Clinical Cancer Research Prevention Award Frontiers in Basic Cancer Research
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Clinical Cancer Research 13, 3660, June 15, 2007. doi: 10.1158/1078-0432.CCR-06-2385
© 2007 American Association for Cancer Research
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Synold, T. W.
Right arrow Articles by Ivy, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Synold, T. W.
Right arrow Articles by Ivy, P.

Cancer Therapy: Clinical

Dose-Escalating and Pharmacologic Study of Oxaliplatin in Adult Cancer Patients with Impaired Hepatic Function: A National Cancer Institute Organ Dysfunction Working Group Study

Timothy W. Synold1, Chris H. Takimoto2, James H. Doroshow1, David Gandara3, Sridhar Mani4, Scot C. Remick5, Daniel L. Mulkerin6, Anne Hamilton7, Sunil Sharma8, Ramesh K. Ramanathan9, Heinz Josef Lenz10, Martin Graham11, Jeffrey Longmate1, Bennett M. Kaufman12 and Percy Ivy13

Authors' Affiliations: 1 City of Hope Comprehensive Cancer Center, Duarte, California; 2 Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas; 3 University of California, Davis Cancer Center, Sacramento, California; 4 Albert Einstein College of Medicine, Bronx, New York; 5 Case Western Comprehensive Cancer Center, Cleveland, Ohio; 6 University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin; 7 New York University Cancer Institute; 8 Memorial Sloan-Kettering Cancer Center, New York, New York; 9 University of Pittsburgh Comprehensive Cancer Center, Pittsburgh, Pennsylvania; 10 University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California; 11 Department of Clinical Pharmacokinetics and Drug Metabolism, Sanofi-Synthelabo, Inc., Malvern, Pennsylvania; 12 PSI International, Inc., Vienna, Virginia; and 13 Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Chris H. Takimoto, Institute for Drug Development, Cancer Therapy and Research Center, 14960 Omicron Drive, San Antonio, TX 78245-3217. Phone: 210-450-3800; Fax: 210-677-0058; E-mail: ctakimot{at}idd.org.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patients with hepatic impairment and to develop formal guidelines for oxaliplatin dosing in this patient population.

Experimental Design: Sixty adult cancer patients with variable hepatic function received i.v. oxaliplatin ranging from 60 to 130 mg/m2 every 3 weeks. Patients were stratified by levels of total bilirubin, aspartate aminotransferase (AST), and alkaline phosphatase (AP) into five cohorts based on the degree of hepatic dysfunction: control group A [bilirubin, AST, and AP ≤ upper limit of normal (ULN)], mild dysfunction group B (bilirubin ≤ ULN, ULN < AST ≤ 2.5 x ULN, or ULN < AP ≤ 5 x ULN), moderate dysfunction group C (ULN < bilirubin ≤ 3.0 mg/dL, AST > 2.5 x ULN, or AP > 5 x ULN), severe dysfunction group D (bilirubin > 3.0 mg/dL, any AST, and any AP), and liver transplantation group E (any bilirubin, any AST, and any AP). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations.

Results: Dose escalation of single-agent oxaliplatin to 130 mg/m2 was well tolerated in all cohorts. Platinum clearance did not correlate with any liver function test. Two of 56 assessable patients with a diagnosis of laryngeal carcinoma and cervical adenocarcinoma experienced partial responses lasting 3 and 5.5 months.

Conclusions: Oxaliplatin at 130 mg/m2 every 3 weeks was well tolerated in all patients with impaired liver function. Dose reductions of single-agent oxaliplatin are not indicated in patients with hepatic dysfunction.

Oxaliplatin (Eloxatin, trans-l-1,2,diaminocyclohexane oxalatoplatinum) is a novel diaminocyclohexane platinum derivative with clinical utility in the treatment of patients with colorectal cancer. Oxaliplatin can block DNA transcription and replication by covalently binding to form interstrand and intrastrand DNA cross-links, ultimately leading to cell death. Single-agent oxaliplatin is generally well tolerated and its predominant clinical side effects are mild myelosuppression, moderate nausea and vomiting, cold sensitivity, and peripheral neuropathy, both acute and chronic. Oxaliplatin neuropathies can manifest as paresthesias or dysesthesias of the hands, feet, and perioral region (laryngopharyngeal dysesthesia; refs. 1, 2). Oxaliplatin does not cause ototoxicity or nephrotoxicity, and its administration does not require aggressive i.v. hydration (1). On August 9, 2002, the Food and Drug Administration approved oxaliplatin in combination with infusional 5-fluorouracil and leucovorin for the second-line treatment of patients with metastatic colorectal cancer. On January 9, 2004, the Food and Drug Administration approved oxaliplatin combination chemotherapy for the first-line treatment of patients with this same disease.

The majority of platinum derivatives are cleared by renal excretion; however, the effect of hepatic impairment on the pharmacology of agents, such as oxaliplatin, may still be clinically important. Over 40% of colorectal cancer patients have hepatic metastases at necropsy, making the liver the most common site of hematogenous spread (3). Furthermore, liver function abnormalities are common in patients with hepatic metastases. Thus, defining the optimal regimen for administering oxaliplatin to cancer patients with liver dysfunction is an important clinical question. Even if oxaliplatin kinetics are unchanged by hepatic impairment, other factors may be altered, such as albumin plasma protein concentrations, which could affect clinical drug effects. Finally, the Food and Drug Administration guidance for industry specifically states that for drugs with minimal hepatic clearance (<20%), hepatic impairment studies may still be of value if the agents have a narrow therapeutic range (4). Anticancer chemotherapeutic drugs, such as the platinum derivatives, are generally considered narrow therapeutic range agents. For these reasons, there is distinct clinical relevance to testing widely used anticancer agents, such as oxaliplatin, in this patient population (5).

Because no formal guidelines exist for oxaliplatin dosing in cancer patients with hepatic impairment, we initiated this dose-escalating, pharmacokinetic, and safety trial of single-agent oxaliplatin in patients with hepatic dysfunction as defined by the following liver function tests: total bilirubin, serum aspartate aminotransferase (AST), and serum alkaline phosphatase (AP). The primary objective was to determine the maximally tolerated dose of oxaliplatin in patients with hepatic dysfunction, and secondary objectives included defining the toxicity profile of this regimen, monitoring platinum pharmacokinetics, and characterizing any antitumor activity. This study was conducted by the National Cancer Institute (NCI) Organ Dysfunction Working Group and coordinated by the NCI Cancer Therapy Evaluation Program. A separate NCI Organ Dysfunction Working Group companion study in renal dysfunction patients was conducted simultaneously (6).


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Patient eligibility. Patients were eligible for this trial if they were ≥18 years of age with histologically confirmed advanced malignancy and if previously treated with ≤3 prior chemotherapy regimens. Prior platinum, but not oxaliplatin, chemotherapy was permitted. Other eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 to 2 (Karnofsky ≥60%), leukocyte count ≥3,000/µL, absolute neutrophil count ≥1,500/µL, platelet count ≥100,000/µL, creatinine within normal institutional limits, or measured creatinine clearance ≥60 mL/min for patients with creatinine levels above institutional normal, and no history of brain metastases or significant peripheral neuropathy. Each participating institution's institutional review board approved the protocol, and written informed consent was obtained from all patients.

Study design. Eight separate institutions in the NCI Organ Dysfunction Working Group enrolled patients into one of five cohorts based on the degree of liver dysfunction (Table 1 ). All liver function tests were completed within 24 h of the start of treatment. Different laboratories at each participating institution were used for assessments, and no cross-standardization or corrections for assay methods were done.


View this table:
[in this window]
[in a new window]

  		Table 1. Definition of liver dysfunction groups

 
Oxaliplatin was infused through a central or peripheral vein over 2 h every 3 weeks at the doses listed in Table 2 . Three patients were enrolled per dose level, and if no cycle 1 dose-limiting toxicities (DLT) were observed, then the dose was increased in three new patients. If one of the first three patients experienced a DLT, then the cohort was expanded up to six total patients. If the total number of DLT patients at any dose level was two or more, then dose escalation was discontinued and additional patients were enrolled at the next lowest dose level. A minimum of six patients were to be treated at the highest dose level deemed to be tolerable in each organ dysfunction group except for group A, in which 12 patients were enrolled as pharmacokinetic controls. If dose escalation was halted in groups B or C, then further escalation above this dose level was not permitted in the more severely impaired cohorts. Similarly, if a dose was shown to be safe in a worse hepatic dysfunction group, then escalation to this same dose was allowed in new patients enrolling in the less severe hepatic dysfunction groups. No dose escalation was permitted >130 mg/m2 in any patient cohort. All patients were treated with a prophylactic antiemetic regimen in common use for platinum-based chemotherapy selected at the discretion of each treating investigator. Typically, this consisted of a serotonin (HT3) receptor antagonist, such as ondansetron, administered i.v. with dexamethasone and a short-acting benzodiazepine, such as lorazepam.


View this table:
[in this window]
[in a new window]

  		Table 2. Organ dysfunction groups and dose levels

 
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/vomiting occurring despite optimal antiemetic therapy; grade 3 or worse diarrhea in association with optimal antidiarrheal therapy; or a treatment delay greater than 4 weeks. The NCI Common Toxicity Criteria, version 2.0, was used to assess all toxicities, with the exception of an oxaliplatin-specific sensory neuropathy scale developed by the NCI and Sanofi-Synthelabo (6). Patients were counseled to avoid cold temperatures because of the potential to induce oxaliplatin paresthesias. Laboratory tests were done weekly, and patients were evaluated for tumor response using Eastern Cooperative Oncology Group criteria (7).

Drug formulation and administration. Oxaliplatin was supplied by NCI/Cancer Therapy Evaluation Program as a sterile freeze-dried powder for i.v. administration in glass vials containing 50 or 100 mg oxaliplatin and lactose monohydrate. Oxaliplatin was provided to the NCI under a cooperative research and development agreement with Sanofi-Synthelabo. Oxaliplatin was diluted into a volume of 250 to 500 mL of 5% dextrose in water and administered as a continuous 2-h i.v. infusion within 8 h of preparation.

Sample acquisition, handling, and analytic methods. Blood samples for plasma and plasma ultrafiltrate platinum concentrations were collected during cycles 1 and 2 before treatment, at the end of the 2-h infusion, at 2.25, 2.75, 3, 5, 8, 24, and 48 h after the start of the infusion, and at 1, 2, and 3 weeks after treatment. Plasma and plasma ultrafiltrate samples were prepared as described previously (6). Total urine output from 0 to 24 and 24 to 48 h was collected during cycle 1 of therapy, and a 10-mL aliquot from each pool was analyzed to determine platinum excretion.

All oxaliplatin assays were done in the Analytical Pharmacology Core facility at the City of Hope using a validated atomic absorption assay. The method has a limit of quantitation of 10 ng/mL and an intraday and interday precision and accuracy within ± 10%.

Pharmacokinetic analysis. Oxaliplatin-associated platinum pharmacokinetics in plasma and ultrafiltrates were analyzed as described previously (6). Mean values of kinetic variables in each liver dysfunction groups A to D were compared by ANOVA methods and by analysis of covariance methods to adjust for dose effect. Terminal elimination half-life from plasma (t1/2) was the only variable with highly skewed distribution, and its corresponding significance tests were evaluated using rank values. The relationships between plasma ultrafiltrate platinum clearance and measured organ dysfunction variables (bilirubin, AST, and AP) were examined by linear regression.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Patient demographics. Sixty patients were enrolled at eight sites between February 2000 and June 2001, with 83% of patients enrolling during the first 10-month period and all 60 patients enrolled within 15 months. Targeted patient accrual goals were met in each organ dysfunction group except the transplant group, where only a single patient was enrolled (group E). Overall, 12 patients were entered in group A, 15 in group B, 16 in group C, and 16 in group D. Patient demographics are summarized in Table 3 .


View this table:
[in this window]
[in a new window]

  		Table 3. Patient demographics

 
Clinical toxicities. Toxicity data were assessable in 187 courses of oxaliplatin administered to 60 patients. One DLT was observed in group B at a dose of 105 mg/m2 (grade 3 cold-induced paresthesia), three DLTs in group C at 80 mg/m2 (grade 3 AP plus grade 3 AST, grade 3 alanine aminotransferase, and grade 3 hyperglycemia), and two DLTs in group D also at 80 mg/m2 (one grade 3 {gamma}-glutamyl transpeptidase and one grade 3 hyperglycemia). The DLTs observed in the group C and group D patients were grade 3 metabolic disorders, and although they were reported initially as oxaliplatin related, after a comprehensive retrospective review, progressive metastatic disease was felt to be the underlying etiology. Furthermore, because no DLTs were observed at the two highest dose levels, the maximally tolerated dose was defined as 130 mg/m2 oxaliplatin for both group C and D patients.

In the control group A, 12 patients received 46 cycles of oxaliplatin. All were started at 130 mg/m2 oxaliplatin, although two patients were later dose reduced to 104 mg/m2 because of grade 4 hyperuricemia (one patient) and lymphopenia (one patient). Overall, myelosuppression was modest (Table 4 ), and nonhematologic toxicities included grade 1 nausea in three patients (25%), grade 1 fatigue (25%), and grade 2 nausea and vomiting (33%). The most common drug-related toxicity was peripheral neuropathy, which was grade 1 in eight (67%) patients and grade 2 in two (16%) patients.


View this table:
[in this window]
[in a new window]

  		Table 4. Drug-related hematologic adverse events by patient in any cycle

 
In group B, five patients were administered a total of 14 cycles at 105 mg/m2, and 10 were treated for 37 cycles at 130 mg/m2. Both dose levels were well tolerated with one grade 3 sensory neuropathy reported at the 105 mg/m2 dose level. Grade 1 nausea and fatigue occurred in 25% of the patients at the 130 mg/m2 dose level, and five (50%) patients experienced grade 1 peripheral neuropathy. One group B patient in the 130 mg/m2 cohort experienced a grade 4 oxaliplatin-related hypersensitivity reaction during the seventh cycle of therapy and was not rechallenged.

In group C, eight patients received 13 cycles of oxaliplatin at 80 mg/m2, three patients received 12 cycles at 105 mg/m2, and 5 patients received 10 cycles at 130 mg/m2. All oxaliplatin dose levels were well tolerated, and no grade 3 or worse hematologic adverse events were reported (Table 4). Two patients in each of the lower dose levels experienced grade 1 neuropathies (25% and 67% of patients in the 80 and 105 mg/m2 groups, respectively) as did four (80%) patients in the highest dose group.

In the severe dysfunction group D, five patients received 13 cycles at 60 mg/m2, four patients received 12 cycles at 80 mg/m2, four patients received 16 cycles at 105 mg/m2, and three patients received 5 cycles at 130 mg/m2. Hematologic adverse events were few, with only one grade 2 decreased hemoglobin in the 60, 80, and 130 mg/m2 dose groups. Likewise, sensory neuropathies were limited, with three instances (75% of patients) of grade 1 at the 105 mg/m2 dose level. The single liver transplant patient in group E received four cycles of oxaliplatin at 60 mg/m2, which were extremely well tolerated (Table 4).

An increase in total bilirubin occurred in later cycles at the lowest dose in one patient with severe hepatic dysfunction, and bilirubin elevations improved in a single group D patient treated at the highest dose level. However, overall, there was no evidence of any consistent drug-related alterations in bilirubin or AST or AP (data not shown) in any cohort of hepatically impaired patients.

Four patients were removed from the study due to treatment-related toxicities. One group A patient withdrew after experiencing grade 2 fatigue, diarrhea, vomiting, and memory loss after four cycles of oxaliplatin (three of which were at a reduced dose of 105 mg/m2). Two patients in group B treated with 130 mg/m2 were removed after one experienced a grade 4 hypersensitivity reaction and another developed worsening neurosensory changes after five courses. A patient in the group C 130 mg/m2 cohort experienced modest thrombocytopenia during the second cycle of treatment that did not resolve in time to continue therapy. No treatment-related toxic death occurred in this study.

Efficacy evaluation. Overall, 56 of the total 60 patients enrolled were evaluated for tumor response. Two patients had partial responses: one in the control group with laryngeal carcinoma and a second in group D at the 130 mg/m2 dose level with cervical adenocarcinoma. Twenty-two patients (39% overall) had stable disease as their best response. One patient in group A with adenocarcinoma with an unknown primary had stable disease for ~6 months, and another patient in group D with hepatocellular carcinoma treated at 80 mg/m2 had stable disease for more than 5 months.

Pharmacokinetics. Plasma platinum pharmacokinetics were monitored in 54 patients in cycle 1 (Fig. 1 ; Table 5 ). At the highest dose level of 130 mg/m2, peak plasma concentrations (Cmax) were comparable across all hepatic dysfunction groups. Clearance of ultrafilterable platinum was also comparable in groups A, B, and C at the 130 mg/m2 dose level (Fig. 1; Table 5). The small number of patients with pharmacokinetic data in groups D and E precludes formal comparisons in these cohorts. Alterations in hepatic function had no effect on ultrafiltrate platinum Cmax or the initial distribution half-life. No correlation was found between urinary platinum elimination and liver dysfunction group (data not shown). Ultrafilterable platinum clearance did not correlate with total bilirubin (correlation coefficient, r = –0.23; P = 0.13), AST (r = 0.01; P = 0.95), or AP (r = –0.09; P = 0.57) concentrations.


Figure 1
View larger version (9K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Ultrafilterable platinum concentration versus time plots for patients receiving a dose 130 mg/m2 in each of the liver function cohorts.

 

View this table:
[in this window]
[in a new window]

  		Table 5. Cycle 1 pharmacokinetic variables of platinum in plasma ultrafiltrates, mean (SD)

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
In our study, the highest dose of single-agent oxaliplatin of 130 mg/m2 every 3 weeks was well tolerated in all patients, independent of the degree of hepatic dysfunction. These data support the recommendation that dose modifications of single-agent oxaliplatin are not required for patients with liver dysfunction. Furthermore, there is no evidence for any cumulative oxaliplatin-induced hepatotoxicity in this patient population, although the number of patients treated with multiple cycles of therapy was relatively small.

As shown in Fig. 1, the liver function variables used to stratify patients into liver dysfunction cohorts (bilirubin, AST, and AP) were not associated with significant differences in oxaliplatin platinum clearance from plasma ultrafiltrates. Only serum creatinine showed a statistically significant association. These data are consistent with our companion study of oxaliplatin pharmacokinetics in patients with renal dysfunction that showed a strong association between platinum clearance from plasma ultrafiltrates and creatinine clearance (6). However, even in patients with moderate renal dysfunction (creatinine clearance ≥ 20 mL/min), dose modifications of single-agent oxaliplatin are not required because the increase in systemic exposure to oxaliplatin-associated platinum species is not associated with increased oxaliplatin-induced toxicities (6).

This apparent paradox is explained, in part, by the poor correlation between the pharmacokinetics of undifferentiated platinum species in plasma ultrafiltrates and clinical drug effects. As summarized by Graham et al. (8), the kinetics of oxaliplatin-associated platinum in plasma ultrafiltrates are well described by a multicompartmental model with a relatively brief initial half-life of 0.28 h, with much longer terminal elimination phase of elimination. The short initial phase half-life of platinum in plasma ultrafiltrates reflects the rapid conversion of oxaliplatin into reactive biotransformation products that quickly form inactive conjugates (9). In contrast, the later phases of platinum clearance reflect the renal elimination of largely inactive platinum species that do not correlate with clinical drug effects. Unfortunately, analysis of platinum species in plasma using inductive-coupled plasma mass spectrometry or atomic absorption spectroscopy cannot distinguish between active and inactive oxaliplatin biotransformation products. Two to 3 h after the infusion, the majority of active oxaliplatin species have disappeared from plasma (9).

Phase I liver dysfunction studies are complicated by the lack of easily measurable variables that are predictive of the clearance of hepatically eliminated drugs (5). In our study, oncology patients were stratified by the NCI Organ Dysfunction Working Group criteria based on bilirubin, AST, and AP measurements. Although, the validity of these variables to predict drug clearance on a consistent basis has not been shown, this stratification provides an easy and practical means to minimize risk for dose escalation studies in cancer patients with hepatic impairment. Current Food and Drug Administration guidelines for hepatic dysfunction studies recommend the stratification of patients by Child-Pugh classification, which is based on assessments of bilirubin, albumin, prothrombin time, encephalopathy, and ascities (4). Because the Child-Pugh criteria were intended originally to assess surgical risk in cirrhotic patients, it has several potential disadvantages for use in oncology patients (10). For example, variables, such as encephalopathy, may not be relevant to solid tumor patients, and albumin levels may reflect a patient's nutritional status in addition to hepatic synthetic capacity. Finally, the majority of our patients had liver dysfunction secondary to hepatic metastases; however, no attempt was made to discern the underlying cause of liver impairment in individual patients. Further studies on the optimal method for reducing risk and predicting hepatic drug clearance in cancer patients are necessary to establish standard stratification criteria for these important types of oncology studies. Nonetheless, the lack of correlation between oxaliplatin clearance and assessments of liver function make these study design issues less relevant for dosing oxaliplatin-based chemotherapy.

In common practice, oxaliplatin is administered in combination with fluoropyrimidine-based therapy and not as a single agent. Thus, our data do not provide direct dosing guidelines for this clinical situation. Nonetheless, the data derived here are compelling in that they suggest that dose reductions are not indicated for oxaliplatin-based chemotherapy in patients with severe hepatic dysfunction.

In summary, full doses of single-agent oxaliplatin at 130 mg/m2 can be safely administered every 3 weeks to cancer patients with hepatic dysfunction. Oxaliplatin-associated platinum clearance from plasma ultrafiltrates did not correlate with any measure of liver function and no increase in oxaliplatin-induced toxicities was observed in patients with any degree of hepatic dysfunction. Our data support the recommendation that dose reductions of single-agent oxaliplatin are not necessary in patients with hepatic dysfunction.


   Acknowledgments
 
We thank Dr. William G. Price, Jr. (Theradex, Princeton, NJ) and Dr. Carolyn Nagler (TRI/PSI, Bethesda, MD) for their invaluable support in conducting this study.


   Footnotes
 
Grant support: National Cancer Institute (Bethesda, MD) grants U01CA062505, U01CA033572, U01CA069853, U01CA062502 and MO1RR00080, U01CA069856, U01CA076642, U01CA062491, U01CA013330, U01CA069855, and RR00056.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/27/06; revised 2/ 6/07; accepted 3/29/07.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

  1. Mani S, Graham MA, Bregman DB, Ivy P, Chaney SG. Oxaliplatin: a review of evolving concepts. Cancer Invest 2002;20:246–63.[CrossRef][Medline]
  2. Misset JL. Oxaliplatin in practice. Br J Cancer 1998;77 Suppl 4:4–7.[Medline]
  3. Weiss L, Grundmann E, Torhorst J, et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol 1986;150:195–203.[CrossRef][Medline]
  4. Food and Drug Administration. Guidance for Industry. Pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. In: Services USDoHaH, editor. 2003.
  5. Egorin M. The effects of organ dysfunction on drug dosing. Clin Adv Hematol Oncol 2006;4:116–8.[Medline]
  6. Takimoto CH, Remick SC, Sharma S, et al. Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study. J Clin Oncol 2003;21:2664–72.[Abstract/Free Full Text]
  7. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649–55.[Medline]
  8. Graham MA, Lockwood GF, Greenslade D, Brienza S, Bayssas M, Gamelin E. Clinical pharmacokinetics of oxaliplatin: a critical review. Clin Cancer Res 2000;6:1205–18.[Abstract/Free Full Text]
  9. Allain P, Heudi O, Cailleux A, et al. Early biotransformations of oxaliplatin after its intravenous administration to cancer patients. Drug Metab Dispos 2000;28:1379–84.[Abstract/Free Full Text]
  10. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646–9.[Medline]



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
E. Chen, D. Jonker, I. Gauthier, M. MacLean, J. Wells, J. Powers, and L. Seymour
Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer
Clin. Cancer Res., February 15, 2009; 15(4): 1481 - 1486.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
H.-J. Wester
Nuclear Imaging Probes: from Bench to Bedside
Clin. Cancer Res., June 15, 2007; 13(12): 3470 - 3481.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Synold, T. W.
Right arrow Articles by Ivy, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Synold, T. W.
Right arrow Articles by Ivy, P.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online