two largest perpendicular diameters of all measurable lesions; and (4) progressive disease (PD)—appearance of new areas of malignant disease, or increase in any measurable lesion of at least 25% in the product of the two largest perpendicular diameters. Patients who had CR, PR, or SD that persisted longer than 4 weeks were considered objective responders. Response duration was defined as the interval from the first scan that showed maximal response (PR or SD) and the first scan that showed PD after best response. An independent pediatric oncologist reviewed the radiologic reports on responders.

Toxicity and MTD
The National Cancer Institute Common Toxicity Scale version 1 was used to grade all adverse events. DLT was defined as any grade 4 hematologic toxicity that did not resolve in 7 days; any grade 4 nonhematologic toxicity; or any grade 3 nonhematologic toxicity except for grade 3 nausea, vomiting, or liver function test abnormality that returns to grade less than 2 within 7 days. The MTD was defined as the dose at which less than one-third of patients had DLT.

Pharmacokinetics
Chemicals. Gemcitabine, 2'2'-difluorodeoxyuridine (dFdU), and internal standard deoxycytidine were obtained from Lilly Research Laboratories (Indianapolis, IN). High-performance liquid chromatography (HPLC) -grade methanol and acetonitrile (EM Science, Gibbstown, NJ) and monobasic potassium phosphate (Baker-Analyzed; J.T. Baker, Phillipsburg, NJ) were used as received. Recovered human plasma from healthy volunteers was purchased from the Mayo Clinic Blood Bank and stored frozen at –20°C.

Specimen collection. Blood samples (2 mL) were collected from a peripheral vein remote from the chemotherapy infusion site into heparinized tubes containing 2.5 mg of the cytidine deaminase inhibitor tetrahydrouridine. Immediately after collection, each blood sample was chilled in an ice-water slurry, centrifuged, and the plasma layer was transferred to a polypropylene tube, capped, immediately frozen, and stored at –70°C. The specimens were drawn before drug administration, at 15 minutes during infusion, at end of infusion and 5, 10, 15, 30, 60, and 90 minutes, and 2, 4, 6, 12, and 24 hours after administration. Urine was collected for 24 hours beginning at the start of the infusion.

Gemcitabine and dFdU analysis. Plasma concentrations of gemcitabine and dFdU were determined by the normal-phase HPLC procedure of Freeman et al.6 Separation of gemcitabine, dFdU, and the internal standard deoxycytidine was achieved on an Adsorbosphere (Alltech, Deerfield, IL) Amino HPLC column (250 cm x 4.6 mm internal diameter, 5 µm) fitted with a Newguard NH2 (Alltech) precolumn (15 x 3.2 mm internal diameter, 7 µm). The mobile phase consisted of a mixture of 630 mL cyclohexane, 150 mL dichloroethane, 220 mL methanol, 1 mL water, 1 mL triethylamine, and 0.5 mL glacial acetic acid. The flow rate and detection wavelength were 1.5 mL/min and 272 nm, respectively. Plasma samples (0.2 mL) were prepared for analysis by protein precipitation with isopropanol (1 mL) followed by solvent extraction with ethylacetate (2.5 mL).

Data Analysis
The ultraviolet absorbance signal was analyzed with a data processor, and the peak height ratio (drug/internal standard) versus standard concentration data were analyzed by linear least-squares regression.

The pharmacokinetics of gemcitabine were estimated using the program WinNonlin version 1.5 (Scientific Consultants Inc, Cary, NC). Gemcitabine distribution () and elimination (ß) rate constants and half-life values (t_1/2 and t_1/2ß, respectively), area under the curve (AUC), steady-state volume of distribution (V_ss), and total plasma clearance (Cl_p) were determined by fitting the plasma concentration–time data (during infusion and postinfusion) to a one- or two-compartment open model using nonlinear least-squares regression analysis. Plasma concentration data were weighted by the reciprocal of the observed concentration. dFdU AUC values were determined by trapezoidal approximation from the start of treatment to the last detectable plasma concentration (C_last). Residual area after C_last was calculated by

where k_el was the terminal elimination rate constant calculated by linear least-squares regression of the last three to four time points in the plasma concentration–time profiles. The t_1/2ß of dFdU was calculated by

The regression model:

was used to assess the joint effects of sex, age and dose level on clearance. C was expressed in mL/min/m², age was expressed in years, and dose level was expressed in mg/m². Backward stepwise regression was used to assess the relative contributions of the characteristics considered.7 Characteristics with an associated significance level of 0.10 or less were considered important for predicting clearance.

	RESULTS

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Patients
Forty-two patients were enrolled onto this study. Two did not receive the study drug. The 40 treated children received a total of 132 courses. One patient was ineligible because she had prior high-dose chemotherapy with autologous stem-cell support. Selected characteristics are described in Table 1. The tumor types with at least two patients are presented in Table 1. In addition, single patients had adenocarcinoma of the intestine, anaplastic astrocytoma, desmoplastic small blue-cell tumor, meningioma, medulloblastoma, nasopharyngeal carcinoma, ovarian germ cell tumor, and synovial-cell sarcoma.

Toxicity
Forty treated children were assessable for toxicity. One patient received granulocyte colony-stimulating factor (G-CSF) by mistake during the first course of therapy, but did not receive cytokine during subsequent courses. Another patient received G-CSF after grade 4 hematologic toxicity and hospitalization for fever and neutropenia.

Weekly-for-3-Weeks Schedule
Twenty patients were enrolled onto the weekly-for-3-weeks schedule. Three patients could not be evaluated for DLT. Two patients had disease progression and were removed from protocol therapy before they received the third dose of gemcitabine. One patient elected to stop protocol therapy before the third dose of gemcitabine.

The MTD of gemcitabine was 1,200 mg/m²/wk for 3 weeks. The dose of 1,500 mg/m²/wk for 3 weeks was not tolerated. The major toxicity was myelosuppression. Hematologic DLT was observed in one of six patients at 1,000 mg/m², and in three of five patients at 1,500 mg/m². At 1,200 mg/m², only one of eight patients had DLT consisting of grade 3 ALT elevation that did not resolve in 1 week. Grade 4 lymphopenia was seen in three patients and five courses on this weekly schedule for 3 weeks.

Weekly-for-2-Weeks Schedule
Twenty-two patients were enrolled onto the weekly-for-2-weeks schedule. Three patients could not be evaluated for DLT. Two of those patients had disease progression after enrollment but before they received gemcitabine, and one received three weekly doses of gemcitabine in error.

All dose levels examined were considered tolerable. Only four patients had DLT. One of the seven patients treated at 1,500 mg/m² had grade 2 and 3 somnolence that lasted 1 to 2 hours after the first and second doses of gemcitabine, respectively. Of the seven patients treated at 1,800 mg/m², two had grade 4 myelosuppression that lasted more than 3 weeks, and one patient with gastrointestinal malignancy and intestinal obstruction had grade 3 bilirubin elevation that lasted longer than 1 week. Only one of six patients had grade 4 myelosuppression when we escalated the dose to 2,100 mg/m². None of the six patients treated at 2,100 mg/m² for 2 weeks had DLT. Grade 4 lymphopenia was noted in eight patients and 20 courses.

Serious adverse events were reported for three patients: one with DLT somnolence; one with fever, hypotension, and infection; and one with a leg rash. The latter two events were considered unrelated to gemcitabine by the treating physicians. The infection responded rapidly to antibiotics, and the associated fever and hypotension did not recur with the next two doses of gemcitabine. The rash was associated with a central line infection and responded to antibiotics.

There were only two episodes of grade 4 nonhematologic toxicity. One patient who was treated with 1,500 mg/m² for 3 weeks developed fever to above 40°C for longer than 24 hours, associated with grade 4 myelosuppression and grade 3 nausea, myalgias, and desquamating rash on the dorsum of both hands. He recovered fully after treatment with antibiotics and G-CSF. The other patient had a seizure that was considered unrelated to gemcitabine.

Other grade 3 adverse events were elevation of partial thromblastin time (two patients), elevation of transaminase (four patients), fever and infection (three patients), constipation (one patient), nausea (one patient), dysuria (one patient), myalgias (two patients), hypokalemia (one patient), hypophosphatemia (one patient), seizure (one patient), and fainting spells (one patient). The seizures were associated with CNS metastasis and death, as a result of tumor progression that was associated with grade 3 weakness and hypertension. Transient grade 1 or 2 proteinuria or hematuria was reported in 11 and 15 patients, respectively. One patient stopped therapy after 16 courses when he developed transient dysuria, proteinuria, and hematuria. None of the patients had associated anemia or change in renal function.

Pharmacokinetics
Pharmacokinetics of gemcitabine and dFdU, the deaminated gemcitabine metabolite, were characterized in 28 patients enrolled. A plasma concentration–time profile for patients treated at the 1,800 mg/m² dose level is illustrated in Figure 1. Plasma elimination of gemcitabine was fit to a one-compartment open model for five patients and to a two-compartment open model for the remaining 23 patients (Table 2). Gemcitabine data for three patients could not be fit by compartmental analysis. The gemcitabine distribution half-life (t_1/2) was very rapid, and could not be measured in the five patients whose plasma concentration-time data was fit to a one-compartment open model. The gemcitabine elimination half-life of 9.6 ± 3.3 minutes for the data fit to a one-compartment open model was similar to the elimination half-life (t_1/2ß) of 13.4 ± 4.0 minutes for data fit to a two-compartment open model. Gemcitabine peak plasma concentration (Fig 2A) and AUC (Fig 3A) increased as a function of dose. Clearance decreased as dose level increased (Fig 4). Multiple adjustment for sex, age, and dose level indicated that only dose level was significantly related to clearance (P = .074).

View larger version (15K): [in this window] [in a new window]   Fig 1. Plasma concentration–time profile of gemcitabine () and 2'2'-difluorodeoxyuridine (dFdU; •) following a 30-minute infusion of 1,800 mg/m2 gemcitabine to children (n = 5). A fit of the data to a two-compartment open model is illustrated by the solid line for gemcitabine and the dotted line for dFdU.

View larger version (14K): [in this window] [in a new window]   Fig 2. Graph of gemcitabine (A) and 2'2'-difluorodeoxyuridine (dFdU; B) peak plasma concentration (Cmax) versus gemcitabine dose level. Patients' gemcitabine plasma concentration–time data fit to a one-compartment () or two-compartment () model.

View larger version (17K): [in this window] [in a new window]   Fig 3. Graph of gemcitabine (A) and 2'2'-difluorodeoxyuridine (dFdU; B) area-under-the-curve (AUC) values as a function of gemcitabine dose level. Patients' gemcitabine plasma concentration–time data fit to a one-compartment () or two-compartment () model.

View larger version (12K): [in this window] [in a new window]   Fig 4. Graph of gemcitabine plasma clearance values as a function of gemcitabine dose level. Patients' gemcitabine plasma concentration–time data fit to a one-compartment () or two-compartment () model.

Objective Response
One patient fulfilled the criteria to be a responder and had a pancreatic tumor that responded after nine courses of therapy. The patient received 16 total courses of therapy. He was considered to have a PR because computed tomography scans no longer showed a definite pancreatic mass. A biopsy was not performed. His disease relapsed after termination of protocol therapy.

Four of 13 patients with osteogenic sarcoma had stable disease for 2, 3, 3, and 6 months, respectively. PD was noted in four patients after one course and in one patient after three courses of gemcitabine. One of four patients with Ewing's sarcoma had 17 courses of gemcitabine and SD shown by bone scans throughout that period. Skeletal x-rays showed a mixed response, but a positron emission tomography scan of the bony lesions was negative for disease progression at the end of therapy. The patient received no further treatment, and his disease relapsed 6 months after the last dose of gemcitabine. One patient with a cervical rhabdoid tumor and lung metastases had SD for 5 months. One patient with nasopharyngeal carcinoma with multiple osseous metastases also had SD for 5 months.

	DISCUSSION

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While gemcitabine was initially approved for treatment of pancreatic cancer, it is active against several adult solid tumors. Response rates in phase II studies of patients with breast cancer have ranged from 25% to 46%, and responses also have been observed in patients with bladder cancer and lung cancer. It is approved as a single agent for pancreatic cancer and in combination with cisplatin for non–small-cell lung cancer.

Initial trials of gemcitabine studied doses administered weekly for 3 weeks with a 1-week rest between courses. However, the third dose was often omitted at higher dosages due to rapid onset of myelosuppression. As a result, an abbreviated regimen of gemcitabine weekly for 2 consecutive weeks was followed by a 1-week rest. This schedule was better suited for combination therapy. After we established the DLT and MTD for the weekly-for-3-weeks schedule, we consulted with the National Cancer Institute and the drug manufacturer. They suggested that investigation of a weekly-for-2-weeks schedule in children would provide helpful data for future pediatric trials, especially for combination chemotherapy. Adult trials had shown that doses greater than 2,100 mg/m² weekly for 2 weeks did not seem to improve the efficacy of gemcitabine. Therefore, we amended the trial to study this schedule, but capped the dose escalation at 2,100 mg/m².

Consistent with adult phase I trials, the major toxicity was myelosuppression. The MTD of 1,200 mg/m², established for the 3-week schedule, was similar to that found for adults. An MTD was not established for the 2-week schedule since hematologic toxicity was not observed at the highest dose level of 2,100 mg/m² on the 2-week schedule. The dose-intensity of 1,200 mg/m² on the 3-week schedule is similar to that of 2,100 mg/m² on the 2-week schedule.

The pharmacokinetics of gemcitabine in pediatric patients who were given a short infusion was similar to those observed for adults. Gemcitabine plasma distribution and elimination were rapid, and fit to a two-compartment open model for most patients. The mean plasma elimination half-life value was 13.7 minutes. The reasons for dose-dependent clearance are not known. Gemcitabine pharmacokinetics after a short infusion has been studied in adult patients over a much broader range (53 to 2,500 mg/m²) than that investigated in these pediatric patients, without evidence of dose-dependent clearance. The mean clearance value of 2,140 mL/min/m² (130 L/h/m²) found in this pediatric trial was similar to the values of 87.5 L/h/m² and 130 L/h/m² reported in adult phase I trials.8,9 The few reports of cytidine deaminase pharmacogenetics suggest that enzyme variants may exist with lower activity for gemcitabine metabolism,10 but a rapid metabolism genotype has not been identified. High clearance values may be an artifact of the sample preparation methodology, which included addition of the cytidine deaminase inhibitor tetrahydrouridine to plasma after specimen collection to stabilize gemcitabine. Delays in specimen processing or addition of the inhibitor could reduce the gemcitabine concentration ex vivo and lead to artificially high clearance estimates.

Gemcitabine plasma concentrations above 20 µmol/L, which was defined as the limit for maximal gemcitabine triphosphate (dFdCTP) accumulation in leukemia cells,11 were quickly achieved at all dosage levels in this trial and maintained for approximately 30 minutes after the end of infusion (Fig 1). Since dFdCTP formation has been considered important to gemcitabine antitumor activity, other schedules that prolong dFdCTP exposure have been evaluated. The constant-rate infusion schedule produces similar steady-state gemcitabine plasma concentrations in pediatric12 and adult patients.13 A biweekly schedule of gemcitabine also has been evaluated in adults, but not children. However, antitumor activity in patients who were given gemcitabine by weekly infusion suggests that other factors that have not yet been identified are important to clinical activity.

Some patients with osteogenic sarcoma, Ewing's sarcoma and soft tissue sarcoma had stable disease despite extensive prior chemotherapy. Phase II trials should explore the efficacy of gemcitabine in these pediatric tumors perhaps in combination with a platinum derivative.

In summary, tolerable doses were found for short infusions of intravenous gemcitabine given every 2 weeks and every 3 weeks. Phase II trials need to be done to estimate response rates in children with solid tumors.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Douglas Hawkins, MD, for review of radiological reports; Shaun Mason for assistance in preparation and editing the manuscript; and the investigators and nursing staff at each of the participating institutions.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Heinemann V, Hertel L, Grindey G, et al: Comparison of the cellular pharmacokinetics and toxicity of 2',2'-difluorodeoxycytidine. Cancer Res 48:4024-4031, 1988[Abstract/Free Full Text]

2. Kaye SB: Gemcitabine: Current status of phase I and II trials. J Clin Oncol 12:1527-1531, 1994[Free Full Text]

3. Abratt RP, Bezwada WR, Folkson G, et al: Efficacy and safety profile of gemcitabine in non-small-cell lung cancer: A phase II study. J Clin Oncol 12:1535-1540, 1994[Abstract/Free Full Text]

4. Carrato A, Garcia-Gomez J, Alberola V, et al: Carboplatin in combination with gemcitabine in advanced non-small cell lung cancer: Comparison of two consecutive phase II trials using different schedules. Proc Am Soc Clin Oncol 18:1992a, 1999 (abstr 1922)

5. Kornek GV, Haider K, Kwasny W, et al: Treatment of advanced breast cancer with docetaxel and gemcitabine with and without human granulocyte conony-stimulating factor. Clin Cancer Res 8:1051-1056, 2002[Abstract/Free Full Text]

6. Freeman KB, Anliker S, Hamilton M, et al: Validated assays for the determination of gemcitabine in human plasma and urine using high-performance liquid chromatography with ultraviolet detection. J Chromatogr B Biomed Appl 665:171-181, 1995[CrossRef][Medline]

7. Draper NR, Smith H: Applied regression analysis. New York, NY, John Wiley and Sons, 1966

8. Storniolo AM, Allerheiligen SRB, Pearce HL: Preclinical, pharmacologic, and phase I studies of gemcitabine. Semin Oncol 24:S7-2-S7-7, 1997 (suppl 7)

9. Abruzzese JL, Grunewald R, Weeks EA, et al: A phase I, clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9:491-498, 1991[Abstract]

10. Yue L, Saikawa Y, Ota K, et al: A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity. Pharmacogenetics 13:29-38, 2003[CrossRef][Medline]

11. Grunewald R, Kantarjian H, Keating MJ, et al: Pharmacologically directed design of the dose rate and schedule of 2',2'-difluorodeoxycytidine (Gemcitabine) administration in leukemia. Cancer Res 50:6823-6826, 1990[Abstract/Free Full Text]

12. Steinherz PG, Seibel NL, Ames MM, et al: Phase I study of gemcitabine (difluorodeoxycytidine) in children with relapsed or refractory leukemia (CCG-0955): A report from the Children's Cancer Group. Leuk Lymphoma 43:1945-1950, 2002[CrossRef][Medline]

13. Grunewald R, Kantarjian H, Du M, et al: Gemcitabine in leukemia: A phase I clinical, plasma, and cellular pharmacology study. J Clin Oncol 10:406-413, 1992[Abstract/Free Full Text]

Submitted October 22, 2003; accepted March 19, 2004.

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