This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takimoto, C. H. Articles by Grem, J. L. Search for Related Content PubMed PubMed Citation Articles by Takimoto, C. H. Articles by Grem, J. L. Social Bookmarking                            What's this?

Dose-Escalating and Pharmacological Study of Oxaliplatin in Adult Cancer Patients With Impaired Renal Function: A National Cancer Institute Organ Dysfunction Working Group Study

Chris H. Takimoto, Scot C. Remick, Sunil Sharma, Sridhar Mani, Ramesh K. Ramanathan, James Doroshow, Anne Hamilton, Daniel Mulkerin, Martin Graham, Graham F. Lockwood, Percy Ivy, Merrill Egorin, Barbara Schuler, Denis Greenslade, Andrew Goetz, Ronald Knight, Rebecca Thomas, Brian P. Monahan, William Dahut, Jean L. Grem

From the Medicine Branch at Navy, National Naval Medical Center, and the Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Centers, National Cancer Institute, Bethesda, MD; Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX; Comprehensive Cancer Center at University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH; Memorial Sloan Kettering Cancer Center, and New York University, New York, and Montefiore Hospital, Albert Einstein College of Medicine, Bronx, NY; University of Pittsburgh Cancer Institute, Pittsburgh, PA; City of Hope, Duarte, CA; University of Wisconsin, Madison, WI; Department of Clinical Metabolism and Pharmacokinetics, Sanofi-Synthelabo, Inc, Malvern, PA, and Alnwick, UK; National Cancer Institute, Bethesda, MD.

Address reprint requests to Chris H. Takimoto, MD, PhD, University of Texas Health Science Center at San Antonio, Cancer Therapy and Research Center, 7979 Wurzbach Rd, Room Z415, San Antonio, TX 78229; email: ctakimot{at}idd.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: This study was undertaken to determine the toxicities, pharmacokinetics, and maximum tolerated doses of oxaliplatin in patients with renal impairment and to develop formal guidelines for oxaliplatin dosing in this patient population.

Patients and Methods: Thirty-seven adult cancer patients with variable renal function received intravenous oxaliplatin at 60 to 130 mg/m² every 3 weeks. Patients were stratified by 24-hour creatinine clearance (CrCL) into four cohorts: group A (controls, CrCL 60 mL/min), group B (mild dysfunction, CrCL 40 to 59 mL/min), group C (moderate dysfunction, CrCL 20 to 39 mL/min), and group D (severe dysfunction, CrCL <20 mL/min). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations.

Results: No dose-limiting toxicities were observed in any patient group during the first cycle of therapy. Escalation of oxaliplatin to the maximum dose of 130 mg/m² was well tolerated in all patient groups with a CrCL 20 mL/min (groups A, B, and C). Pharmacokinetic analysis showed that patients with decreased CrCL had a corresponding decrease in the clearance of plasma ultrafiltrable platinum (r² = 0.765). However, oxaliplatin-induced side effects were not more common or severe in patients with mild to moderate renal dysfunction, despite the decrease in ultrafiltrable platinum clearance.

Conclusion: Oxaliplatin at 130 mg/m² every 3 weeks is well tolerated by patients with mild to moderate degrees of renal dysfunction. These data strongly support the recommendation that dose reductions of single-agent oxaliplatin are not necessary in patients with a CrCL greater than 20 mL/min.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
OXALIPLATIN (ELOXATIN, trans-l-1,2,diaminocyclohexane oxalatoplatinum) is a novel diaminocyclohexane (DACH) platinum derivative with activity in advanced colorectal cancer. Oxaliplatin covalently binds to DNA forming inter- and intrastrand cross-links that block DNA transcription and replication, ultimately resulting in cell death. Oxaliplatin-induced DNA adducts have greater cytotoxic potency than those formed by other platinum analogues, such as cisplatin and carboplatin.^1–3 Furthermore, cell lines resistant to cisplatin as a result of defective mismatch repair⁴ or enhanced replicative bypass activity⁵ are not cross-resistant to oxaliplatin. In preclinical studies, oxaliplatin is broadly active in human tumor xenograft models of colon,^6,7 ovarian,^1,6 head and neck,⁸ breast,⁷ testicular,⁹ and lung cancers.⁸

Oxaliplatin was recently approved by the United States Food and Drug Administration as second-line therapy for patients with advanced colorectal cancer in combination with fluorouracil and leucovorin.¹⁰ As a single agent, oxaliplatin is well tolerated with its major side effects consisting of mild myelosuppression, moderate nausea and vomiting, and dose-limiting neuropathies, which can include paresthesias and dysesthesias of the hands, feet, and perioral region (laryngopharyngeal dysesthesia).^11,12 Neurological symptoms can be acute and/or cumulative and may be exacerbated by cold exposure. Ototoxicity and nephrotoxicity are not prominent, and extensive intravenous hydration is not required after oxaliplatin administration.¹² Oxaliplatin is also active against other malignancies, including non-Hodgkin’s lymphomas¹³ and ovarian^14,15 and non–small-cell lung¹⁶ cancers.

Formal oxaliplatin dosing guidelines in renally impaired patients have not been established; therefore, we initiated this dose-escalating, pharmacokinetic and safety trial of single-agent oxaliplatin in adult cancer patients with renal dysfunction. The primary objective was to determine the maximally tolerated dose of oxaliplatin in patients with renal dysfunction as defined by a 24-hour urinary creatinine clearance (CrCL). The secondary objectives were to define the spectrum and degree of toxicity, to measure pharmacokinetics and pharmacodynamics, and to document any antitumor activity. Rapid accrual of cancer patients to impaired organ function studies is difficult; therefore, the Cancer Treatment Evaluation Program (CTEP) of the National Cancer Institute (NCI) organized the Organ Dysfunction Working Group (ODWG) to study oxaliplatin in special patient populations. A separate NCI ODWG companion study of oxaliplatin in hepatic dysfunction patients was conducted simultaneously.¹⁷

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Eligibility
Enrollment was limited to adult cancer patients with histologically confirmed advanced malignancy. Previous chemotherapy was permitted except for previous treatment with oxaliplatin. Other eligibility criteria included age 18 years, Eastern Cooperative Oncology Group performance status of 0 to 2 (Karnofsky 60%), life expectancy 4 weeks, leukocyte count 3,000/µL, absolute neutrophil count (ANC) 1,500/µL, platelet count 100,000/µL, total bilirubin within normal institutional limits, and hepatic transaminases 1.5 times the upper limit of normal. Peripheral neuropathy judged to be clinically significant by the treating investigator was not permitted. No patients on hemodialysis or peritoneal dialysis were enrolled. Each participating institution’s institutional review board approved the protocol, and written informed consent was obtained from all patients.

Study Design
Nine separate institutions in the NCI Organ Dysfunction Group enrolled patients into one of four cohorts on the basis of measured CrCL (Table 1). In group A (healthy control patients), patients had CrCL more than 60 mL/min; in group B (mild dysfunction), the CrCL was 40 to 59 mL/min; in group C (moderate dysfunction), the CrCL was 20 to 39 mL/min; and in group D (severe dysfunction), the CrCL was less than 20 mL/min. Two separate 24-hour urinary CrCL determinations that did not deviate from each other by more than 25% were required, with the most recent performed within 1 week of study treatment. Stratification was based on the most recent single CrCL measurement. No minimum volume of urine collection in a 24-hour period was required. Different laboratories at each participating institution were used for creatinine assessments, and no cross-site standardization or corrections for creatinine laboratory assay methods were performed

The definition of DLT was as follows: any grade 3 or 4 nonhematologic or hematologic drug-related adverse events, including grade 3 or worse nausea and/or vomiting that occurred despite antiemetic therapy; grade 3 or worse diarrhea that occurred despite antidiarrheal therapy; or a treatment delay of greater than 4 weeks. The NCI Common Toxicity Criteria, Version 2.0, was used to assess all toxicities (http://ctep.info.nih.gov/CTC3/ctc_ind_term.htm) with the exception of an oxaliplatin-specific sensory neuropathy toxicity scale developed by the NCI and Sanofi-Synthelabo (Table 2). Patients were counseled to avoid exposure to cold temperatures because of the potential thermal exacerbation of oxaliplatin neurotoxicity. Laboratory tests were performed weekly, and patients were evaluated for tumor response using traditional, non-RECIST criteria.¹⁸

Sample Acquisition, Handling, and Analytic Methods
Blood samples for plasma and plasma ultrafiltrate platinum concentrations were obtained during cycles 1 and 2 at the following times: before treatment and at the end of the 2-hour infusion; and 2.25, 2.50, 2.75, 3, 5, 8, 24, and 48 hours 1 week, 2 weeks, and 3 weeks after the start of the infusion. Eight milliliters of blood was drawn in heparinized tubes, kept on ice, and centrifuged within 1 hour at 1,000 x g at 4°C to isolate plasma. Approximately 1 mL of plasma was frozen for total platinum analysis, and the remaining plasma was loaded onto an Amicon Centrifree micropartition filter (Millipore, Bedford, MA) and spun at 3,000 x g for 30 minutes at 4°C. The protein-free ultrafiltrates and plasma specimens were frozen and stored at -20°C until shipped to the central laboratory. Total urine output from 0 to 24 hours and 24 to 48 hours was collected, and a 10-mL aliquot from each batch was analyzed for platinum excretion.

All assays were performed at the analytic facilities of Sanofi-Synthelabo Research (Alnwick, United Kingdom) using a validated inductively coupled plasma–mass spectroscopy assay that measures total atomic platinum in plasma, plasma ultrafiltrate, and urine.¹⁹ This method has a limit of quantification of 1 ng/mL in plasma and in plasma ultrafiltrate and 0.1 ng/mL in urine.

Pharmacokinetic Analysis
Oxaliplatin-associated platinum concentrations in plasma and ultrafiltrates were analyzed using compartmental and noncompartmental pharmacokinetic analytic methods. The area-under-concentration versus time curve (AUC) from time 0 to the last measured concentration was calculated for cycles 1 and 2 using the linear trapezoidal rule. Extrapolation of the remaining AUC out to infinity was calculated from the formula C_last/, where C_last is the last measured concentration and is terminal elimination constant that was estimated by linear regression of the terminal elimination portion of the log-linear concentration versus time curve. Most patients had measurable plasma ultrafiltrate platinum concentrations at the last sampling time of 504 hours; therefore, the percentage AUC extrapolated was generally small, averaging less than 11%. All calculations were performed using WinNonLin (Pharsight Corporation, Menlo Park, CA). Clearance was calculated by dividing the dose by the AUC from time 0 to infinity (AUC_0-inf). The platinum excreted in the urine over the first 48 hours in cycles 1 and 2 was expressed as the percentage of total platinum administered during each cycle.

Descriptive statistics (mean ± standard deviation) were calculated for all pharmacokinetic parameters. The relatively small sample sizes of patients precluded formal statistical comparisons of patient groups by organ dysfunction cohort. The relationship between plasma ultrafiltrate platinum clearance and measured CrCL was examined by linear regression.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Demographics
Thirty-seven patients were enrolled at nine sites between December 1999 and March 2001, with 95% of patients enrolling during a 10-month period. Targeted patient accrual goals were met in each organ dysfunction group except in the most severe dysfunction group D. Overall, 12 patients were entered in group A (CrCL 60 mL/min), 10 in group B (CrCL 40 to 59 mL/min), 14 in group C (CrCL 20 to 39 mL/min), and one in group D (CrCL <20 mL/min; Table 1). Patient demographics are summarized in Table 3.

In the moderate renal dysfunction group C, three patients received a total of nine cycles at 80 mg/m², three patients were treated with six cycles at 105 mg/m², and eight patients received 31 cycles at 130 mg/m². Once again, all oxaliplatin dose levels were well tolerated (Tables 4 and 5). At the highest dose level, grade 1 peripheral sensory neuropathy occurred in five patients (63%), and grade 2 was seen in one patient (13%). Hematological toxicities at this dose level included thrombocytopenia that was grade 2 in two patients (26%) and grade 3 in two patients (26%).

The only group D patient was an 82-year-old male pancreatic cancer patient with an additional previous history of bladder cancer treated with a cystectomy and diverting urostomy. His CrCL was 13 mL/min; after his second cycle of oxaliplatin at 60 mg/m², he developed nonneutropenic urosepsis requiring hospitalization. He recovered with supportive care and antibiotics but declined further study treatment.

Other common drug-related toxicities seen in all treatment groups at all dose levels included anemia, fatigue, constipation, injection site irritation, hyperglycemia, anorexia, hypocalcemia, thrombocytopenia, lymphopenia, liver transaminase elevations, and abdominal pain. All were reversible and mild to moderate in severity and were easily managed.

The effect of multiple doses of oxaliplatin on renal function was also explored. One group C patient with a history of obstructive uropathy was treated at 80 mg/m² and experienced a rise in serum creatinine from 1.8 to 3.1 mg/dL after five cycles of therapy. This patient was a 51-year-old woman with a diagnosis of cervical cancer recurrent in the pelvis. She had a history of left-sided nephrostomy tube placements and previous insertion of a left-sided ureteral stent. At the time of study entry, she had a history of chronic mild left-sided hydronephrosis, and after three cycles of oxaliplatin, she was noted to have stable pelvic disease. During her fifth cycle, her serum creatinine began to rise and she noted worsening pelvic pain that was attributed to tumor progression. She was removed from the study, but no follow-up imaging studies of her tumor or kidneys were reported. At 130 mg/m², another group C patient developed an abrupt rise in serum creatinine from a baseline of 2.6 to 4.2 mg/dL after six cycles of oxaliplatin. This patient was a 47-year-old woman with rectal cancer who developed recurrent pelvic and perineal disease after receiving pelvic radiation and chemotherapy. She had a history of chronic hydronephrosis that was stable after two cycles of oxaliplatin. After her sixth cycle, her creatinine began to rise and a magnetic resonance imaging scan revealed 24% increase in the bidimensional measurements of her pelvic tumor. However, no comment was made regarding her kidneys or hydronephrosis. Thus, both patients had a history of obstructive uropathy, and disease progression was the presumed cause of the rising creatinine in both patients; however, a direct drug-related effect could not be completely excluded. However, when all patients were examined collectively, the mean serum creatinine concentration in each treatment cohort did not worsen as the cumulative dose of oxaliplatin increased (Table 6).

Pharmacokinetics
Plasma ultrafiltrate platinum pharmacokinetic data were obtained from 29 patients in cycle 1 (Table 7). At the highest dose level of 130 mg/m², peak concentrations (C_max) were comparable across all renal dysfunction groups (Fig 1). In contrast, systemic platinum exposures increased with increasing renal impairment with mean AUCs of 16.4 ± 5.0 µg/h/mL (n = 11), 39.7 ± 11.5 µg/h/mL (n = 6), and 44.6 ± 14.6 µg/h/mL (n = 5) observed in groups A, B, and C, respectively (Fig 1). Platinum concentrations in unfiltered plasma were more than 10-fold higher than in plasma ultrafiltrate (data not shown), consistent with the known high protein binding of platinum species after oxaliplatin administration. At the end of the infusion, the ratio of unbound to bound C_max platinum concentrations did not correlate with CrCL (r² = 0.00002). Thus, there was no evidence that that renal dysfunction altered the acute protein-binding kinetics of oxaliplatin.

View larger version (17K): [in this window] [in a new window]   Fig 1. Mean ± standard deviation plasma ultrafilterable platinum concentrations in patients with normal, mild, and moderate renal function treated with 130 mg/m2 of oxaliplatin during cycle 1.

View larger version (13K): [in this window] [in a new window]   Fig 2. Relationship between ultrafiltrate platinum clearance (UF Platinum CL) and measured creatinine clearance (CrCL).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Our results are in close agreement with an earlier pharmacokinetic and safety study performed by Massari et al²⁰ that compared 10 patients with an estimated CrCL less than 60 mL/min (median CrCL, 42 mL/min) with a control group of 13 patients (median CrCL, 70.5 mL/min) After a single dose of 130 mg/m² of oxaliplatin, significantly lower plasma ultrafiltrate platinum clearances were observed in the renally impaired patients (14.23 ± 6.04 L/h v 25.70 ± 8.53 L/h; P = .005); however, no increase in clinical toxicity was seen. These investigators also concluded that oxaliplatin dose adjustments were not required for this degree of renal dysfunction. However, in their study, 90% of patients received only one dose of oxaliplatin, and CrCL was estimated instead of measured.

In our study, patients with diminished renal function were exposed to greater amounts of circulating unbound platinum than patients with normal renal function; however, no corresponding increase in oxaliplatin toxicity was observed. Because the unbound platinum fraction is usually considered to be biologically active, this creates an apparent paradox. However, the inductively coupled plasma–spectroscopy assay used in the current study does not distinguish between active and inactive platinum species in ultrafiltrates. In plasma, oxaliplatin is quickly converted into reactive biotransformation products that rapidly form inactive conjugates.²¹ This biotransformation process occurs rapidly after the drug is infused, and the resulting inactive low-molecular-weight platinum species are then excreted by glomerular filtration. Thus, the increased platinum exposure seen in renally impaired patients is to nonreactive drug byproducts. In this regard, oxaliplatin resembles cisplatin in its high plasma reactivity, high protein binding, and rapid biotransformation to inactive drug forms. In contrast, carboplatin is less rapidly inactivated and is less highly protein bound, resulting in greater renal clearance of the active drug. Consequently, carboplatin’s measured platinum AUC is more closely linked to its biologic activity.²²

In a recent review, Graham et al²³ demonstrated that the kinetics of oxaliplatin platinum in plasma ultrafiltrates are well described by a triexponential model with a short initial alpha-phase half-life of 0.28 hours, a longer beta-phase of approximately 16.3 hours, and a very long terminal gamma-phase of 273 hours. The short initial alpha-phase half-life of platinum in plasma ultrafiltrate likely represents the rapid clearance of the biologically relevant intact oxaliplatin and its reactive biotransformation products via reactions with large macromolecules and via distribution into tissue compartments.²¹ We hypothesize that these processes are independent of renal function and are more relevant to systemic exposures to the pharmacologically active drug species. In our study, all patients who were treated at 130 mg/m², regardless of renal function, had comparable platinum exposures during the first 2 hours of drug infusion as evidenced by the uniform C_max values (Table 7). In contrast, the subsequent beta elimination phase represents the renal clearance of inactive platinum species that did not correlate with drug toxicity. Recent studies have shown that as early as 3 hours after an oxaliplatin infusion, most of the parent oxaliplatin species has disappeared from plasma ultrafiltrates.²¹ Finally, the long terminal gamma-phase is hypothesized to represent the slow release of inactive platinum-amino acid conjugates arising from the degradation of cellular macromolecules. Proof of this complex hypothesis will require sensitive chromatographic techniques that can distinguish between active and inactive oxaliplatin biotransformation products.²¹ Unfortunately, such methods are technically challenging and cannot be applied to stored plasma specimens because of the instability of these metabolites; hence, oxaliplatin biotransformation products were not measured in the current study.²⁴

Our patients were stratified by their CrCL uncorrected for body size; however, oxaliplatin dosing was individually scaled to body-surface area (BSA; mg/m²). Several prominent experts have denounced the uncritical application of BSA-adjusted drug dosing in medical oncology in general^25–28 and in our study specifically.²⁹ In retrospect, it would have been logical to stratify our patients by CrCL indexed for BSA (expressed as mL/min/1.73m²) to match the BSA-based dosing scheme. Indexing CrCL to a standard BSA of 1.73 m² is a common practice in nephrology²⁹ and would avoid penalizing smaller patients by placing them in lower categories of renal function. Future studies of this type should strongly consider the routine use of corrections for BSA when stratifying patients by CrCL. In the current report, we have recalculated all clearance parameters in terms of BSA (Table 7); however, we have maintained the original CrCL stratification scheme used during the actual conduct of the study to provide consistency in the treatment and dosing groups. Fortunately, use of a BSA-indexed CrCL would not greatly alter our study design, because only three patients would require reclassification. One group A patient treated at 130 mg/m² would have moved to group B (CrCL of 69 mL/min v 58.5 mL/min/1.73 m²), a group B patient treated at 105 mg/m² would have been reassigned to group A (57 mL/min v 62 mL/min/1.73 m²), and a single patient in group C treated at 80 mg/m² would have moved to group B (38 mL/min v 44.7 mL/min/1.73 m²). These changes do not alter the overall conclusions of our study. Another potential source of bias was the lack of standardization of the methods used for measuring creatinine at different participating sites in our study. A recent report by Leger et al³⁰ demonstrates that the uncorrected use of the older Jaffe colorimetric assay for serum creatinine instead of the biochemical creatinine amidohydrolase enzymatic assay results in underestimation of the creatinine clearance potentially leading to underdosing of carboplatin. Fortunately, this bias is less clinically relevant for our study as a result of lack of association between oxaliplatin dosing and renal function.

Finally, completion of this oxaliplatin renal dysfunction study was relatively rapid for this difficult-to-accrue patient population. This multicenter trial highlights how close collaboration among industry, academia, and the federal government can address fundamentally important clinical questions in a timely manner for the benefit of cancer patients. Currently, the second generation of NCI-sponsored Organ Dysfunction Group clinical trials of novel anticancer agents in patients with liver and renal dysfunction is ongoing, and future studies are planned.

In summary, full doses of single-agent oxaliplatin at 130 mg/m² can be safely administered repeatedly every 3 weeks to patients with mild to moderate renal dysfunction (measured CrCL 20 mL/min). Overall, the clearance of platinum from plasma ultrafiltrates strongly correlates with measured CrCL; however, increased platinum exposures are not associated with increased oxaliplatin-induced toxicities. Our data strongly support the clinical recommendation that dose reductions of oxaliplatin administered as a single-agent are not necessary in patients with a CrCL greater than 20 mL/min.

	ACKNOWLEDGMENTS

 
We thank Dr William G. Price, Jr at Theradex (Princeton, NJ) and Dr Bennett Kauffman, Dr Carolyn Nagler, and Dr Jane H. Ransom at TRI/PSI (Bethesda, MD) for invaluable support in the conduct of this study and to Stuart McDougall, Peter White, and Jane Atkinson at Sanofi-Synthelabo for excellent technical help in providing the platinum bioanalytical data. We also recognize the efforts of NIH-supported General Clinical Research Centers that provided support for the pharmacokinetic monitoring of patients enrolled in this trial (MO1 RR-00080).

	NOTES

 
Supported in part by National Cancer Institute (Bethesda, MD) grants U01CA069853, U01CA062502, U01CA069856, U01CA076642, U01CA062505, U01CA062491, and U01CA069855.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Rixe O, Ortuzar W, Alvarez M, et al: Oxaliplatin, tetraplatin, cisplatin, and carboplatin: Spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute’s Anticancer Drug Screen panel. Biochem Pharmacol 52:1855–1865, 1996[CrossRef][Medline]

2. Woynarowski JM, Chapman WG, Napier C, et al: Sequence- and region-specificity of oxaliplatin adducts in naked and cellular DNA. Mol Pharmacol 54:770–777, 1998[Abstract/Free Full Text]

3. Schmidt W, Chaney SG: Role of carrier ligand in platinum resistance of human carcinoma cell lines. Cancer Res 53:799–805, 1993[Abstract/Free Full Text]

4. Fink D, Nebel S, Aebi S, et al: The role of DNA mismatch repair in platinum drug resistance. Cancer Res 56:4881–4886, 1996[Abstract/Free Full Text]

5. Vaisman A, Varchenko M, Umar A, et al: The role of hMLH1, hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: Correlation with replicative bypass of platinum-DNA adducts. Cancer Res 58:3579–3585, 1998[Abstract/Free Full Text]

6. Pendyala L, Creaven PJ: In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin. Cancer Res 53:5970–5876, 1993[Abstract/Free Full Text]

7. Silvestro L, Anal H, Sommer F, et al: Comparative effects of a new platinum analog (trans-1-diamine-cyclohexane oxalato-platinum; L-OHP) with CDDP on various cells: Correlation with intracellular accumulation. Anticancer Res 10:1376, 1990

8. Fukuda M, Ohe Y, Kanzawa F, et al: Evaluation of novel platinum complexes, inhibitors of topoisomerase I and II in non-small cell lung cancer (NSCLC) sublines resistant to cisplatin. Anticancer Res 15:393–398, 1995[Medline]

9. Dunn TA, Schmoll HJ, Grunwald V, et al: Comparative cytotoxicity of oxaliplatin and cisplatin in non- seminomatous germ cell cancer cell lines. Invest New Drugs 15:109–114, 1997[CrossRef][Medline]

10. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947, 2000[Abstract/Free Full Text]

11. Misset JL: Oxaliplatin in practice. Br J Cancer 77:4–7, 1998 (suppl 4)

12. Mani S, Graham MA, Bregman DB, et al: Oxaliplatin: A review of evolving concepts. Cancer Invest 20:246–263, 2002[CrossRef][Medline]

13. Chau I, Webb A, Cunningham D, et al: An oxaliplatin-based chemotherapy in patients with relapsed or refractory intermediate and high-grade non-Hodgkin’s lymphoma. Br J Haematol 115:786–792, 2001[CrossRef][Medline]

14. Chollet P, Bensmaine MA, Brienza S, et al: Single agent activity of oxaliplatin in heavily pretreated advanced epithelial ovarian cancer. Ann Oncol 7:1065–1070, 1996[Abstract/Free Full Text]

15. Dieras V, Bougnoux P, Petit T, et al: Multicentre phase II study of oxaliplatin as a single-agent in cisplatin/carboplatin +/- taxane-pretreated ovarian cancer patients. Ann Oncol 13:258–266, 2002[Abstract/Free Full Text]

16. Monnet I, Brienza S, Hugret F, et al: Phase II study of oxaliplatin in poor-prognosis non-small cell lung cancer (NSCLC). ATTIT. Association pour le Traitement des Tumeurs Intra Thoraciques. Eur J Cancer 34:1124–1127, 1998[CrossRef][Medline]

17. Doroshow JH, Synold T, Longmate J, et al: Phase I pharmacokinetic (PK) trial of oxaliplatin (OX) in solid tumor patients (Pts) with Varying degrees of liver dysfunction (LD). Proc Am Soc Clin Oncol 20:113a, 2001

18. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655, 1982[Medline]

19. Morrison JG, White P, McDougall S, et al: Validation of a highly sensitive ICP-MS method for the determination of platinum in biofluids: Application to clinical pharmacokinetic studies with oxaliplatin. J Pharm Biomed Anal 24:1–10, 2000[CrossRef][Medline]

20. Massari C, Brienza S, Rotarski M, et al: Pharmacokinetics of oxaliplatin in patients with normal versus impaired renal function. Cancer Chemother Pharmacol 45:157–164, 2000[CrossRef][Medline]

21. Allain P, Heudi O, Cailleux A, et al: Early biotransformations of oxaliplatin after its intravenous administration to cancer patients. Drug Metab Dispos 28:1379–1384, 2000[Abstract/Free Full Text]

22. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748–1756, 1989[Abstract]

23. Graham MA, Lockwood GF, Greenslade D, et al: Clinical pharmacokinetics of oxaliplatin: A critical review. Clin Cancer Res 6:1205–1218, 2000[Abstract/Free Full Text]

24. Gamelin E, Boisdron-Celle M, Lebouil A, et al: Determination of unbound platinum after oxaliplatin administration: Comparison of currently available methods and influence of various parameters. Anticancer Drugs 9:223–228, 1998[Medline]

25. Grochow LB, Baraldi C, Noe D: Is dose normalization to weight or body surface area useful in adults? J Natl Cancer Inst 82:323–325, 1990[Free Full Text]

26. Loos WJ, Gelderblom H, Sparreboom A, et al: Inter- and intrapatient variability in oral topotecan pharmacokinetics: Implications for body-surface area dosage regimens. Clin Cancer Res 6:2685–2689, 2000[Abstract/Free Full Text]

27. Dobbs NA, Twelves CJ: What is the effect of adjusting epirubicin doses for body surface area? Br J Cancer 78:662–666, 1998[Medline]

28. Gurney H: Dose calculation of anticancer drugs: A review of the current practice and introduction of an alternative. J Clin Oncol 14:2590–2611, 1996[Abstract]

29. Ratain MJ: Dear doctor: We really are not sure what dose of capecitabine you should prescribe for your patient. J Clin Oncol 20:1434–1435, 2002[Free Full Text]

30. Leger F, Seronie-Vivien S, Makdessi J, et al: Impact of the biochemical assay for serum creatinine measurement on the individual carboplatin dosing: A prospective study. Eur J Cancer 38:52–56, 2002[Medline]

Submitted November 4, 2002; accepted February 21, 2003.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				J. Gibbons, M. J. Egorin, R. K. Ramanathan, P. Fu, D. L. Mulkerin, S. Shibata, C. H.M. Takimoto, S. Mani, P. A. LoRusso, J. L. Grem, et al. Phase I and Pharmacokinetic Study of Imatinib Mesylate in Patients With Advanced Malignancies and Varying Degrees of Renal Dysfunction: A Study by the National Cancer Institute Organ Dysfunction Working Group J. Clin. Oncol., February 1, 2008; 26(4): 570 - 576. [Abstract] [Full Text] [PDF]

				S. M. Lichtman Pharmacology of Antineoplastic Agents for Older Patients ASCO Educational Book, January 1, 2008; 2008(1): 210 - 214. [Abstract] [Full Text] [PDF]

				L. Gamelin, O. Capitain, A. Morel, A. Dumont, S. Traore, L. B. Anne, S. Gilles, M. Boisdron-Celle, and E. Gamelin Predictive Factors of Oxaliplatin Neurotoxicity: The Involvement of the Oxalate Outcome Pathway Clin. Cancer Res., November 1, 2007; 13(21): 6359 - 6368. [Abstract] [Full Text] [PDF]

				D. Superfin, A. A. Iannucci, and A. M. Davies Commentary: Oncologic Drugs in Patients with Organ Dysfunction: A Summary Oncologist, September 1, 2007; 12(9): 1070 - 1083. [Abstract] [Full Text] [PDF]

				C. H. Takimoto, M. A. Graham, G. Lockwood, C. M. Ng, A. Goetz, D. Greenslade, S. C. Remick, S. Sharma, S. Mani, R. K. Ramanathan, et al. Oxaliplatin Pharmacokinetics and Pharmacodynamics in Adult Cancer Patients with Impaired Renal Function Clin. Cancer Res., August 15, 2007; 13(16): 4832 - 4839. [Abstract] [Full Text] [PDF]

				K. Shitara, M. Munakata, O. Muto, R. Okada, S. Mitobe, M. Mino, I. Ikami, and Y. Sakata Hepatic Arterial Infusion of Oxaliplatin for a Patient with Hepatic Metastases from Colon Cancer Undergoing Hemodialysis Jpn. J. Clin. Oncol., August 4, 2007; (2007) hym044v1. [Abstract] [Full Text] [PDF]

				T. W. Synold, C. H. Takimoto, J. H. Doroshow, D. Gandara, S. Mani, S. C. Remick, D. L. Mulkerin, A. Hamilton, S. Sharma, R. K. Ramanathan, et al. Dose-Escalating and Pharmacologic Study of Oxaliplatin in Adult Cancer Patients with Impaired Hepatic Function: A National Cancer Institute Organ Dysfunction Working Group Study Clin. Cancer Res., June 15, 2007; 13(12): 3660 - 3666. [Abstract] [Full Text] [PDF]

				S. M. Lichtman, H. Wildiers, E. Chatelut, C. Steer, D. Budman, V. A. Morrison, B. Tranchand, I. Shapira, and M. Aapro International Society of Geriatric Oncology Chemotherapy Taskforce: Evaluation of Chemotherapy in Older Patients--An Analysis of the Medical Literature J. Clin. Oncol., May 10, 2007; 25(14): 1832 - 1843. [Abstract] [Full Text] [PDF]

				O Mir, J Alexandre, S Ropert, and F Goldwasser Oxaliplatin in inoperable or metastatic bladder cancer Ann. Onc., December 1, 2006; 17(12): 1853 - 1854. [Full Text] [PDF]

				P. T. Murray and M. J. Ratain Estimation of the Glomerular Filtration Rate in Cancer Patients: A New Formula for New Drugs J. Clin. Oncol., July 15, 2003; 21(14): 2633 - 2635. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takimoto, C. H. Articles by Grem, J. L. Search for Related Content PubMed PubMed Citation Articles by Takimoto, C. H. Articles by Grem, J. L. Social Bookmarking                            What's this?