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Journal of Clinical Oncology, Vol 26, No 13 (May 1), 2008: pp. 2078-2079 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.9609
Will We Ever Be Ready for Blood Level–Guided Therapy?University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina Schools of Pharmacy and Medicine, and the Lineberger Comprehensive Cancer Center, Chapel Hill, NC We live in an amazing era of oncology practice. The molecular mechanisms driving many cancers are being deciphered, and with this information come new targeted treatment approaches. Indeed, we now have kinase inhibitors and growth factor antagonists to treat cancers for which many had given up hope of progress (such as renal cell carcinoma). Improvements in imaging technology and radiologic technique allow greater functional insights into the metabolism, blood flow, and cellular homogeneity of tumors. The use of genomic technology is now providing tools for the prediction of disease recurrence, drug sensitivity, or invasive potential. Yet, in the midst of all the excitement, we still find ourselves not able to apply some simple principles in daily practice. Therapeutic drug monitoring (TDM) is considered relatively standard practice for select antimicrobial drugs and immunosuppressants for organ transplants, where the measurement of drug concentrations in blood allows an optimal balance of efficacy and toxicity. Yet, TDM continues to struggle to gain acceptance in the practice of oncology, where this balance of efficacy and toxicity is considered in nearly all chemotherapy regimens and where the loss of this balance can have devastating effects on patients. The chemotherapeutics we use to treat our patients are perhaps the best example in the practice of medicine of drugs with a narrow therapeutic index. Obviously, not all chemotherapeutics would be ideal candidates for TDM. The prototype drug would not only have a narrow therapeutic index, but would have efficacy or toxicity that is clearly and robustly correlated with drug concentrations in plasma, serum, or another easily accessible body fluid. A timely method for assaying drug concentrations that would lend itself to implementation in the standard clinical lab setting is also needed. Finally, the drug should demonstrate variability in toxicity or efficacy to justify the use of resources for performing TDM. There are a few examples where TDM is extensively used in oncology. Blood level monitoring typically accompanies the use of busulfan for stem-cell transplantation for toxicity avoidance. Methotrexate levels are measured in most cases to guide the use of folinic acid rescue in order to avoid delayed toxicity. In addition, creatinine clearance is used as a biomarker of carboplatin systemic clearance, also in the setting of toxicity management (ie, thrombocytopenia). However, we rarely employ the tool of TDM to optimize patient therapy in the most commonly prescribed anticancer drugs. Fluorouracil (FU) embodies many of these characteristics, making it a good candidate for TDM. Multiple reports over the last decade have demonstrated a 20% to 40% interpatient variability in drug clearance and a relationship between tumor response and FU area under the concentration-time curve (AUC).1-4 Additionally, a predictable relationship appears to exist between FU pharmacokinetics (PK) and dose.3,5 The potential benefit of using TDM to direct FU dosing is demonstrated by Gamelin et al in this issue of the Journal.6 The investigators randomly assigned 186 assessable patients with metastatic colorectal cancer across seven clinical centers to receive either traditional body-surface area (BSA)–based FU dosing at 1,500 mg/m2 or novel pharmacokinetically-guided therapy to target an AUC of 20 to 25 mg*hr/L as a weekly 8-hour infusion. The patients randomly assigned to PK-directed therapy received an initial dose of FU at 1,500 mg/m2, with blood drawn for FU plasma concentrations at 3 and 7 hours during the 8-hour infusion. These concentrations were used to determine the dose needed for the next cycle in order to reach the target systemic exposure. This process was repeated for each subsequent weekly cycle until the target AUC was maintained for 3 consecutive weeks. After this, plasma concentrations were checked every 3 weeks. Dose adjustments were made using an algorithm previously developed and utilized by the authors, which gave definitive instructions on the FU dose adjustments needed for subsequent treatment. The authors were successful in demonstrating that individualized therapy led to a statistically significant improvement in objective response rate in the presence of less toxicity, with a trend toward improved median overall survival (OS). The objective response rate was 18.3% for patients receiving traditional BSA-based therapy and 33.7% for those receiving PK-targeted therapy (P = .004). Median OS was 16 months for the BSA-based and 22 months for PK-targeted patients (P = .08). The authors do not address if patients crossed over to combination therapies, with the subsequent influence on OS. Toxicity was seen in more patients receiving BSA-based therapy (P = .003), with diarrhea and hand-foot syndrome as the most common adverse effects. Successful FU dose adjustment to the target AUC was achieved in 94% of the patients requiring a mean of four cycles to determine the necessary individualized dose. Also notable, the mean dosage to achieve the target AUC was 1,790 mg/m2/wk—higher than the initial dose of 1,500 mg/m2—and ranged nearly four-fold from 765 mg/m2 to 3,300 mg/m2. The authors also obtained PK samples from 49 patients receiving BSA-based therapy and found only four patients (8%) to have an AUC within the target range, further supporting the PK variability of the drug. The authors are to be commended for their efforts to develop level 1 evidence-based medicine criteria for the concept of individualizing therapy by blood levels. Is this clinical data strong enough to mandate the use of TDM and integrate it into standard practice? Considering the results of improved response rates and a trend towards improved survival, if the comparative arm was a new drug combination instead of a PK-guided FU regimen, it is likely that we would be excited about this improvement in therapy. Indeed, a major obstacle to TDM-directed therapy is our own biases, well founded or not. However, there are some difficulties in practical interpretation of this specific study. It is not clear why it took the authors 9 years from their previous publication to fine tune this approach. Is this method so tedious that it was difficult to perform in routine practice? Are the authors using this approach as a standard for their own patients, or is this an academic exercise? The FU regimen used in this study is one rarely used in current practice in most countries. The finding of an OS of 22 months with single agent treatment is intriguing and will be of interest to countries where combination therapy is not affordable. However, the addition of oxaliplatin, irinotecan, or bevacizumab to the FU foundation has demonstrated improved response rates and overall survival for metastatic colorectal cancer, rendering it difficult to change prescribing practices to revert back to single agent FU. It is hoped that Gamelin et al will be generating the data on the impact of PK-guided FU in the context of oxaliplatin or other commonly used combination therapy regimens. If we are comfortable with the idea that PK-guided dosing of FU is superior to a standard infusion approach, what challenges must be overcome before implementation? Clinicians often shy away from pharmacokinetically-guided therapy for some practical reasons. Firstly, multiple disciplines are needed to ensure the correct administration of the drug, collection and processing of blood samples for analysis, assay performance, and interpretation of the raw drug concentrations into a meaningful direction for dose adjustment. Most oncology practices in the United States do not have direct access to the laboratory medicine and pharmacy expertise needed for TDM. Nor do most practices have the technical infrastructure to adequately process samples for clinical pharmacokinetic analysis, even something as simple as a centrifuge. A complicating factor in this process is that all of these steps must often happen in a relatively short time frame to prepare a recommended dose before the next scheduled treatment. This requires an assay method that provides robust and rapid results, yet is relatively easy and utilizes route analytic methods. A key element of the current study, as well as previous randomized controlled trials of PK-guided therapy,7 is the improved therapeutic index. TDM is more labor intensive than standard approaches, so there must be a net gain to make it worthwhile. As we move toward a results-based reimbursement system, methods that enhance antitumor outcome and minimize patient toxicity will be in demand. However, it will likely take market forces to drive the implementation of TDM in the same way that it has driven use of molecular pathology for trastuzumab and some of the newer kinase inhibitors. The study of Gamelin et al6 does offer hope. Minimal blood sampling and dose adjustment algorithms, such as the one developed by Gamelin et al, help to make FU TDM a more practical consideration. Drug regimens that utilize every-2-week or every-3-week dosing schedules also allow for a more realistic time frame to complete the necessary steps of the process. Finally, companies are developing robust enzyme-linked immunosorbent assays for determining drug concentrations that are compatible with equipment used in many common clinical laboratories. Ultimately, it is data like that presented by Gamelin et al that will cause oncologists, patients, and payers to start thinking of TDM as a serious modality for modern oncology. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Manuscript writing: Christine M. Walko, Howard L. McLeod Final approval of manuscript: Howard L. McLeod REFERENCES 1. Felici A, Verweij J, Sparreboom A: Dosing strategies for anticancer drugs: The good, the bad and body-surface area. Eur J Cancer 38:1677-1684, 2002[CrossRef][Medline] 2. Gamelin E, Boisdron-Celle M, Delva R, et al: Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: Results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients. J Clin Oncol 16:1470-1478, 1998 3. Milano G, Etienne MC, Renee N, et al: Relationship between fluorouracil systemic exposure and tumor response and patient survival. J Clin Oncol 12:1291-1295, 1994 4. Trump DL, Egorin MJ, Forrest A, et al: Pharmacokinetic and pharmacodynamic analysis of fluorouracil during 72-hour continuous infusion with and without dipyridamole. J Clin Oncol 9:2027-2035, 1991 5. Gamelin EC, Danquechin-Dorval EM, Dumesnil YF, et al: Relationship between 5-fluorouracil (FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing FU. Cancer 77:441-451, 1996[CrossRef][Medline] 6. Gamelin E, Delva R, Jacob J, et al: Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: Results of a multicenter randomized trial in patients with metastatic colorectal cancer. J Clin Oncol 26:2099-2105, 2008 7. Evans WE, Relling MV, Rodman JH, et al: Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 338:499-505, 1998 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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