|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 26, No 11 (April 10), 2008: pp. 1797-1802 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.8388 Phase I Study of a Novel Capecitabine Schedule Based on the Norton-Simon Mathematical Model in Patients With Metastatic Breast Cancer
From the Memorial Sloan-Kettering Cancer Center, New York, NY; and Roche Laboratories, Nutley, NJ Corresponding author: Tiffany A. Traina, MD, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: trainat{at}mskcc.org
Purpose This study was conducted to determine, in patients with advanced-stage breast cancer, the maximum tolerated dose (MTD) of capecitabine administered orally for 7 days followed by a 7-day rest (7/7), a schedule based on a mathematical method for the optimization of anticancer drug scheduling. Patients and Methods Eligible patients had measurable, metastatic breast cancer. There was no limit to number of prior treatments. A standard, three-patients-per-cohort dose-escalation scheme used flat-dose capecitabine beginning at 1,500 mg orally twice daily (bid) on a 7/7 schedule. Each cohort was monitored for 28 days before escalation to the next cohort to assess for delayed toxicity. Response was evaluated radiographically every 12 weeks; toxicity was assessed every 2 weeks. Results Twenty-one patients were treated on study. The most frequently reported treatment-related grade 2/3 adverse events were hand-foot syndrome (29%), leukopenia/neutropenia (24%), and fatigue (19%). Grade 3 toxicity was transient and easily managed. Three patients experienced grade 3 hand-foot syndrome; one of these patients had grade 3 diarrhea. There were no grade 4 events. The MTD of capecitabine 7/7 is 2,000 mg twice daily. Conclusion As predicted by mathematical modeling, capecitabine dosing for 7 days followed by a 7-day rest is well tolerated. Efficacy of this schedule is being determined in a phase II clinical trial in patients with advanced breast cancer.
Despite advances in the diagnosis and therapy of primary breast cancer, metastatic disease remains a major public health problem, accounting for more than 40,000 deaths in the United States annually.1 Hence significant improvements in managing advanced disease—including the development of highly active cytotoxic, hormonal, and molecularly targeted agents—have not by themselves provided universally curative regimens. It is clear that possessing effective anticancer drugs is insufficient without better strategies for their application. Mathematical approaches to the description of tumor growth have been shown to predict chemotherapy dosing schedules that increase the efficacy of anticancer drugs without increasing toxicity.2-9 We have used mathematical methods to predict a more effective, less toxic dose schedule for the cytotoxic agent capecitabine (Xeloda; Hoffman-LaRoche, Nutley, NJ) and here describe our initial experience in the clinical application of this regimen.
Mathematical Modeling Optimizes Chemotherapy Delivery Presently, chemotherapy schedules are designed by time-consuming, expensive, and laborious laboratory and clinical experiments. Norton et al13 recently described a method whereby chemotherapy dosing schedules may be optimized by the use of mathematical models of tumor cell growth. An advantage of this approach is that the optimal schedule may be determined more rapidly, more parsimoniously, and more easily. The method, briefly outlined in the Appendix (online only), focuses on rates of change of tumor volume as a function of time, finding the maximum cumulative perturbation within constraints of host tolerance.
Capecitabine
A Novel Capecitabine Dosing Schedule This phase I trial evaluated the tolerability and MTD of the capecitabine 7/7 dosing schedule in patients with advanced breast cancer.
Eligibility Criteria Patients enrolled in this study were more than 18 years of age with histologically confirmed metastatic breast carcinoma that was measurable by Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines criteria. Patients could have received any number of prior endocrine, biologic, or chemotherapy regimens except fluoropyrimidine-containing therapy for the treatment of metastatic breast cancer or as adjuvant therapy within 6 months of enrollment. At least 3 weeks were elapsed from last cytotoxic or biologic therapy. Patients with breast cancer amplified for human epidermal growth factor receptor 2 (HER-2) by fluorescence in-situ hybridization or overexpressed by immunohistochemistry (3+) could not have been candidates for trastuzumab therapy. Patients were required to have an Eastern Cooperative Oncology Group performance status  2, absolute neutrophil count more than 1.5 x 109/L, platelets more than 100 x 109/L, creatinine clearance  50 mL/min by the Cockcroft-Gault equation, bilirubin less than 1.5 times the upper limit of normal, and AST/ALT/alkaline phosphatase less than 2.5 times the upper limit of normal. Pregnant or lactating patients were excluded. Patients could not have had a life expectancy less than 3 months, known dihydropyrimidine dehydrogenase deficiency, untreated symptomatic brain metastases, or uncontrolled gastrointestinal malabsorption. All patients provided signed, informed consent. The protocol was approved by the Memorial Sloan-Kettering Cancer Center institutional review board. The study was conducted in accordance with the Declaration of Helsinki.
Safety Assessments
Trial Design and Study Treatment A standard three-patients-per-cohort dose-escalation schedule began with flat-dose capecitabine 1,500 mg orally bid. There was no intrapatient dose escalation. Dose levels increased by 500-mg increments, as presented in Table 1. All patients within a cohort were monitored for 28 days before accrual to the next dose level. If none of the patients within a cohort experienced DLT, then patients enrolled onto the next dose level. If one of three patients in a cohort experienced a DLT, three additional patients were treated at that dose level; escalation continued if only one of these six patients had a DLT. If more than two patients in a cohort experienced DLT, then the previous dose level was considered the MTD.
Capecitabine was supplied as 500-mg tablets. Patients self-administered capecitabine for 7 days followed by a 7-day rest and maintained a drug diary. Diaries were reviewed and pill counts performed on days 1 and 15 of each cycle. Treatment continued until disease progression, intolerable treatment-related toxicities, or withdrawal of consent. Figure 1 depicts the treatment schema.
Evaluation of Clinical Activity Disease status was established less than 4 weeks before start of therapy with a computed tomography scan of the chest, abdomen, and pelvis and a bone scan. Response assessment was performed every 12 weeks using RECIST criteria.
Patient Characteristics Twenty-one patients were enrolled at Memorial Sloan-Kettering Cancer Center between July 2005 and January 2007. Patient characteristics are listed in Table 2. Nineteen patients (90%) had prior chemotherapy; 17 patients (81%) had prior anthracycline- and taxane-containing regimens. The median number of chemotherapy regimens for metastatic disease was 0 (range, 0 to 2). Thirteen patients received a median of one (range, one to four) endocrine therapy for metastatic disease before capecitabine. Two patients received prior bevacizumab. One patient received prior trastuzumab. The median number of 4-week capecitabine cycles administered was four (range, one to 15), which translates to a median of 105 days on study (range, 6 to 400 days).
Safety and Tolerability Thirteen (62%) of 21 patients experienced treatment-related, grade 2/3 AEs. The most frequently reported grade 2/3 drug-related AEs were HFS (29%), leukopenia/neutropenia (24%), and fatigue (19%). Treatment-related, grade 2/3 toxicity is shown per dose cohort in Table 3. Most AEs were mild and easily managed. Two patients experienced grade 3 elevations of AST. One of these patients also had grade 3 elevation in alkaline phosphatase. Both patients had disease progression associated with these values; therefore, relatedness is unlikely. There were no grade 4 or 5 AEs. One patient from cohort 2 (2,000 mg bid) experienced grade 3 HFS, a DLT, during her second treatment cycle. This improved after a 2-week treatment delay and dose reduction to 1,500 mg bid. Two patients from cohort 3 (2,000 mg/2,500 mg) developed grade 3 HFS; one of these women also had grade 3 diarrhea. In the first patient, HFS improved with a treatment delay of 1 week and dose reduction to 1,500 mg/2,000 mg during cycle 3. With her fifth treatment cycle, she had a 1-week treatment delay and dose reduction to 1,000 mg/1,500 mg for grade 2 HFS. She remained on study for an additional 4 months. The second patient developed grade 3 HFS and grade 3 diarrhea with her eighth treatment cycle. These both resolved after a 1 week treatment delay and dose reduction to 1,500 mg/2,000 mg. On the basis of the two DLTs at the 2,000 mg/2,500 mg dose level, the MTD was observed to be 2,000 mg bid.
Five serious AEs occurred; however, none of these were considered treatment-related. One patient (cohort 0) was hospitalized with nausea/vomiting after registration and before beginning capecitabine; she later withdrew from the trial. Two patients were hospitalized for symptom management related to disease progression and study treatment was discontinued for reasons as follows: (1) a patient (cohort 0) developed paraspinal pain from enlarging epidural disease at T10, and (2) a patient (cohort 2) became dyspneic and fatigued from a large, malignant pericardial effusion requiring hospitalization and management. One patient (cohort 2) with hypertension treated with an angiotensin-converting enzyme inhibitor developed angioedema of the face and lips 5 months after starting capecitabine. She was hospitalized for observation and treated with antihistamines and corticosteroids. It is unlikely that this adverse event was related to capecitabine, although an association could not be ruled out. One patient from cohort 1 developed grade 2 diarrhea and nausea/vomiting for 24 hours after her third cycle. Family members experienced the same symptoms concurrently. She recovered with hydration and antiemetics. These symptoms were felt to be unrelated to capecitabine. She resumed treatment without dose reduction.
Clinical Activity Two patients from the 2,000 mg/2,500 mg cohort continue on study. The protocol stipulates treatment modification guidelines for individual patient safety. One patient has tolerated more than 10 cycles of capecitabine without need for dose reduction. The second patient experienced a DLT after eight cycles, requiring dose reduction and delay. She now receives capecitabine 1,500 mg/2,000 mg and is in her 15th cycle.
Experience has confirmed that mathematical modeling based on growth curve analysis can predict improved chemotherapy schedules.8-10 In animal models, this conceptual approach has determined that the 7/7 schedule of capecitabine preserves efficacy and reduces toxicity sufficiently to allow for significant dose escalation.11,20 Longer than 7 days of daily administration subjects the tumor-bearing host to greater toxicity and diminishing efficacy. That is, in preclinical models, capecitabine 7/7 provides the greatest acceptable dose-intensity and dose-density. We sought to determine the tolerability of this schedule in patients with advanced breast cancer. The novel capecitabine schedule investigated in this population seems to be well tolerated, achieving an MTD of 2,000 mg bid when administered for 7 consecutive days followed by a 7-day rest. Patients were accrued to dose cohorts in consecutive, nonrandomized fashion. There is a trend toward older age and greater exposure to prior chemotherapy for patients in the highest cohort (2,000 mg/2,500 mg), two of whom experienced DLTs. The most common capecitabine-related, grade 3 toxicities were HFS (17%) and diarrhea (6%). There were no grade 4/5 adverse events with this schedule. These toxicity rates are comparable and perhaps a bit lower than previously reported for capecitabine in larger trials. A multicenter trial of conventional capecitabine 14/7 in patients with advanced breast cancer who had received more than two prior chemotherapy regimens reported grade 3/4 diarrhea in 14% of patients and grade 3/4 HFS in 10% of patients.16 Other grade 3 treatment-related toxicities included fatigue (7%), nausea (4%), and vomiting (4%).16 O'Shaughnessy et al20 reported rates of grade 3/4 HFS (16%) and grade 3/4 diarrhea (8%) in patients receiving single-agent capecitabine 14/7. We recognize that cross-trial comparisons are wrought with confounding variables as a result of patient population differences, such as extent of prior therapy. Further testing in large, phase II and III trials will be necessary to better characterize tolerability and activity. We chose to use fixed dosing of capecitabine rather than body-surface area (BSA)–calculated dosing, because evidence for dose selection based on BSA is limited. In fact, it has been recognized that drug clearance cannot be reliably predicted by BSA, and significant interpatient variability exists despite the use of BSA in dose calculation.22-27 Several trials have explored fixed-dose rather than BSA-based dosing of capecitabine. Sharma et al28 reported the use of capecitabine 2,000 mg bid administered conventionally in patients with advanced colorectal cancer. Additional trials have retrospectively explored fixed-dose capecitabine in advanced malignancies29 and prospectively in combination with irinotecan.30 In our trial, the dose of capecitabine 7/7 delivered exceeded the BSA-based, daily recommended capecitabine dose for five (28%) of 18 patients. However, direct comparisons of flat- versus BSA-based dose are difficult to interpret in this manner; if this schedule of administration is truly optimal as predicted by the model, then improved efficacy, better tolerability, and prolonged use of this active agent may be observed with this schedule. The tolerability of capecitabine is known to be influenced by factors other than BSA. Regional differences in tolerability of fluoropyrimidines have been acknowledged. In an analysis of more than 3,000 patients with colorectal cancer treated with fluorouracil-based regimens, fluoropyrimidine therapy was best tolerated in Asian patients and least well tolerated in American patients.31 An emerging factor that may play an important role in drug disposition are genetic polymorphisms in drug-metabolizing enzymes and transport proteins.32-35 An ongoing correlative component of this study explores the impact of germline single nucleotide polymorphisms (SNPs) related to capecitabine metabolism, transport, and resistance and their possible correlation with toxicity and response. Specific SNPs are being explored for the following genes: DYPD, ECGF, TYMS, SLC28A1, and MTHFR. Several alternative dosing strategies for capecitabine have been reported, using traditional methods for determining schedule. These trials, in patients with nonbreast solid tumors, often tested capecitabine in combination with other cytotoxic therapy without conclusion as to optimal schedule. This speaks to the need for a mathematical model that can efficiently predict the optimal schedule for drug development and therefore minimize use of patient and financial resources. For example, two prospective studies tested biweekly capecitabine in colorectal36 and pancreatic37 adenocarcinomas. A dose-escalation trial of biweekly capecitabine in combination with oxaliplatin for the treatment of colorectal cancer defined the MTD of capecitabine as 3,500 mg/m2/d.36 DLTs included gastrointestinal symptoms and HFS. A second, randomized phase II trial explored high-dose gemcitabine with or without biweekly capecitabine for the treatment of metastatic pancreatic cancer. Patients received capecitabine at 2,500 mg/m2/d (7/7). Results suggest that the combination regimen was well tolerated.37 Unfortunately, efficacy attributable to the biweekly capecitabine schedule is impossible to assess in these studies because of trial design. However, these data support the feasibility of this novel schedule. A randomized, phase II trial in patients with colorectal cancer found no difference in efficacy between continuous, low-dose capecitabine (1,331 mg/m2/d) and 2,510 mg/m2/d administered intermittently (14/7).38 However, the intermittent schedule allowed for higher dose-intensity. The dose-intensity of 2,000 mg twice daily (7/7) exceeds that of actual drug delivered on the intermittent monotherapy arm over a 12-week period; however, we are reluctant to draw such comparisons because of significant differences between these two trials. The colorectal trial had participating sites throughout Europe and Australia. There are known differences in drug tolerability regionally; therefore, the amount of drug actually delivered would not likely be achieved in the United States, where we already see that 2,510 mg/m2/d in the conventional schedule often requires dose reductions/delays in practice. We would also contend that the optimal schedule may improve tolerability, allow for prolonged administration of this active agent, and improve efficacy. The results reported here provide preliminary indication that biweekly capecitabine is a potentially optimized alternative to the conventional 14/7 schedule based on mathematical modeling and preclinical evidence. Full validation of the model might require results from ongoing phase II testing and possibly randomized comparison with the conventional 14/7 schedule in a proof-of-principle trial. We recommend a regimen of capecitabine 2,000 mg bid for 7 consecutive days followed by a 7-day rest for phase II evaluation as monotherapy. A phase II program is ongoing at our institution to assess the efficacy of capecitabine 7/7 in patients with advanced breast cancer in terms of response rate, time to progression, and duration of response. This schedule is being tested in combination with bevacizumab, an antivascular endothelial growth factor antibody with activity in breast cancer. Pharmacogenomic correlative studies explore SNPs that might predict for response or toxicity to capecitabine. For patients with HER-2–amplified or –overexpressed breast cancer, capecitabine 7/7 will be tested in combination with HER-2–targeted therapies. We intend to apply this and related mathematical methods to established and investigational cytotoxic agents and to new biologic agents, such as small molecule tyrosine kinase inhibitors. This work and the various capecitabine regimens in development may influence randomized phase III trials evaluating the potential contributions of new agents and novel dose-scheduling strategies.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Ute Dugan, Roche (C) Consultant or Advisory Role: Tiffany A. Traina, Roche (C); Larry Norton, Roche (C); Clifford Hudis, Roche (C) Stock Ownership: Ute Dugan, Roche Honoraria: Tiffany A. Traina, Roche; Larry Norton, Roche; Clifford A Hudis, Roche Research Funding: Tiffany A. Traina, Roche; Maria Theodoulou, Roche; Kimberly Feigin, Roche; Sujata Patil, Roche; K. Lee Tan, Roche; Charles Edwards, Roche; Larry Norton, Roche; Clifford Hudis, Roche Expert Testimony: None Other Remuneration: None
Conception and design: Tiffany A. Traina, Maria Theodoulou, Kimberly Feigin, Sujata Patil, Ute Dugan, Larry Norton, Clifford Hudis Financial support: Ute Dugan, Larry Norton, Clifford Hudis Administrative support: Maria Theodoulou, Charles Edwards, Ute Dugan, Larry Norton, Clifford Hudis Provision of study materials or patients: Tiffany A. Traina, Maria Theodoulou, Kimberly Feigin, K. Lee Tan, Larry Norton, Clifford Hudis Collection and assembly of data: Tiffany A. Traina, Maria Theodoulou, Sujata Patil, K. Lee Tan, Charles Edwards, Larry Norton, Clifford Hudis Data analysis and interpretation: Tiffany A. Traina, Maria Theodoulou, Sujata Patil, Charles Edwards, Larry Norton, Clifford Hudis Manuscript writing: Tiffany A. Traina, Larry Norton, Clifford Hudis Final approval of manuscript: Tiffany A. Traina, Maria Theodoulou, Kimberly Feigin, Sujata Patil, K. Lee Tan, Charles Edwards, Ute Dugan, Larry Norton, Clifford Hudis
The Gompertzian tumor growth of N cells as a function of time t in the unperturbed state is described by the differential equation
where k1 and k2 are constants. In the perturbed state, with treatment starting at time t1, it has been shown that for t
where D(t)
Let treatment be administered daily on day t1, t2, t3... ti for i consecutive days. Then we have observed that for capecitabine and other agents, if a sufficiently large number of administrations i are used, there is a day tm less than ti such that D(tm)/dt is maximal. The proper cycle length is hence m days in duration. In many situations, repeating such cycles of therapy with minimal inter-treatment interval length n maximizes the total growth perturbation of a regimen, expressed as
for the purposes of clinical extrapolation, we are here using m = 7 and n = 7, as determined empirically.
We thank the many patients and investigators who have made this work possible.
Supported by Roche Laboratories Inc. Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007 Chicago, IL (abstr 1045) and at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 14-17, 2006 (abstr 6077). This article is an update and the first complete reporting of the Phase I study. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Jemal A, Siegel R, Ward E, et al: Cancer statistics: 2006. CA Cancer J Clin 56:106-130, 2006 2. Norton L, Simon R, Brereton HD, et al: Predicting the course of Gompertzian growth. Nature 264:542-545, 1976[CrossRef][Medline] 3. Norton L, Simon R: The growth curve of an experimental solid tumor following radiotherapy. J Natl Cancer Inst 58:1735-1741, 1977[Medline] 4. Norton L, Simon R: Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 61:1307-1317, 1977[Medline] 4. Skipper HE: Kinetics of mammary tumor cell growth and implications for treatment. Cancer 28:1479-1499, 1971[CrossRef][Medline] 5. Norton L, Simon R: The Norton-Simon hypothesis revisited. Cancer Treat Rep 70:163-169, 1986[Medline] 6. Speer J, Petrosky VE, Retsky MW, et al: A stochastic numerical model of breast cancer that simulates clinical data. Cancer Res 44:4124-4130, 1984 7. Spratt JA, von Fournier D, Spratt JS, et al: Mammographic assessment of human breast cancer growth and duration. Cancer 71:2020-2026, 1993[CrossRef][Medline] 8. Spratt JA, von Fournier D, Spratt JS, et al: Decelerating growth and human breast cancer. Cancer 71:2013-2019, 1993[CrossRef][Medline] 9. Koscielny S, Tubiana M, Valleron AJ: A simulation model of the natural history of human breast cancer. Br J Cancer 52:515-524, 1985[Medline] 10. Norton L: Conceptual and practical implications of breast tissue geometry: Toward a more effective, less toxic therapy. Oncologist 10:370-381, 2005 11. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003 12. Citron M, Berry DA, Cirrincione C, et al: Dose-dense (DD) AC followed by paclitaxel is associated with moderate, frequent anemia compared to sequential (S) and/or less DD Treatment: Update by CALGB on Breast Cancer Intergroup Trial C9741 with ECOG, SWOG, & NCCTG. J Clin Oncol 23:33s, 2005 (abstr 620) 13. Norton L, Dugan U, Hudis C, et al: Optimizing chemotherapeutic dose-schedule (CDS) by Norton-Simon modeling: Capecitabine (Xeloda). Proc Am Assoc Cancer Res 46:1182, 2005 (abstr 5007) 15. Blum JL, Dieras V, Lo Russo PM, et al: Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 92:1759-1768, 2001[CrossRef][Medline] 16. Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485-493, 1999 17. Reichardt P, Von Minckwitz G, Thuss-Patience PC, et al: Multicenter phase II study of oral capecitabine (Xeloda) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol 14:1227-1233, 2003 18. United States Food and Drug Administration: FDA approves Xeloda for breast cancer. Washington, DC, United States Department of Health and Human Services, 1998 19. Mackean M, Planting A, Twelves C, et al: Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol 16:2977-2985, 1998 20. Oshaughnessy JA, Blum J, Moiseyenko V, et al: Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 12:1247-1254, 2001 21. Traina T, Theodoulou M, Higgins B, et al: In vivo activity of a novel regimen of capecitabine in a breast cancer xenograft model. Breast Cancer Res Treat 100:S279, 2006 (suppl 1; abstr 6071) 22. 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] 23. Sawyer M, Ratain MJ: Body surface area as a determinant of pharmacokinetics and drug dosing. Invest New Drugs 19:171-177, 2001[CrossRef][Medline] 24. Ratain MJ: Body-surface area as a basis for dosing of anticancer agents: Science, myth, or habit? J Clin Oncol 16:2297-2298, 1998[Medline] 25. Miller AA: Body surface area in dosing anticancer agents: Scratch the surface! J Natl Cancer Inst 94:1822-1823, 2002 26. Miller AA, Rosner GL, Egorin MJ, et al: Prospective evaluation of body surface area as a determinant of paclitaxel pharmacokinetics and pharmacodynamics in women with solid tumors: Cancer and Leukemia Group B Study 9763. Clin Cancer Res 10:8325-8331, 2004 27. Baker SD, Verweij J, Rowinsky EK, et al: Role of body surface area in dosing of investigational anticancer agents in adults: 1991-2001. J Natl Cancer Inst 94:1883-1888, 2002 28. Sharma R, Ong S, Li K, et al: Phase II study of fixed dose capecitabine and assessment of thymidine and folate concentration as predictor of toxicity in advanced colorectal cancer patients. Proc Am Soc Clin Oncol 21:143, 2003 (abstr 573) 29. Lokich J: Capecitabine: Fixed daily dose and continuous (noncyclic) dosing schedule. Cancer Invest 22:713-717, 2004[CrossRef][Medline] 30. Dickson N, et al: Flat-dose capecitabine with irinotecan in 1st line advanced colorectal cancer: Early results of a phase II trial. Proc Am Soc Clin Oncol 21:369, 2003 (abstr 1480) 31. Haller D, et al: Tolerability of fluoropyrimidines appears to differ by region. J Clin Oncol 24:149s, 2006 (abstr 3514) 32. Danesi R, De Braud F, Fogli S, et al: Pharmacogenetic determinants of anti-cancer drug activity and toxicity. Trends Pharmacol Sci 22:420-426, 2001[CrossRef][Medline] 33. McLeod HL, Evans WE: Pharmacogenomics: Unlocking the human genome for better drug therapy. Annu Rev Pharmacol Toxicol 41:101-121, 2001[CrossRef][Medline] 34. Innocenti F, Ratain MJ: Update on pharmacogenetics in cancer chemotherapy. Eur J Cancer 38:639-644, 2002[CrossRef][Medline] 35. Relling MV, Dervieux T: Pharmacogenetics and cancer therapy. Nat Rev Cancer 1:99-108, 2001[CrossRef][Medline] 36. Scheithauer W, Kornek GV, Raderer M, et al: Intermittent weekly high-dose capecitabine in combination with oxaliplatin: A phase I/II study in first-line treatment of patients with advanced colorectal cancer. Ann Oncol 13:1583-1589, 2002 37. Scheithauer W, Schüll B, Ulrich-Pur H, et al: Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: A randomized phase II trial. Ann Oncol 14:97-104, 2003 38. Van Cutsem E, Findlay M, Osterwalder B, et al: Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: Results of a randomized phase II study. J Clin Oncol 18:1337-1345, 2000 Submitted August 6, 2007; accepted October 10, 2007.
Related Editorial
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
