American Journal of Health-System Pharmacy

doi: 10.1093/ajhp/63.9_supplement_2.s22pmid: N/A

Learning objectives After studying these articles, the reader should be able to Describe the epidemiology, natural history, patient presentation, prognosis, and staging of colon cancer. Recommend a chemotherapeutic agent or regimen for the treatment of a patient with advanced or metastatic colon cancer or as adjuvant therapy after surgery in a patient with less extensive disease. Name a chemotherapeutic agent used in the treatment of colorectal cancer that may be affected by pharmacogenetic differences, and explain the impact of these differences on the disposition of the agent and the implications for use of the agent. Identify a patient-specific factor to consider in individualizing chemotherapy in patients with colorectal cancer, and name the tumor marker of choice for monitoring for progression of colorectal cancer. Identify a way in which MMA is expected to affect the management of colorectal cancer from the perspective of both health care providers and patients. Self-assessment questions For each question there is only one best answer. Which of the following statements about the diagnosis of colon cancer is correct? It usually is diagnosed early because of rectal bleeding. It usually is diagnosed early because of changes in bowel habits. It usually is not diagnosed early because it is asymptomatic. It usually is not diagnosed early because it is confused with other diseases. Which of the following factors is associated with a good prognosis in patients with colon cancer? A Grade 1 tumor. DNA aneuploidy. A high S-phase fraction. A chromosome 18q deletion. In which of the following stages of colon cancer is a cure considered feasible? Stages 0 and I only. Stages 0, I, and II only. Stages 0, I, II, and III only. All stages (0, I, II, III, and IV). Which of the following therapeutic modalities is recommended for patients with stage III colon cancer? Chemotherapy alone. Surgery alone. Surgery and adjuvant chemotherapy. Chemotherapy with or without surgery. With which of the following chemotherapeutic regimens does one need to be concerned about toxicity precipitated by exposure to cold? CAPIRI. FOLFIRI. FOLFOX. IFL. Which of the following agents selectively targets VEGF and inhibits angiogenesis? Bevacizumab. Capecitabine. Cetuximab. Oxaliplatin. Which of the following first-line chemotherapy regimens provides the longest survival in patients with metastatic colorectal cancer? 5-FU plus leucovorin. IFL. FOLFOX4. IFL plus bevacizumab. Which of the following chemotherapy regimens should be considered for a patient with metastatic colorectal cancer that has progressed despite first-line treatment with IFL and bevacizumab? FOLFIRI. CAPOX. Irinotecan FOLFOX. Which of the following chemotherapeutic agents or regimens might be recommended as adjuvant therapy after resection of stage III colorectal cancer? FOLFOX. FOLFIRI. IFL. Irinotecan plus cetuximab. Which of the following can be a limitation of comparing overall survival in a randomized control trial between standard of care and a new chemical entity? Patients failing standard therapy may not have access to the investigational therapy. Patients failing investigational therapy are resistant to the standard therapy. Blinding prevents patients from receiving the appropriate second-line therapy. Patients who are cured do not need second-line therapy. Which of the following statements about the role of pharmacogenetics in 5-FU-related toxicity and genetic testing is correct? The UGT1A1 7/7 genotype may be associated with toxicity from 5-FU, and a molecular assay that measures the UGT1A1 genotype in whole blood is readily available. The pretreatment total bilirubin concentration reflects UGT1A1 genotype and may be used to predict toxicity from 5-FU. DPD deficiency may be associated with toxicity from 5-FU, and a PCR-based assay may be used to detect DPD deficiency. DPD deficiency may be associated with toxicity from 5-FU, but DPD deficiency may be associated with as many as 23 allelic variants that cannot be tested with a clinical test. Which of the following is reliably linked with UGT1A1 genotype? Glucuronidation of SN-38. Inactivation of 5-FU. Formation of TGN. Formation of FdUMP. Which of the following patient-specific factors increases the risk of toxicity from irinotecan? Serum creatinine >1.5 mg/dL. Total bilirubin >0.1 mg/dL. Prior chemotherapy. Prior pelvic or abdominal radiation therapy. Which of the following might explain the conflicting findings from studies of the relationship between UGT1A1 genotype and irinotecan-related toxicity? A lack of a reliable relationship between genotype and phenotype. Differences in irinotecan dose or schedule among published studies. A lack of sensitivity in the UGT1A1 genotyping method. A lack of racial or ethnic differences in genotype. Which of the following statements about IHC testing of EGFR expression is correct? It is necessary only in patients receiving cetuximab who are at risk for toxicity because they are elderly or have a poor performance status. There is evidence to suggest that it is not necessary in any patient receiving cetuximab because it does not predict therapeutic response or toxicity. It is necessary in all patients receiving cetuximab to predict therapeutic response and toxicity. It is necessary in patients refractory to regimens containing cetuximab to predict response to second-line use of the drug. Which of the following limitations is associated with the use of IHC testing for EGFR expression in patients with colorectal cancer? The low specificity of the test. The substantial rate of true-negative results. The substantial rate of false-negative results. The substantial rate of false-positive results. Which of the following is the tumor marker of choice to monitor for progression of colorectal cancer? CA 19-9. CEA. Interleukin-6. The ras oncogene. Which of the following statements about the use of ASP plus 6% for Medicare reimbursement of medications is correct? It provides incentive to use inexpensive drugs. It provides incentive to use expensive drugs. It eliminates drug cost as a factor in selecting therapy. It provides a large margin to cover administration expenses. Which of the following may be used for Medicare drug reimbursement rates in 2006? 85% of the AWP. 95% of the AWP. 95% of the ASP. 106% of the ASP. Which of the following effects of MMA on the treatment of patients with colorectal cancer is likely? An increase in patients treated in physician offices. An increase in distance traveled to receive treatment. An increase in quality of life. A decrease in waiting time to receive treatment. AJHP continuing education AJHP CE process The continuing-education (CE) test for this supplement can only be taken online through ASHP’s CE Testing Center. If you score 70% or better on the test, you will be able to immediately print your own CE statement for your records. You will have two opportunities to pass the CE test, and you may stop and return to the test at any time before submitting your final answers. ASHP will keep a record of the credits you have earned from this and other CE activities, and you will be able to view your own transcript through the online CE service. To view the list of available AJHP CE articles, go to www.ashp.org/ce-selfstudy/ajhp-ce.cfm. Supplement: Evolution in the management of colorectal cancer ACPE #: 204-000-06-003-H01 CE credit: 1.5 hours (0.15 CEU) Expiration date: May 1, 2009 Instructions ASHP Advantage supplements are free to both members and nonmembers. ASHP members may go directly to www.ashp.org/ce/, select “Enter CE Testing Center,” type in your ASHP ID and password, and then select the supplement for which CE credit is desired. Nonmembers may also go directly to www.ashp.org/ce/, select “Enter CE Testing Center,” and then select the option to obtain an ASHP ID# and password for use with the free ASHP Advantage CE programs. Questions? Call ASHP Processing Center: 866-279-0681 (toll free) +1-240-646-7082 (international callers) The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Copyright © 2006. American Society of Health-System Pharmacists, Inc. All rights reserved. Copyright © 2006. American Society of Health-System Pharmacists, Inc. All rights reserved.

Crews, Kristine, R.

doi: 10.2146/ajhp060113pmid: 16641252

Abstract Purpose. Patient-specific factors that enter into decisions about the chemotherapy used to treat colorectal cancer are illustrated in several case studies. Summary. Genetic polymorphisms in genes that encode drug-metabolizing enzymes may affect the disposition and the risk for toxicity from chemotherapy agents used to treat colorectal cancer. Severe toxicity from 5-fluorouracil has been attributed to a deficiency in dihydropyrimidine dehydrogenase (DPD), but currently there is no widely used genetic test for DPD deficiency. An assay is available for genotypic testing of the enzyme UGT1A1, which is predictive of toxicity from irinotecan. Advanced age, prior pelvic or abdominal radiotherapy, a poor performance status, and increased pretreatment total bilirubin concentration also are associated with irinotecan-related toxicity. A reduction in irinotecan dosage or use of an alternative agent may be warranted in patients with risk factors for toxicity. Positive epidermal growth factor receptor (EGFR) expression by immunohistochemical (IHC) staining does not necessarily predict the response to cetuximab, a monoclonal antibody that binds EGFR, possibly because of the low sensitivity of the test. Carcinoembryonic antigen (CEA) is the tumor marker of choice for monitoring for progression of colorectal cancer. Conclusion. Individualizing chemotherapy based on disease stage, pharmacogenetics, prior therapy, patient age, performance status, and CEA level may help to optimize outcomes from chemotherapy for patients with colorectal cancer. Age, Antineoplastic agents, Cetuximab, Colorectal neoplasms, Dosage, Drugs, Drugs, body distribution, Fluorouracil, Irinotecan, Metabolism, Pharmacogenetics, Polymorphism, Tests, laboratory, Toxicity Several new chemotherapeutic agents for treating colorectal cancer have been introduced in recent years, increasing the available therapeutic options. The choice of therapy for this disease is guided by the stage of the disease and other patient-specific factors. Pharmacogenetics (inherited factors that affect pharmacokinetics and drug disposition) is one such factor for certain antineoplastic agents. Clinicians now appreciate the role of pharmacogenetics in the therapeutic success of and toxicity from cancer chemotherapy. The role of pharmacogenetics and other patient-specific factors in individualizing chemotherapy for colorectal cancer is illustrated in the following case studies. Dihydropyrimidine dehydrogenase deficiency RM is a 57-year-old Caucasian man with right-sided abdominal pain and a 19-lb weight loss over a 6-month period. A colonoscopy and biopsy followed by a computed tomography scan of chest and abdomen and surgical resection reveal T4, N1, and M0 (i.e., stage IIIB) colon cancer. According to practice guidelines of the National Comprehensive Cancer Network (NCCN), the options for adjuvant chemotherapy include the three-drug combination of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin; capecitabine (a 5-FU prodrug) alone; and the two-drug combination of 5-FU plus leucovorin.1 An inquisitive pharmacy student making rounds with the oncology team raises the question whether there is any way to predict the therapeutic response or from chemotherapy in RM. Fluorouracil is a prodrug that requires activation through a series of anabolic steps. A small portion of each dose is metabolized sequentially to 5-fluorodeoxyuridine and then 5-fluorodeoxyuridine monophosphate (FdUMP), the active drug, by thymidine kinase.2 In most patients, more than 85% of a 5-FU dose is inactivated by dihydropyrimidine dehydrogenase (DPD).3 Polymorphisms in genes that encode drug-metabolizing enzymes such as DPD might be clinically important if they have a reliable effect on enzyme activity and drug disposition (i.e., genotype can affect phenotype). Three patterns of inherited alleles are possible for autosomal co-dominant genes: (1) two normal (also known as “wild type”) alleles, (2) one variant allele and one normal allele, and (3) two variant alleles. These three patterns correspond to high, intermediate, and low (i.e., deficient) enzyme activity. Low DPD activity in a patient receiving 5-FU can increase plasma concentrations of the active drug (FdUMP) and lead to toxicity. In a study of 57 patients with head or neck cancer who received 5-day continuous intravenous (i.v.) infusions of 5-FU 1000 mg/m2/day, there was a linear correlation between DPD activity and 5-FU clearance.4 Patients with the lowest DPD activity had the lowest 5-FU clearance. Severe hematologic and gastrointestinal toxicities have been associated with DPD deficiency in patients receiving 5-FU.3 An estimated 3–5% of the American population experience 5-FU-related toxicity that might be attributed to DPD deficiency.5,6 In a prospective study of 48 patients with colorectal cancer who were receiving 5-FU and leucovorin as adjuvant therapy after surgery, DPD activity in lymphocytes correlated with 5-FU-related toxicity.7 Nine (82%) of the 11 patients with low DPD activity experienced 5-FU-related side effects (e.g., mucositis, diarrhea, myelotoxicity, angina pectoris, hypertension). Symptoms were reversed by reducing the dosage in three patients, and interruption of 5-FU therapy was required in another three patients. Five (17%) of the 29 patients with medium DPD activity experienced mild toxicity (e.g., diarrhea, transient hypertension), with no need for 5-FU dosage reduction or interruption in therapy. One (13%) of eight patients with high DPD activity experienced toxicity, but no dosage reduction or interruption in therapy was required. Deficiency in DPD activity may reflect allelic variation in the DPYD (DihydroPYrimidine Dehydrogenase) gene that encodes the DPD enzyme.3 However, there are 23 known allelic variants with varied relationships to DPD activity, and deficient enzyme activity has not been attributed to any one variant.8 Thus, the molecular mechanisms that control DPD activity are complex and have not yet been fully elucidated. Currently there is no genetic test for DPD deficiency. Current phenotypic assays that measure DPD activity are cumbersome to perform and involve the use of radioisotopes. Many clinical laboratories are not equipped to conduct these assays. Moreover, prospective studies are needed that demonstrate that adjusting 5-FU dosage based on pretreatment DPD activity can decrease the incidence of toxicity. A reliable relationship between DPD genotype and 5-FU toxicity phenotype has not been established. Nevertheless, the possibility of DPD deficiency might be suspected in a patient with severe toxicity from 5-FU. All of the adjuvant chemotherapy options for RM involve the use of 5-FU (or its prodrug capecitabine) and a risk for toxicity. However, it is not recommended to measure DPD activity before selecting adjuvant therapy for RM. Therefore, FOLFOX4 (i.e., oxaliplatin 85 mg/m2 i.v. over 2 hours on day 1, leucovorin 200 mg/m2 i.v. over 2 hours on days 1 and 2, and 5-FU 400 mg/m2 as an i.v. bolus followed by 600 mg/m2 i.v. over 22 hours on days 1 and 2) is initiated in RM. When RM returns to the clinic after two treatment cycles for a follow-up visit, the inquisitive pharmacy student asks about the use of tumor markers to monitor for disease progression in RM. Tumor markers Carcinoembryonic antigen (CEA) is the tumor marker of choice for monitoring for progression of colorectal cancer.1 It should be monitored every 3 months for 2 or 3 years and every 6 months thereafter until 5 years have elapsed since RM completed his adjuvant therapy.1,9 False elevations in CEA have occurred in patients treated with 5-FU, so the test should be repeated if results suggest that RM’s CEA level is elevated.10 Two elevated CEA levels confirm disease progression.9 Lipid-associated sialic acid, CA 19-9, DNA index (DNA flow cytometrically derived ploidy), p53 expression or mutation, and the ras oncogene all have been considered as markers for colorectal cancer progression, but data are insufficient to recommend their routine use.9 Several independent prognostic factors that might serve as tumor markers in the future have been identified in multivariate analyses of patients with colorectal cancer.9 These tumor markers with potential clinical utility in colorectal cancer include serum interleukin-6 levels, intratumoral expression of the cyclin-dependent kinase inhibitor p27Kip1 (a tumor suppressor gene), the deleted-in-colorectal-cancer gene (DCC, a tumor-suppressor gene), and micro-satellite instability (abnormally long or short DNA sequences resulting from mutations in mismatched repair genes).9 In addition, the intratumoral expression of thymidylate synthase (an enzyme targeted by 5-FU therapy) may correlate with response to 5-FU.9,11 UGT1A1 genotype and bilirubin YF is a 68-year-old African American woman with colorectal cancer that has metastasized to her liver. The disease has progressed despite first-line treatment with 5-FU, leucovorin, and bevacizumab. The plan is to use a regimen containing irinotecan as second-line therapy because the drug was not used as part of the first-line regimen, an approach that is consistent with NCCN practice guidelines.1 The pharmacy student rounding with the oncology team expresses concern about YF’s ability to tolerate this regimen. Irinotecan, a topoisomerase I inhibitor, is a prodrug that undergoes complex metabolism (Figure 11). The prodrug is activated by carboxylesterases to SN-38, the active form. Glucuronidation of SN-38 by several UDP-glucuronosyltransferase (UGT) enzymes yields SN-38 glucuronide, which is excreted in the urine and bile.12 Figure 1. Open in new tabDownload slide Irinotecan Metabolic Pathways. Figure 1. Open in new tabDownload slide Irinotecan Metabolic Pathways. The enzyme UGT1A1 is responsible for glucuronidation of bilirubin as well as several drugs, including estradiol and irinotecan. The promoter region of the gene that encodes this enzyme exhibits a genetic polymorphism. There is variability in the number of repeats in what is known as the TATA box. A normal allele contains six TA repeats, and a variant allele contains seven TA repeats (also known as UGT1A1*28). Several UGT1A1 genotypes are possible based upon the number of TA repeats: the most common genotypes are homozygous 7/7, heterozygous 6/7, and homozygous 6/6. The frequency of the homozygous 7/7 variant UGT1A1 genotype varies among different racial and ethnic groups (Table 11).13 Table 1. UGT1A1 Genotype Frequency (%)13 Genotype Patient Population 6/6 6/7 7/7 Caucasian American 51 37 11 Asian American 70 28 2 African American 26–28 36–37 17–19 Genotype Patient Population 6/6 6/7 7/7 Caucasian American 51 37 11 Asian American 70 28 2 African American 26–28 36–37 17–19 Open in new tab Table 1. UGT1A1 Genotype Frequency (%)13 Genotype Patient Population 6/6 6/7 7/7 Caucasian American 51 37 11 Asian American 70 28 2 African American 26–28 36–37 17–19 Genotype Patient Population 6/6 6/7 7/7 Caucasian American 51 37 11 Asian American 70 28 2 African American 26–28 36–37 17–19 Open in new tab The homozygous 7/7 variant genotype is associated with reduced gene expression. A lower rate of estradiol glucuronide formation was observed in individuals with the homozygous 7/7 variant genotype compared with the heterozygous 6/7 and the homozygous 6/6 genotypes.13 Gilbert’s syndrome, characterized by a mild unconjugated hyperbilirubinemia, is also associated with the 7/7 genotype.14 Thus, the UGT1A1 genotype is reliably related to glucuronidation phenotype. Late-onset diarrhea and myelo-suppression are dose-limiting toxicities from irinotecan.15 The possibility that UGT1A1 genotype might be useful for predicting severe toxicity from irinotecan was explored in a prospective study of 66 patients with advanced solid tumors or lymphoma who received irinotecan 350 mg/m2 as a 90-minute i.v. infusion every 3 weeks.16 Toxicity (absolute neutrophil count [ANC] nadir and diarrhea) and pharmacokinetic data were measured during the first treatment cycle. Six (9.5%) of 63 patients assessable for toxicity developed grade 4 neutropenia.16 Grade 4 neutropenia was significantly more common in patients with the UGT1A1 7/7 genotype than in patients with the 6/7 or 6/6 genotype (Table 22). The relative risk for grade 4 neutropenia was 9.3 in patients with the 7/7 genotype compared with other genotypes. One patient died of neutropenia-related sepsis; this patient had the highest total bilirubin level (1.2 mg/dL) and the 7/7 genotype. Table 2. Relationship Between Pharmacogenetics, Irinotecan-Related Toxicity and Pharmacokinetics, and Pretreatment Bilirubin Levela,b,16 UGT1A1 Genotype No. of Patients No. (%) of Patients with Grade 4 Neutropenia Mean SN- 38 AUC (ng·hr/mL) Mean Pretreatment Total Bilirubin Level (mg/dL) aAUC = area under the concentration–time curve bPatients had advanced solid tumors or lymphoma and received irinotecan 350 mg/m2 as a 90-minute i.v. infusion every 3 weeks. cValue is the mean for the 6/6 and 6/7 genotypes combined. 6/6 29 0 (0) 336 ± 168 0.48 ± 0.03c 6/7 24 3 (12.5) 458 ± 380 0.48 ± 0.03c 7/7 6 3 (50) 542 ± 195 0.8 ± 0.12 UGT1A1 Genotype No. of Patients No. (%) of Patients with Grade 4 Neutropenia Mean SN- 38 AUC (ng·hr/mL) Mean Pretreatment Total Bilirubin Level (mg/dL) aAUC = area under the concentration–time curve bPatients had advanced solid tumors or lymphoma and received irinotecan 350 mg/m2 as a 90-minute i.v. infusion every 3 weeks. cValue is the mean for the 6/6 and 6/7 genotypes combined. 6/6 29 0 (0) 336 ± 168 0.48 ± 0.03c 6/7 24 3 (12.5) 458 ± 380 0.48 ± 0.03c 7/7 6 3 (50) 542 ± 195 0.8 ± 0.12 Open in new tab Table 2. Relationship Between Pharmacogenetics, Irinotecan-Related Toxicity and Pharmacokinetics, and Pretreatment Bilirubin Levela,b,16 UGT1A1 Genotype No. of Patients No. (%) of Patients with Grade 4 Neutropenia Mean SN- 38 AUC (ng·hr/mL) Mean Pretreatment Total Bilirubin Level (mg/dL) aAUC = area under the concentration–time curve bPatients had advanced solid tumors or lymphoma and received irinotecan 350 mg/m2 as a 90-minute i.v. infusion every 3 weeks. cValue is the mean for the 6/6 and 6/7 genotypes combined. 6/6 29 0 (0) 336 ± 168 0.48 ± 0.03c 6/7 24 3 (12.5) 458 ± 380 0.48 ± 0.03c 7/7 6 3 (50) 542 ± 195 0.8 ± 0.12 UGT1A1 Genotype No. of Patients No. (%) of Patients with Grade 4 Neutropenia Mean SN- 38 AUC (ng·hr/mL) Mean Pretreatment Total Bilirubin Level (mg/dL) aAUC = area under the concentration–time curve bPatients had advanced solid tumors or lymphoma and received irinotecan 350 mg/m2 as a 90-minute i.v. infusion every 3 weeks. cValue is the mean for the 6/6 and 6/7 genotypes combined. 6/6 29 0 (0) 336 ± 168 0.48 ± 0.03c 6/7 24 3 (12.5) 458 ± 380 0.48 ± 0.03c 7/7 6 3 (50) 542 ± 195 0.8 ± 0.12 Open in new tab In this study, three (5%) patients developed grade 3 diarrhea (no patients developed grade 4 diarrhea).16 There was no statistically significant association between diarrhea and UGT1A1 genotype (one patient with diarrhea had the 7/7 genotype and two patients with diarrhea had the 6/7 genotype). The SN-38 area under the concentration–time curve (AUC) correlated with the UGT1A1 genotype.16 Patients with the 7/7 genotype had a higher SN-38 AUC than patients with the other genotypes, reflecting low UGT1A1 activity in patients with the 7/7 genotype that resulted in decreased SN-38 glucuronidation and accumulation of the active drug. The pretreatment total bilirubin concentration was significantly higher in patients with the UGT1A1 7/7 genotype than in patients with the 6/7 or 6/6 genotype.16 Pretreatment total bilirubin level also correlated with the low ANC nadir values associated with grade 4 neutropenia. In another prospective study, 95 patients with metastatic colorectal cancer were treated with one of four irinotecan-based chemotherapy regimens.17 Severe diarrhea developed in seven (70%) of 10 patients with the UGT1A1 7/7 genotype, 15 (33%) of 45 patients with the 6/7 genotype, and 7 (18%) of 40 patients with the 6/6 genotype. The differences among the groups in incidence of severe diarrhea were significant. However, in this study, no correlation was found between hematologic toxicity and UGT1A1 genotype. A third prospective study of 75 patients with metastatic colorectal cancer who were treated with irinotecan and 5-FU found a correlation between the UGT1A1 genotype and incidence of grade 3 or 4 neutropenia but not between genotype and grade 4 diarrhea.18 The conflicting findings from these three studies might be due to the differences in irinotecan dose or schedule or in other characteristics in the patient populations (e.g., age) among the studies. Changes to the product labeling for irinotecan approved by the Food and Drug Administration (FDA) in 2005 call for consideration of a reduced initial irinotecan dosage for patients known to be homozygous for the UGT1A1*28 allele (i.e., the 7/7 genotype).19 The FDA-approved product labeling for irinotecan also recognizes several other known risk factors for toxicity that may warrant a reduction in initial dosage.19 These risk factors include age 65 years or older, prior pelvic or abdominal radiation therapy, a performance status of 2 or greater, and increased total bilirubin levels.19 An elevated pretreatment total bilirubin level (e.g., >1 mg/dL) might be a criterion for deciding whether to perform genotype testing in patients without other risk factors for irinotecan toxicity. The combined use of genotypic testing and pretreatment total bilirubin concentrations may help identify patients at particularly high risk for severe toxicity from irinotecan so that alternative therapy can be chosen instead of merely reducing the starting irinotecan dosage. A molecular assay that measures the UGT1A1 genotype in whole blood was approved by FDA in 2005. Use of the assay is feasible in clinics and other health-care institutions. The equipment required for the assay is readily available in most clinical laboratories. Results can be obtained quickly on site without sending blood samples out for testing at an outside laboratory, although it may be more cost-effective to send out samples if the volume of patients tested is low. In the case of YF, UGT1A1 genotype testing is particularly important because her age is greater than 65 and she is an African American woman with a nearly one in five chance that she has the 7/7 genotype (Table 11). Testing YF’s total bilirubin concentration in conjunction with genotype testing might help determine whether to avoid using irinotecan. EGFR expression RM is a 52-year-old Caucasian woman with metastatic colorectal cancer whose disease has progressed despite first-line treatment with 5-FU, leucovorin, and irinotecan—a regimen known as FOLFIRI—plus bevacizumab. The oncology team is considering using irinotecan plus cetuximab as second-line therapy based on NCCN practice guidelines.1,20 Cetuximab is a recombinant human/mouse chimeric monoclonal antibody that binds specifically to human epidermal growth factor receptors (EGFR). In most published phase II and phase III clinical trials of cetuximab in patients with colorectal cancer, evidence of positive EGFR expression by immunohistochemical (IHC) staining was an inclusion criterion based on the assumption that EGFR expression would be prognostic for cetuximab activity.21,22 When cetuximab was approved by FDA, the drug received indications specific for EGFR-expressing metastatic colorectal carcinoma.23 The inquisitive pharmacy student rounding with the oncology team questions whether it is necessary to use IHC to test for positive EGFR expression in RM before choosing to use cetuximab. Researchers have challenged the hypothesis that cetuximab activity requires EGFR expression by IHC because no relationship between the intensity of EGFR expression by IHC and cetuximab activity has been observed among patients with EGFR-expressing colorectal carcinomas.21,22,24 In a retrospective study, 16 patients were identified with colorectal cancer who had failed to respond to an irinotecan-based regimen and who received cetuximab despite negative EGFR expression by IHC.24 Four (25%) of the 16 patients experienced a partial response, and another two patients had a minor response. This response rate is similar to that reported in an earlier trial of cetuximab in patients with EGFR-expressing colorectal cancer.21 The researchers concluded that the practice of requiring positive EGFR expression by IHC for the use of cetuximab in patients with colorectal cancer is inappropriate because it might exclude patients who could benefit from treatment. The finding of comparable response rates regardless of EGFR expression by IHC may reflect a lack of sensitivity in the testing method (i.e., a substantial rate of false-negative results). IHC involves the staining of tumor cells and measurement of the amount and intensity of staining, which is semi-quantitative and somewhat subjective. Approximately 70% of human colorectal carcinomas express EGFR when IHC stains are used,24 although EGFR expression is thought to be almost universal in colorectal cancer.25 In the case of RM, IHC testing of EGFR expression does not appear to be warranted. She may benefit from the use of irinotecan plus cetuximab regardless of IHC test results. Conclusion Several patient-specific factors may influence decisions about the choice of chemotherapy used to treat colorectal cancer. These factors include pharmacogenetics, prior therapy, patient age, and performance status as well as disease stage. The tumor marker of choice for monitoring progression of colorectal cancer is CEA, although other markers with potential clinical utility are under investigation. Footnotes Based on the proceedings of a symposium held December 4, 2005, during the ASHP Midyear Clinical Meeting, Las Vegas, NV, and supported by an educational grant from Sanofi-Synthelabo Inc. and Aventis Pharmaceuticals, members of the sanofi-aventis group. Dr. Crews received an honorarium for her participation in the symposium and for the preparation of this article. Dr. Crews reports that she has no affiliations with or financial interest in a commercial organization that poses a conflict of interest with this article. References 1 The National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Colon Cancer version 2.2006. http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf (accessed 2006 Jan 14). 2 McEvoy GK, ed. Fluorouracil. In: AHFS Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists; 2005 :1020–4. 3 Ezzeldin H, Diasio R. Dihydropyrimidine dehydrogenase deficiency, a pharmaco-genetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration. Clin Colorectal Cancer . 2004 ; 4 : 181 –9. Crossref Search ADS PubMed 4 Fleming RA, Milano G, Thyss A et al. Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res . 1992 ; 52 : 2899 –902. PubMed 5 Etienne MC, Lagrange JL, Dassonville O et al. Population study of dihydropyrimidine dehydrogenase in cancer patients. J Clin Oncol . 1994 ; 12 : 2248 –53. Crossref Search ADS PubMed 6 Lu Z, Zhang R, Carpenter JT et al. Decreased dihydropyrimidine dehydrogenase activity in a population of patients with breast cancer: implication for 5-fluorouracil-based chemotherapy. Clin. Cancer Res . 1998 ; 4 : 325 –9. PubMed 7 Katona C, Kralovanszky J, Rosta A et al. Putative role of dihydropyrimidine dehydrogenase in the toxic side effect of 5-fluorouracil in colorectal cancer patients. Oncology . 1998 ; 55 : 468 –74. Crossref Search ADS PubMed 8 Mattison LK, Soong R, Diasio RB. Implications of dihydropyrimidine dehydrogenase on 5-fluorouracil pharmacogenetics and pharmacogenomics. Pharmacogenomics . 2002 ; 3 : 485 –92. Crossref Search ADS PubMed 9 Bast RC Jr, Ravdin P, Hayes DF et al. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol . 2001 ; 19 : 1865 –78. Crossref Search ADS PubMed 10 Moertel CG, Fleming TR, Macdonald JS et al. An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. JAMA . 1993 ; 270 : 943 –7. Crossref Search ADS PubMed 11 Maring JG, Groen HJ, Wachters FM et al. Genetic factors influencing pyrimidine-antagonist chemotherapy. Pharmacogenomics J . 2005 ; 5 : 226 –43. Crossref Search ADS PubMed 12 Santos A, Zanetta S, Cresteil T et al. Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin Cancer Res . 2000 ; 6 : 2012 –20. PubMed 13 Fisher MB, Vandenbranden M, Findlay K et al. Tissue distribution and interindividual variation in human UDP-glucuronosyltransferase activity: relationship between UGT1A1 promoter genotype and variability in a liver bank. Pharmacogenetics . 2000 ; 10 (8): 727 –39. Crossref Search ADS PubMed 14 Burchell B, Hume R. Molecular genetic basis of Gilbert’s syndrome. J Gastroenterol Hepatol . 1999 ; 14 : 960 –6. Crossref Search ADS PubMed 15 McEvoy GK, ed. Irinotecan hydrochloride. In: AHFS Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists; 2005 :1076–81. 16 Innocenti F, Undevia SD, Iver L et al. Genetic variants in the UDP-glucuronosyl-transferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol . 2004 ; 22 : 1382 –8. Crossref Search ADS PubMed 17 Marcuello E, Altes A, Menovo A et al. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer . 2004 ; 91 : 678 –82. Crossref Search ADS PubMed 18 Rouits E, Boisdron-Celle M, Dumont A et al. Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients. Clin Cancer Res . 2004 ; 10 : 5151 –9. Crossref Search ADS PubMed 19 Camptosar package insert. New York, NY: Pfizer, Inc.; July 2005 . 20 The National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Rectal Cancer version 2.2006. http://www.nccn.org/professionals/physician_gls/PDF/rectal.pdf (accessed 2006 Jan 14). 21 Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med . 2004 ; 351 : 337 –45. Crossref Search ADS PubMed 22 Saltz LB, Meropol NJ, Loehrer PJ Sr et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol . 2004 ; 22 : 1201 –8. Crossref Search ADS PubMed 23 Erbitux package insert. Princeton, NJ: Bristol-Myers Squibb Company; August 2005 . 24 Chung KY, Shia J, Kemeny NE et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol . 2005 ; 23 : 1803 –10. Crossref Search ADS PubMed 25 Baselga J. Does epidermal growth factor receptor status predict activity of cetuximab in colorectal cancer patients? Nat Clin Pract Oncol . 2005 ; 2 : 284 –5. Crossref Search ADS PubMed Copyright © 2006. American Society of Health-System Pharmacists, Inc. All rights reserved.

doi: 10.1093/ajhp/63.9_Supplement_2.S22pmid: N/A

Learning objectives After studying these articles, the reader should be able to Describe the epidemiology, natural history, patient presentation, prognosis, and staging of colon cancer. Recommend a chemotherapeutic agent or regimen for the treatment of a patient with advanced or metastatic colon cancer or as adjuvant therapy after surgery in a patient with less extensive disease. Name a chemotherapeutic agent used in the treatment of colorectal cancer that may be affected by pharmacogenetic differences, and explain the impact of these differences on the disposition of the agent and the implications for use of the agent. Identify a patient-specific factor to consider in individualizing chemotherapy in patients with colorectal cancer, and name the tumor marker of choice for monitoring for progression of colorectal cancer. Identify a way in which MMA is expected to affect the management of colorectal cancer from the perspective of both health care providers and patients. Self-assessment questions For each question there is only one best answer. Which of the following statements about the diagnosis of colon cancer is correct? It usually is diagnosed early because of rectal bleeding. It usually is diagnosed early because of changes in bowel habits. It usually is not diagnosed early because it is asymptomatic. It usually is not diagnosed early because it is confused with other diseases. Which of the following factors is associated with a good prognosis in patients with colon cancer? A Grade 1 tumor. DNA aneuploidy. A high S-phase fraction. A chromosome 18q deletion. In which of the following stages of colon cancer is a cure considered feasible? Stages 0 and I only. Stages 0, I, and II only. Stages 0, I, II, and III only. All stages (0, I, II, III, and IV). Which of the following therapeutic modalities is recommended for patients with stage III colon cancer? Chemotherapy alone. Surgery alone. Surgery and adjuvant chemotherapy. Chemotherapy with or without surgery. With which of the following chemotherapeutic regimens does one need to be concerned about toxicity precipitated by exposure to cold? CAPIRI. FOLFIRI. FOLFOX. IFL. Which of the following agents selectively targets VEGF and inhibits angiogenesis? Bevacizumab. Capecitabine. Cetuximab. Oxaliplatin. Which of the following first-line chemotherapy regimens provides the longest survival in patients with metastatic colorectal cancer? 5-FU plus leucovorin. IFL. FOLFOX4. IFL plus bevacizumab. Which of the following chemotherapy regimens should be considered for a patient with metastatic colorectal cancer that has progressed despite first-line treatment with IFL and bevacizumab? FOLFIRI. CAPOX. Irinotecan FOLFOX. Which of the following chemotherapeutic agents or regimens might be recommended as adjuvant therapy after resection of stage III colorectal cancer? FOLFOX. FOLFIRI. IFL. Irinotecan plus cetuximab. Which of the following can be a limitation of comparing overall survival in a randomized control trial between standard of care and a new chemical entity? Patients failing standard therapy may not have access to the investigational therapy. Patients failing investigational therapy are resistant to the standard therapy. Blinding prevents patients from receiving the appropriate second-line therapy. Patients who are cured do not need second-line therapy. Which of the following statements about the role of pharmacogenetics in 5-FU-related toxicity and genetic testing is correct? The UGT1A1 7/7 genotype may be associated with toxicity from 5-FU, and a molecular assay that measures the UGT1A1 genotype in whole blood is readily available. The pretreatment total bilirubin concentration reflects UGT1A1 genotype and may be used to predict toxicity from 5-FU. DPD deficiency may be associated with toxicity from 5-FU, and a PCR-based assay may be used to detect DPD deficiency. DPD deficiency may be associated with toxicity from 5-FU, but DPD deficiency may be associated with as many as 23 allelic variants that cannot be tested with a clinical test. Which of the following is reliably linked with UGT1A1 genotype? Glucuronidation of SN-38. Inactivation of 5-FU. Formation of TGN. Formation of FdUMP. Which of the following patient-specific factors increases the risk of toxicity from irinotecan? Serum creatinine >1.5 mg/dL. Total bilirubin >0.1 mg/dL. Prior chemotherapy. Prior pelvic or abdominal radiation therapy. Which of the following might explain the conflicting findings from studies of the relationship between UGT1A1 genotype and irinotecan-related toxicity? A lack of a reliable relationship between genotype and phenotype. Differences in irinotecan dose or schedule among published studies. A lack of sensitivity in the UGT1A1 genotyping method. A lack of racial or ethnic differences in genotype. Which of the following statements about IHC testing of EGFR expression is correct? It is necessary only in patients receiving cetuximab who are at risk for toxicity because they are elderly or have a poor performance status. There is evidence to suggest that it is not necessary in any patient receiving cetuximab because it does not predict therapeutic response or toxicity. It is necessary in all patients receiving cetuximab to predict therapeutic response and toxicity. It is necessary in patients refractory to regimens containing cetuximab to predict response to second-line use of the drug. Which of the following limitations is associated with the use of IHC testing for EGFR expression in patients with colorectal cancer? The low specificity of the test. The substantial rate of true-negative results. The substantial rate of false-negative results. The substantial rate of false-positive results. Which of the following is the tumor marker of choice to monitor for progression of colorectal cancer? CA 19-9. CEA. Interleukin-6. The ras oncogene. Which of the following statements about the use of ASP plus 6% for Medicare reimbursement of medications is correct? It provides incentive to use inexpensive drugs. It provides incentive to use expensive drugs. It eliminates drug cost as a factor in selecting therapy. It provides a large margin to cover administration expenses. Which of the following may be used for Medicare drug reimbursement rates in 2006? 85% of the AWP. 95% of the AWP. 95% of the ASP. 106% of the ASP. Which of the following effects of MMA on the treatment of patients with colorectal cancer is likely? An increase in patients treated in physician offices. An increase in distance traveled to receive treatment. An increase in quality of life. A decrease in waiting time to receive treatment. AJHP continuing education AJHP CE process The continuing-education (CE) test for this supplement can only be taken online through ASHP’s CE Testing Center. If you score 70% or better on the test, you will be able to immediately print your own CE statement for your records. You will have two opportunities to pass the CE test, and you may stop and return to the test at any time before submitting your final answers. ASHP will keep a record of the credits you have earned from this and other CE activities, and you will be able to view your own transcript through the online CE service. To view the list of available AJHP CE articles, go to www.ashp.org/ce-selfstudy/ajhp-ce.cfm. Supplement: Evolution in the management of colorectal cancer ACPE #: 204-000-06-003-H01 CE credit: 1.5 hours (0.15 CEU) Expiration date: May 1, 2009 Instructions ASHP Advantage supplements are free to both members and nonmembers. ASHP members may go directly to www.ashp.org/ce/, select “Enter CE Testing Center,” type in your ASHP ID and password, and then select the supplement for which CE credit is desired. Nonmembers may also go directly to www.ashp.org/ce/, select “Enter CE Testing Center,” and then select the option to obtain an ASHP ID# and password for use with the free ASHP Advantage CE programs. Questions? Call ASHP Processing Center: 866-279-0681 (toll free) +1-240-646-7082 (international callers) The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Copyright © 2006. American Society of Health-System Pharmacists, Inc. All rights reserved.

Adams, Val, R.

doi: 10.2146/ajhp060111pmid: N/A

Colorectal cancer is among the most commonly diagnosed malignancies in the United States, exceeded in numbers only by breast, prostate, and lung cancers.1 In 2005, an estimated 145,290 new cases of colorectal cancer were diagnosed in the United States. An estimated 56,290 Americans died from the disease in 2005, with similar numbers of deaths in men and women.2 Screening is highly effective for preventing colorectal cancer because precancerous adenomatous polyps can be detected and removed before they become malignant.1 Screening also increases the likelihood of detecting malignancy at an early stage, when treatment is most effective. The American Cancer Society recommends screening for colorectal cancer beginning at the age of 50, but less than half of Americans 50 years of age or older have had a recent screening test.1 The treatment of colorectal cancer has changed considerably in recent years as a result of the introduction of new chemotherapeutic agents and insight into the role of pharmacogenetics and other patient-specific factors that affect response to chemotherapy. Changes in reimbursement for chemotherapy and supportive therapy associated with the Medicare Prescription Drug Improvement and Modernization Act (MMA) may have a large impact on the management of colorectal cancer in the near future. The first article in this supplement provides an overview of the epidemiology, natural history, patient presentation, and staging of colon cancer. Various chemotherapy regimens recommended in current practice guidelines for the treatment of advanced or metastatic colon cancer and as adjuvant therapy after surgery in patients with less extensive disease are discussed in detail. In the second article, the role of pharmacogenetics and other patient-specific factors in individualizing chemotherapy for patients with colorectal cancer is illustrated in several patient cases. The third article takes a look back at a patient case from 30 years ago to provide contrast with the current standard of care and illustrate the advances that have been made in treatment options since then. The potential impact of the MMA on health care providers and patients is discussed. Footnotes Based on the proceedings of a symposium held December 4, 2005, during the ASHP Midyear Clinical Meeting, Las Vegas, NV, and supported by an educational grant from Sanofi-Synthelabo Inc. and Aventis Pharmaceuticals, members of the sanofi-aventis group. Dr. Adams received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Adams reports that he has no affiliations with or financial interest in a commercial organization that poses a conflict of interest with this article. References 1 American Cancer Society. Colorectal Cancer Facts & Figures—Special Edition 2005. http://www.cancer.org/downloads/STT/CAFF2005CR4PWSecured.pdf (accessed 2006 Jan 14). 2 American Cancer Society. Cancer Facts & Figures 2005. http://www.cancer.org/downloads/STT/CAFF2005f4PWSecured.pdf (accessed 2006 Jan 14). Copyright © 2006. American Society of Health-System Pharmacists, Inc. All rights reserved.

Adams, Val, R.

doi: 10.2146/ajhp060112pmid: 16641256

Abstract Purpose. The epidemiology, natural history, patient presentation, staging, prognosis, and treatment of colorectal cancer are described. Summary. Colorectal cancer is a common malignancy that usually is not diagnosed when it is localized because it typically is asymptomatic in the early stages. Various cancer chemotherapeutic agents with different toxicities are available, including the recently introduced recombinant humanized immunoglobulin G1 monoclonal antibodies cetuximab and bevacizumab. Chemotherapy may be used with or without surgery in patients with advanced or metastatic colorectal cancer, usually for palliation rather than a cure. The results of clinical trials suggest that patients with advanced or metastatic colorectal cancer probably should receive 5-fluorouracil (5-FU)/leucovorin, irinotecan, oxaliplatin, bevacizumab, and cetuximab at some time in the course of treatment, although the preferred combinations and sequence of these agents remain to be determined. After surgery, adjuvant chemotherapy may be used for curative purposes in patients with stage III disease and some patients with stage II disease at high risk for disease recurrence and death. Although 5-FU plus leucovorin has been the standard adjuvant therapy, clinical trials have demonstrated that adding oxaliplatin or using capecitabine alone instead is an alternative. Conclusion. Several recently introduced chemotherapeutic agents appear promising for the treatment of colorectal cancer, but additional clinical research is needed to identify the ideal combinations and sequence of these agents. Antineoplastic agents, Bevacizumab, Capecitabine, Cetuximab, Colorectal neoplasms, Combined therapy, Drugs, Epidemiology, Fluorouracil, Irinotecan, Leucovorin, Neoplasm metastasis, Oxaliplatin, Surgery, Toxicity Colorectal cancer is an age-related disease. Most (91%) new cases occur in people over the age of 50, with an incidence in the age group 60–79 years of age that is 50 times higher than that in the age group less than 40 years of age.1 Colorectal cancer is more common in industrialized nations than in developing nations.2 A diet high in fat and low in fiber is thought to increase the risk for colorectal cancer.1 Colorectal cancer usually begins as precancerous adenomatous polyps that grow and become malignant. In the early stages, the malignancy usually is asymptomatic because the polyps are small.1 Blood in the stool from bleeding polyps is an early warning sign of colorectal cancer. Malignant polyps tend to grow from the inner basement membrane of the bowel wall outward into the mucosa, submucosa, muscularis, and serosa. Local invasion of the bowel wall is followed by metastatic spread via lymphatic and hematogenous routes to the lymph nodes, lungs, liver, and bones. The high mortality rate from colorectal cancer may be attributed in part to the fact that it usually is not diagnosed when it is localized. As the polyps grow, they typically cause symptoms that are vague, subtle, or nonspecific (e.g., a change in bowel habits). Colorectal cancer often is not diagnosed until a patient presents with intestinal obstruction, perforation of the bowel wall, or hemorrhage. Intestinal obstruction may manifest as constipation, abdominal distention and pain, nausea, and vomiting. Perforation of the bowel wall can lead to infection, fever, and an elevated white blood cell count. Anemia, weakness, and fatigue may develop in a patient with slow blood loss that goes undetected for a long time. The presence of jaundice suggests a malignancy that has metastasized to the liver. Pathology More than 95% of colorectal cancers are adenocarcinomas.1 Tumor morphology (i.e., the extent of cellular differentiation) may be categorized in one of four grades, with G1 for well-differentiated, G2 for moderately differentiated, G3 for poorly differentiated, and G4 for undifferentiated tumors. Poorly differentiated tumors are more aggressive and have a worse prognosis (i.e., a greater risk of disease recurrence and death after treatment) than well-differentiated tumors.3 Other pathology indicators of a poor prognosis include tumor adherence or fixation to adjacent structures, perforation, complete intestinal obstruction, DNA aneuploidy (i.e., having an abnormal balance of chromosomes), high S-phase fraction (i.e., a high fraction of cells in the DNA synthesis phase of the cell cycle), and deletion of chromosome 18q.4,5 Staging Colorectal cancer may be staged using the American Joint Committee on Cancer TNM staging system for colorectal cancer,6 with T for the invasiveness of the primary tumor, N for regional lymph node involvement, and M for the presence of distant metastases (Figure 11). Stage 0 (carcinoma in situ) is confined to the basement membrane (intraepithelial) or lamina propria (intramucosal), without extension through the muscularis mucosae into the submucosa (Tis) or spread to regional lymph nodes (N0) or distant metastases (M0).6 Stage I disease also is limited, invading the submucosa (T1) or muscularis propria (T2), without spread to regional lymph nodes (N0) or distant metastases (M0). Figure 1. Open in new tabDownload slide Schematic Representation of TNM Staging System for Colorectal Cancer. Figure 1. Open in new tabDownload slide Schematic Representation of TNM Staging System for Colorectal Cancer. Stage II disease is more invasive than stage I. Stage IIA disease involves tumor invasion through the muscularis propria into the subserosa or non-peritonealized pericolic or perirectal tissues (T3), and stage IIB disease involves invasion into other organs or structures or perforation of the visceral peritoneum (T4). Spread to the lymph nodes and distant metastases are absent (i.e., N0, M0) in stages IIA and IIB. Stage III disease involves spread to the lymph nodes without distant metastases (M0). This stage is divided into three categories based on the extent of the primary tumor and number of regional lymph nodes involved. In stage IIIA, the primary tumor invades the submucosa (T1) or muscularis propria (T2) and metastasis to one, two, or three regional lymph nodes has occurred (N1). Lymph node involvement is the same in stage IIIB as in stage IIIA (N1), but the primary tumor is more invasive (i.e., T3 or T4). Stage IIIC involves metastasis to four or more regional lymph nodes (N2), regardless of the invasiveness of the primary tumor (any T). Stage IV disease is characterized by distant metastases (M1), regardless of the invasiveness of the primary tumor (any T) or regional lymph node involvement (any N). Staging of colorectal cancer at the time of diagnosis provides useful information about prognosis. The five-year survival rates for each of the stages are stage I (T1–2 N0)—93%, stage IIA (T3 N0)—85%, stage IIB (T4 N0)—72%, stage IIIA (T1–2 N1)—83%, stage IIIB (T3–4 N1)—64%, stage IIIC (N2)—44%, and stage IV (M1)—8%.7,8 These survival rates demonstrate that a cure is feasible in all stages except stage IV. Treatment Staging is the primary consideration in choosing treatment for colorectal cancer. Stages 0 and I are treated with surgery alone, without adjuvant chemotherapy because chemotherapy provides no benefit in this patient population.3,9 Treatment for stage II disease includes surgery, with or without adjuvant chemotherapy. Adjuvant chemotherapy is more likely to be used in patients with colon cancer who are at high risk for mortality or recurrence (e.g., with a poorly differentiated or undifferentiated T4 tumor invading other organs or structures) than in patients with a T3 lesion. The survival benefit from adjuvant chemotherapy in patients with stage II colon cancer is no more than 5%.3 Nevertheless, chemotherapy is often used in patients with a poor prognosis.10 Surgery and adjuvant chemotherapy are recommended for stage III colorectal cancer.3,9 Adjuvant chemotherapy improves cure rates and survival.11,12 Chemotherapy with or without surgery is used for stage IV disease.3,9 Some patients may have liver or lung metastases that are resectable, but surgical treatment for the majority of patients is palliative, not curative. Prolonging and improving quality of life are the primary therapeutic goals in patients with stage IV colorectal cancer. Chemotherapy drugs and regimens. Various combinations of cancer chemotherapeutic agents are used to treat colorectal cancer. The most experience has been obtained with the anti-metabolite 5-fluorouracil (5-FU) plus leucovorin, a regimen that has been available for decades and has been considered standard therapy.3 Regimens containing oxaliplatin in combination with 5-FU and leucovorin are referred to as FOLFOX (e.g., FOLFOX4, FOLFOX6). Similar regimens containing 5-FU and leucovorin in which irinotecan is substituted for oxaliplatin are known as FOLFIRI. A regimen referred to as IFL or the Saltz regimen contains irinotecan, 5-FU, and leucovorin, with the 5-FU and leucovorin doses administered by bolus injection instead of by slow intravenous (i.v.) infusion.13 A regimen known as CAPOX contains capecitabine (an oral 5-fluorouracil prodrug14) and oxaliplatin. Capecitabine also may be used alone. Cetuximab is sometimes used in combination with irinotecan, although it may be used alone. Bevacizumab may be used with 5-FU plus leucovorin, FOLFOX, FOLFIRI, IFL, or CAPOX.3 Adverse effects from the chemotherapeutic agents used to treat colorectal cancer vary. The primary toxicity from 5-FU involves the gastrointestinal (GI) mucosa and the bone marrow, manifesting as stomatitis, diarrhea, and neutropenia.15 Diarrhea and myelosuppression are dose-limiting toxicities from irinotecan.16 The drug causes early, transient cholinergic-mediated diarrhea and late-onset diarrhea that parallel the development of neutropenia. The late-onset diarrhea can be particularly severe in patients receiving IFL.16 Oxaliplatin can cause acute sensory neuropathies (e.g., a sensation of dyspnea without laryngospasm or bronchospasm) precipitated by exposure to cold temperatures, objects, or beverages.17 The reaction has been attributed to the release of an oxalate metabolite, and it may be attenuated by infusion of calcium gluconate and magnesium sulfate.18 Abdominal pain, dose-limiting diarrhea, and hand-foot syndrome (a condition characterized by painful swelling, erythema, blistering, and peeling of the palms of the hands and soles of the feet) are the most problematic adverse effects from capecitabine.14 Cetuximab. Cetuximab is a recombinant human/mouse chimeric immunoglobulin G1 (IgG1) monoclonal antibody that binds specifically to human epidermal growth factor receptors (EGFR) and competitively inhibits binding of epidermal growth factor and other ligands to the receptor.19 Epidermal growth factor receptors often are overexpressed in colorectal cancer.20 Binding of epidermal growth factor to the receptor initiates a cascade of intracellular signals that regulate cell proliferation, migration, adhesion, differentiation, and survival.19 Cetuximab inhibits cell growth, induces apoptosis, and decreases the production of matrix metalloproteinase and vascular endothelial growth factor (VEGF), both of which are thought to be involved in tumor growth and metastasis.21 Humanization of the murine antibody decreases its immunogenicity and increases the half-life.19 Cetuximab has a long elimination half-life (a mean of 97 hours, with a range of 41–213 hours).22 The drug exhibits activity in patients with metastatic colorectal cancer that is refractory to irinotecan.19 Cetuximab is approved by the Food and Drug Administration (FDA) for use alone or in combination with irinotecan to treat patients with EGFR-expressing metastatic colorectal cancer who are intolerant of or refractory to irinotecan, respectively.22 An acne-like rash and diarrhea are among the most common adverse effects from cetuximab.22 Bevacizumab. Bevacizumab is a recombinant humanized IgG1 monoclonal antibody. The estimated half-life of bevacizumab is approximately 20 days (range 11–50 days).23 Bevacizumab selectively binds to and inhibits the biological activity of VEGF and prevents it from interacting with VEGF receptors on the surface of endothelial cells.24,25 The activity of VEGF binding to its receptors prevents endothelial cell proliferation and angiogenesis (i.e., new blood vessel formation).26 There are at least four isoforms of VEGF, all of which are recognized by bevacizumab.25 VEGF plays an important role in tumor angiogenesis. Expression of VEGF is excessive in most types of cancer.24 Early tumors typically are small and avascular. Tumor growth and metastasis can occur when proangiogenic factors (e.g., VEGF) are secreted by the tumor and stromal cells in response to various intracellular and environmental signals.27 VEGF recruits new blood vessels, resulting in tumor vascularization, growth, and metastasis. The new blood vessels are needed to deliver nutrients to the tumor. Tumor-associated blood vessels differ from normal blood vessels.24 The former are tortuous, which likely contributes to high tumor interstitial pressure (Figure 22). The high interstitial pressure in tumors impedes the delivery of both nutrients and chemotherapeutic agents. Angiogenesis inhibitors such as bevacizumab can prevent new vascularization, tumor growth, and metastasis and normalize the tumor vasculature by inducing vascular regression and reducing interstitial pressure.29,30 Figure 2. Open in new tabDownload slide Normalization of Abnormal Tumor Vasculature by Angiogenesis Inhibitors.28 Figure 2. Open in new tabDownload slide Normalization of Abnormal Tumor Vasculature by Angiogenesis Inhibitors.28 Angiogenesis is involved in wound healing, so bevacizumab can impair the healing process. Therefore, the drug should not be initiated for at least 28 days after surgery.23 Gastrointestinal perforation, hypertension, and proteinuria also are associated with bevacizumab.23 Bevacizumab exhibits synergy with cancer chemotherapeutic agents in most solid tumors.31 It should not be used alone. Bevacizumab is approved by FDA for use in combination with i.v. 5-FU-based chemotherapy for the first-line treatment of metastatic carcinoma of the colon or rectum.23 Metastatic colorectal cancer A meta-analysis of randomized controlled trials in patients with advanced or metastatic colorectal cancer found a median survival of approximately 12 months with the use of 5-FU plus leucovorin compared with 7.5–8 months with best supportive care (Figure 33).32 Use of IFL instead (i.e., adding irinotecan) increased the survival to 14 months. The use of FOLFOX4 (i.e., using oxaliplatin instead of irinotecan with 5-FU plus leucovorin) further increased survival to 19 months. The longest survival (20 months) was associated with the use of IFL plus bevacizumab. Figure 3. Open in new tabDownload slide Impact of Various Interventions on Survival in Patients with Metastatic Colorectal Cancer. BSC = best supportive care; 5FU/LCV = 5-fluorouracil plus leucovorin; IFL = irinotecan, 5-fluorouracil, and leucovorin; FOLFOX4 = 5-fluorouracil, leucovorin, and oxaliplatin; Bevac = bevacizumab. Reprinted from reference 32. Figure 3. Open in new tabDownload slide Impact of Various Interventions on Survival in Patients with Metastatic Colorectal Cancer. BSC = best supportive care; 5FU/LCV = 5-fluorouracil plus leucovorin; IFL = irinotecan, 5-fluorouracil, and leucovorin; FOLFOX4 = 5-fluorouracil, leucovorin, and oxaliplatin; Bevac = bevacizumab. Reprinted from reference 32. First-line therapy. One of five regimens containing bevacizumab plus (1) FOLFOX, (2) FOLFIRI, (3) IFL, (4) 5-FU and leucovorin, or (5) CAPOX is recommended by the National Comprehensive Cancer Network (NCCN) as first-line therapy for advanced or metastatic colorectal cancer.3,9 The regimen with 5-FU, leucovorin, and bevacizumab is recommended for patients who are unable to tolerate irinotecan or oxaliplatin. The regimen containing CAPOX and bevacizumab was recently added to the NCCN guidelines, although there is less evidence supporting its use than for other regimens (i.e., the role of capecitabine is not yet clear).3,9 Currently, no one regimen is preferred as the standard of care for patients with advanced or metastatic colorectal cancer. Support for adding bevacizumab to 5-FU-based regimens as first-line therapy for advanced or metastatic colorectal cancer came from phase II and phase III clinical trials. A higher response rate, a longer median time to disease progression, and an increase in median survival were demonstrated when bevacizumab was added to 5-FU plus leucovorin in a phase II trial of 144 patients with previously untreated metastatic colorectal cancer.33 Patients were randomized to receive 5-FU 500 mg/m2 plus leucovorin 500 mg/m2 weekly for 6 weeks of every 8-week cycle in combination with bevacizumab 5 mg/kg or 10 mg/kg or placebo every 2 weeks. All medications were given i.v. The response rate was 40%, 24%, and 17% with bevacizumab 5 mg/kg, bevacizumab 10 mg/kg, and placebo, respectively. The median time to disease progression was 9.0 months, 7.2 months, and 5.2 months, respectively. The median survival was 21.5 months, 16.1 months, and 13.8 months, respectively. These findings were the basis for choosing 5 mg/kg as the recommended bevacizumab dosage for patients with metastatic colorectal cancer. An 11% increase in response rate (from 15% to 26%) and a 3.7-month increase in both median time to progression (from 5.5 months to 9.2 months) and median survival (from 12.9 months to 16.6 months) were observed when bevacizumab 5 mg/kg was added to 5-FU plus leucovorin in a larger phase II placebo-controlled trial of 209 patients with previously untreated metastatic colorectal cancer.34 The incidence of grade 3 hypertension was higher with bevacizumab treatment (16% versus 3% without bevacizumab), but blood pressure was controlled with oral medication. The safety and efficacy of adding bevacizumab to IFL were evaluated in a phase III placebo-controlled trial of 813 previously untreated patients with metastatic colorectal cancer.35 Significant improvements in response rate (from 35% to 45%), time to disease progression (from 6.2 months to 10.6 months), and survival (from 15.6 to 20.3 months) were associated with IFL plus bevacizumab compared with IFL alone. The group treated with bevacizumab had a higher incidence of grade 3 hypertension (11%) than the placebo group (2%) but blood pressure was easily controlled. How the efficacy of FOLFOX4 plus bevacizumab compares with that of IFL plus bevacizumab for first-line treatment of advanced or metastatic colorectal cancer remains to be determined in clinical trials. Second- and third-line therapy. Chemotherapeutic regimens used for second- and third-line treatment of advanced or metastatic colorectal cancer depend on what agents were used previously. At least one new agent that was not used as first-line therapy should be used for second-line therapy. If irinotecan was used as part of the first-line regimen, oxaliplatin (i.e., FOLFOX) should be considered for second-line therapy. Conversely, if oxaliplatin was used as first-line therapy, irinotecan (as FOLFIRI alone or in combination with cetuximab) should be considered for second-line therapy. If neither oxaliplatin nor irinotecan was used as first-line therapy (i.e., if 5-FU, leucovorin, and bevacizumab were used), FOLFOX, FOLFIRI, or irinotecan alone may be used as second-line therapy.3,9 The role of cetuximab in second-and third-line treatment of advanced or metastatic colorectal cancer was explored in a study of 329 patients with metastatic disease that had progressed despite treatment with an irinotecan-based regimen.36 Eligibility criteria included immunohistochemical evidence of EGFR expression and a Karnofsky performance score of 60 or more (i.e., a good performance status). Patients were randomized to receive cetuximab (400 mg/m2 i.v. as a loading dose followed by 250 mg/m2 i.v. weekly) alone or in combination with the irinotecan dosage and schedule used previously. The response rate and median time to disease progression were significantly higher in the cetuximab plus irinotecan group (23% and 4.1 months, respectively) than in the group that received cetuximab alone (11% and 1.5 months, respectively). The differences are significant. The median overall survival also was longer with combination therapy (8.6 months) than with cetuximab monotherapy (6.9 months), although the difference is not significant. Adverse effects (especially diarrhea and neutropenia) were more common in the group receiving combination therapy, but they were no more common or severe than would be expected with irinotecan monotherapy. An acne-like rash occurred in 80% of patients in both treatment groups. These findings support the use of cetuximab in combination with irinotecan as second- or third-line therapy for advanced or metastatic colorectal cancer. Although current NCCN guidelines recommend the use of bevacizumab as part of first-line combination regimens, they do not yet recommend use of the drug as part of second- or third-line regimens because of limited data.3,9 The benefit from second-line use of bevacizumab in combination with FOLFOX4 was demonstrated in a phase III trial of 579 patients with colorectal cancer that had been treated with a regimen containing 5-FU, irinotecan, or both.37 Prior bevacizumab use was not allowed. Patients were randomized to receive biweekly FOLFOX4 (oxaliplatin 85 mg/m2 i.v. over 2 hours on day 1, leucovorin 200 mg/m2 i.v. over 2 hours on days 1 and 2, and 5-FU 400 mg/m2 by i.v. bolus injection followed by 600 mg/m2 i.v. over 22 hours on days 1 and 2), high-dose bevacizumab (10 mg/kg every 2 weeks), or both. The treatment arm receiving bevacizumab alone was stopped early because it lacked activity (closed by the data safety monitoring board). After a median follow-up of 18.7 months, the median overall survival was significantly greater in the group receiving FOLFOX4 plus bevacizumab (12.5 months) than in the group receiving FOLFOX4 alone (10.7 months). These findings suggest a potential benefit from second- or third-line use of bevacizumab in patients with advanced or metastatic colorectal cancer who have not received the drug as part of first-line therapy, but additional clinical research is needed to clarify the role of bevacizumab in this patient population. Third-line therapeutic options for advanced or metastatic colorectal cancer include irinotecan plus cetuximab for patients refractory to FOLFOX, FOLFIRI, or irinotecan alone.3,9 Irinotecan might be used alone in patients who never received the drug as part of a first- or second-line regimen (e.g., if 5-FU, leucovorin, and bevacizumab were used first followed by FOLFOX). FOLFOX might be used as third-line therapy in patients who received FOLFIRI or IFL plus bevacizumab followed by irinotecan plus cetuximab.3,9 Capecitabine may have a role in third-line therapy but this role currently is unclear. Current therapeutic approach. Patients with advanced or metastatic colorectal cancer probably should receive all five chemotherapeutic agents (5-FU/leucovorin, irinotecan, oxaliplatin, bevacizumab, and cetuximab) at some time in the course of treatment, although the preferred sequence remains to be determined. Strong evidence supports the use of IFL plus bevacizumab as first-line therapy,35 FOLFOX4 as second-line therapy, and irinotecan plus cetuximab36 as third-line therapy.35,–37 Interestingly, a recent survey shows the majority of oncologists use FOLFOX4 and bevacizumab as first-line therapy. Whether bevacizumab is best used as part of first-line regimens, second-line regimens, or both has not been determined. Interpreting research. Part of the difficulty in comparing the efficacy of different chemotherapy regimens is inherent in the research methodology used in clinical trials. Patients who fail to respond to the standard treatment frequently do not have access to the investigational treatment, although patients who fail to respond to the investigational treatment have access to and frequently receive the standard treatment. This arrangement can skew the overall survival results in favor of investigational agents. Although an oxaliplatin-based regimen (FOLFOX4) appeared to provide a much longer survival than an irinotecan-based regimen (IFL), the results may be due to differences in second-line therapy. Sixty percent of patients randomized to the FOLFOX4 arm received second-line therapy with irinotecan, while less than 24% of IFL patients received second-line therapy with oxaliplatin (investigational at the time). The results of a European randomized, crossover study comparing similar regimens illustrate the impact of the study methodology on outcomes.39 In the European study, 220 patients with advanced colorectal cancer received FOLFOX6 (oxaliplatin 100 mg/m2 i.v. over 2 hours on day 1, leucovorin 400 mg/m2 i.v. over 2 hours on day 1, and 5-FU 400 mg/m2 by i.v. bolus injection on day 1 followed by 1200 mg/m2/day i.v. for 2 days [i.e., 2400 mg/m2 over 46–48 hours]) or FOLFIRI (the same leucovorin and 5-FU dosages plus irinotecan 180 mg/m2 i.v. over 90 minutes instead of oxaliplatin) every 2 weeks.39 Both groups were crossed over to the other regimen at the time of disease progression. There was no significant difference in survival between the two treatment groups; the median survival was 22 months in patients who received FOLFIRI followed by FOLFOX6 and 21 months in patients who received FOLFOX6 followed by FOLFIRI (Figure 33). This study provided preliminary data on sequencing and the impact of drug exposure. No significant differences in second-progression-free survival, overall survival, or first-line response rates between the two sequences were found. Adjuvant chemotherapy Although the most active agents used to treat metastatic disease in theory ought to be most useful for adjuvant chemotherapy, the role of bevacizumab and cetuximab in adjuvant therapy currently is being actively investigated. Regimens currently recommended by NCCN for use as adjuvant chemotherapy in patients with stage III colorectal cancer and high-risk patients with stage II disease include (1) capecitabine, (2) 5-FU plus leucovorin, and (3) FOLFOX4.3 Overall survival and disease-free survival have been used as endpoints in studies comparing adjuvant chemotherapy regimens. The FDA prefers 5-year overall survival data when evaluating new chemotherapeutic agents, but the agency has approved agents based on 3-year disease-free survival because these data are highly predictive of 5-year overall survival.40 The standard adjuvant chemotherapy regimen for stage II and stage III colon cancer has been 5-FU plus leucovorin. The benefit from adjuvant 5-FU plus leucovorin (rapid i.v. injection of 5-FU 425 mg/m2/day and leucovorin 20 mg/m2/day for 5 consecutive days every 4 to 5 weeks) was demonstrated in a randomized study of 317 patients with stage III or high-risk stage II colon cancer.41 The overall survival rate after 5 years was 74% with 5-FU plus leucovorin and 63% with observation (i.e., no adjuvant chemotherapy). The percentage of relapse-free patients after 5 years was 74% with adjuvant chemotherapy and 58% without such chemotherapy. Toxicity from 5-FU (primarily grade 3 stomatitis, diarrhea, and leukopenia) was managed by reducing the dosage. The efficacy of adding oxaliplatin to 5-FU plus leucovorin as adjuvant chemotherapy was evaluated in 2246 patients who underwent curative resection for stage II or stage III colon cancer.42 Adjuvant chemotherapy was given for six months. The rate of disease-free survival after three years was 78% in the group receiving oxaliplatin, 5-FU, and leucovorin (i.e., FOLFOX4) and 73% in the group receiving 5-FU plus leucovorin, a difference that is significant. A survival benefit has not yet been observed. The final analysis will answer overall survival questions. Neutropenia, paresthesia, diarrhea, and vomiting were the most common severe (i.e., grade 3 or grade 4) adverse effects in patients treated with oxaliplatin, affecting 41%, 12%, 11%, and 6% of patients, respectively. These findings suggest that FOLFOX4 is likely to supersede 5-FU plus leucovorin as the adjuvant chemotherapy regimen of choice for patients with stage II or stage III disease in future practice guidelines. Capecitabine (1250 mg/m2 orally twice daily for the first 14 days of every 21 days for eight cycles) was compared with six cycles of 5-FU (Mayo Clinic Regimen: 20 mg/m2 i.v. bolus of leucovorin followed by 425 mg/m2 i.v. bolus of 5-FU; both given daily for 5 days, cycle repeated every 28 days) as adjuvant therapy in 1987 patients with resected stage III colon cancer.43 There was no significant difference between treatment groups in the 3-year disease-free survival rate (64% with capecitabine and 61% with 5-FU plus leucovorin) or overall survival (81% and 78%, respectively). Significantly fewer adverse effects were associated with capecitabine than 5-FU plus leucovorin. Controlled studies are needed to determine how capecitabine compares with FOLFOX as adjuvant therapy in patients with high-risk stage II or III colon cancer. Conclusion Colorectal cancer is associated with substantial mortality because it usually is not localized when it is detected. The recombinant humanized IgG1 monoclonal antibodies bevacizumab and cetuximab increase the activity of chemotherapeutic agents and may contribute to improved survival. The ideal chemotherapy combinations and sequences for the treatment of colorectal cancer remain to be determined. Footnotes Based on the proceedings of a symposium held December 4, 2005, during the ASHP Midyear Clinical Meeting, Las Vegas, NV, and supported by an educational grant from Sanofi-Synthelabo Inc. and Aventis Pharmaceuticals, members of the sanofi-aventis group. Dr. Adams received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Adams reports that he has no affiliations with or financial interest in a commercial organization that poses a conflict of interest with this article. References 1 American Cancer Society. Colorectal Cancer Facts & Figures—Special Edition 2005. http://www.cancer.org/downloads/STT/CAFF2005CR4PWSecured.pdf (accessed 2006 Jan 14). 2 Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin . 1999 ; 49 : 33 –64, 1. Crossref Search ADS PubMed 3 The National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Colon Cancer version 2.2006. http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf (accessed 2006 Jan 14). 4 Bazan V, Migliavacca M, Zanna I et al. DNA ploidy and S-phase fraction, but not p53 or NM23-H1 expression, predict outcome in colorectal cancer patients. Result of a 5-year prospective study. J Cancer Res Clin Oncol . 2002 ; 128 : 650 –8. Crossref Search ADS PubMed 5 Jen J, Kim H, Piantadosi S et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med . 1994 ; 331 : 213 –21. Crossref Search ADS PubMed 6 Colon and rectum. In: American Joint Committee on Cancer. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002 , pp 113–24 [AJCC]. 7 Compton CC, Greene FL. The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin . 2004 ; 54 : 295 –308. Crossref Search ADS PubMed 8 O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst . 2004 ; 96 : 1420 –5. Crossref Search ADS PubMed 9 The National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Rectal Cancer version 2.2006. http://www.nccn.org/professionals/physician_gls/PDF/rectal.pdf (accessed 2006 Jan 14). 10 Benson AB 3rd, Schrag D, Somerfield MR et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol . 2004 ; 22 : 3408 –19. Crossref Search ADS PubMed 11 Gill S, Loprinzi CL, Sargent DJ et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol . 2004 ; 22 : 1797 –806. Crossref Search ADS PubMed 12 Sargent DJ, Goldberg RM, Jacobson SK et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med . 2001 ; 345 : 1091 –7. Crossref Search ADS PubMed 13 Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med . 2000 ; 343 : 905 –14. Crossref Search ADS PubMed 14 McEvoy GK, ed. Capecitabine. In: AHFS Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists; 2005 :924–32. 15 McEvoy GK, ed. Fluorouracil. In: AHFS Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists; 2005 :1020–4. 16 McEvoy GK, ed. Irinotecan hydrochloride. In: AHFS Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists; 2005 :1076–81. 17 McEvoy GK, ed. Oxaliplatin. In: AHFS Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists; 2005 :1121–4. 18 Gamelin L, Boisdron-Celle M, Delva R et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res . 2004 ; 10 (12 pt 1): 4055 –61. Crossref Search ADS PubMed 19 Chung KY, Saltz LB. Antibody-based therapies for colorectal cancer. Oncologist . 2005 ; 10 : 701 –9. Crossref Search ADS PubMed 20 Porebska I, Harlozinska A, Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERB B2, ERB B3) in colorectal adenocarcinomas and adenomas. Tumour Biol . 2000 ; 21 : 105 –15. Crossref Search ADS PubMed 21 Alekshun T, Garrett C. Targeted therapies in the treatment of colorectal cancers. Cancer Control . 2005 ; 12 : 105 –10. Crossref Search ADS PubMed 22 Erbitux package insert. Princeton, NJ: Bristol-Myers Squibb Company; August 2005 . 23 Avastin package insert. South San Francisco, CA: Genentech, Inc.; January 2005 . 24 Bergsland EK. Vascular endothelial growth factor as a therapeutic target in cancer. Am J Health-Syst Pharm . 2004 ; 61 (21 suppl 5): S4 –11. 25 Presta LG, Chen H, O’Connor SJ et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res . 1997 ; 57 : 4593 –9. PubMed 26 Fernando NH, Hurwitz HI. Inhibition of vascular endothelial growth factor in the treatment of colorectal cancer. Semin Oncol . 2003 ; 30 (3 suppl 6): 39 –50. Crossref Search ADS 27 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature . 2000 ; 407 : 249 –57. Crossref Search ADS PubMed 28 Jain RK. 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This version first published online: 24 January 2000 in Issue 1, 2000. Date of most recent substantive amendment: 16 November 1999. 33 Kabbinavar F, Hurwitz HI, Fehrenbacher L et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol . 2003 ; 21 : 60 –5. Crossref Search ADS PubMed 34 Kabbinavar FF, Schulz J, McCleod M et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol . 2005 ; 23 : 3697 –705. Crossref Search ADS PubMed 35 Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med . 2004 ; 350 : 2335 –42. Crossref Search ADS PubMed 36 Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med . 2004 ; 351 : 337 –45. Crossref Search ADS PubMed 37 Giantonio BJ, Catalano PJ, Meropol NJ et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. Presented at the 2005 American Society of Clinical Oncology Annual Meeting, Orlando, FL: May 13–17, 2005 . http://asco.org/asco/publications/abstract_print_view/1,1148,_12-002643-00_18-0034-00_19-0034047,00.html. 38 Love N, Grothey A. Management of early and advanced cancer of the colon and rectum. Patterns of Care in Medical Oncology . 2005 ; 2 : 1 –43. 39 Tournigand C, Andre T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol . 2004 ; 22 : 229 –37. 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American Society of Health-System Pharmacists, Inc. All rights reserved.

Siegel,, Jerry

doi: 10.2146/ajhp060114pmid: 16641253

Abstract Purpose. The potential impact of changes in reimbursement for drugs and biologicals associated with the Medicare Prescription Drug Improvement and Modernization Act (MMA) on the management of colorectal cancer is described from the perspectives of health care providers and patients. Summary. The introduction of new chemotherapeutic agents and supportive therapies over the past several decades has increased survival in patients with colorectal cancer. The changes in reimbursement for these therapies associated with MMA may affect the financial viability of private physician office practices and hospital-based outpatient clinics where such therapies are administered. The MMA-related changes also have the potential to decrease patient access to treatment and adversely affect treatment choices, scheduling, and outcomes. Conclusion. The reimbursement changes brought about by implementation of MMA could affect health care delivery and patient care. Antineoplastic agents, Biologicals, Colorectal neoplasms, Health-benefit programs, Laws, Medicare Prescription Drug Improvement and Modernization Act, Reimbursement The chemotherapeutic agents available for the treatment of colorectal cancer and other malignancies, supportive therapies used to manage cancer pain and toxicity from chemotherapy, and clinicians’ awareness of the cost of these therapies—what might be referred to as “chemotherapy cost consciousness”—have increased greatly in the past 25 to 30 years. The large impact of these changes is illustrated by considering the current standard of care and taking a look back at the following patient case from long ago. Looking back MAS was a 66-year-old man who presented with constipation and black stool in 1976. Results of a guaiac-based fecal occult blood test were positive, so MAS was referred to a gastroenterology specialist for a complete diagnostic workup. A barium enema revealed a partial obstruction of the transverse colon. The results of a sigmoidoscopy were normal. A surgeon was consulted for a laparoscopy and, based on the findings, a 10-inch bowel segment was resected without the need for a colostomy. A 3-cm malignant tumor with polyps was removed at the time of surgery. The liver appeared normal. The surgeon told MAS and his family that all of the malignancy had been removed. No chemotherapy or radiation therapy was recommended because the assumption of the surgeon was that they “got it all.” Lifestyle changes, with an increase in dietary fiber and exercise as tolerated, were the only recommendations made to MAS at the time of discharge from the hospital. Two years later MAS presented with worsening fatigue. His hemoglobin concentration and hematocrit values were 7.2 g/dL and 25%, respectively (i.e., much lower than normal). MAS appeared jaundiced, which raised suspicions of a recurrence of colon cancer with liver metastases. A diagnostic workup confirmed these suspicions. In 1978, oral 5-fluorouracil and leucovorin were the primary treatment options for metastatic colon cancer. Alternative therapy included direct infusion into the hepatic artery with 5-fluorouracil. The impact of pharmacogenetics on drug disposition had not yet been explored, and monoclonal antibodies were yet to be developed. Blood transfusions, immediate-release and injectable opioid analgesics, and rectal suppositories containing antiemetic agents with limited efficacy and substantial adverse effects were the therapeutic options available for managing cancer pain and toxicity from chemotherapy in 1978. Chemotherapy often was interrupted or modified because of neutropenia, with an adverse effect on survival. In 1978, treatment was provided primarily in hospitals, although it was available at some outpatient clinics at cancer specialty hospitals. Many patients were required to travel long distances frequently to receive treatment for the disease or its complications. Administering chemotherapy in the home-care setting was a new approach designed to minimize patient exposure to hospital-based pathogens, decrease health care costs, and improve patient convenience. Fast forward to the present The management of cancer pain and common toxicities from cancer chemotherapy has changed dramatically since 1978 because of the introduction of new supportive therapies (Table 11). The advances have improved the tolerability of chemotherapy and patient survival.1 Table 1. Management Approach for Cancer Pain and Common Chemotherapy-Related Toxicities: 1978 and Presenta Management Approach Symptom or Type of Toxicity 1978 Present a 5-HT3 = type 3 5-hydroxytryptamine; NK1 = neurokinin-1. Alopecia Use wigs Use wigs Anemia Administer blood transfusions Administer erythropoietic agents (e.g., epoetin alfa, darbepoetin alfa) and, if anemia is severe, blood transfusions Neutropenia Discontinue or modify chemotherapy Administer granulocyte colony-stimulating factors (e.g., filgrastim, pegfilgrastim) Pain Administer immediate-release oral or injectable opioid analgesics Administer transdermal fentanyl or extended-release oral or injectable opioid analgesics Nausea and vomiting Administer rectal suppositories containing phenothiazines (e.g., prochlorperazine) or antihistamines (e.g., trimethobenzamide) or recommend marijuana use Administer oral or injectable 5-HT3 receptor antagonist or the oral NK1 receptor antagonists aprepitant Management Approach Symptom or Type of Toxicity 1978 Present a 5-HT3 = type 3 5-hydroxytryptamine; NK1 = neurokinin-1. Alopecia Use wigs Use wigs Anemia Administer blood transfusions Administer erythropoietic agents (e.g., epoetin alfa, darbepoetin alfa) and, if anemia is severe, blood transfusions Neutropenia Discontinue or modify chemotherapy Administer granulocyte colony-stimulating factors (e.g., filgrastim, pegfilgrastim) Pain Administer immediate-release oral or injectable opioid analgesics Administer transdermal fentanyl or extended-release oral or injectable opioid analgesics Nausea and vomiting Administer rectal suppositories containing phenothiazines (e.g., prochlorperazine) or antihistamines (e.g., trimethobenzamide) or recommend marijuana use Administer oral or injectable 5-HT3 receptor antagonist or the oral NK1 receptor antagonists aprepitant Open in new tab Table 1. Management Approach for Cancer Pain and Common Chemotherapy-Related Toxicities: 1978 and Presenta Management Approach Symptom or Type of Toxicity 1978 Present a 5-HT3 = type 3 5-hydroxytryptamine; NK1 = neurokinin-1. Alopecia Use wigs Use wigs Anemia Administer blood transfusions Administer erythropoietic agents (e.g., epoetin alfa, darbepoetin alfa) and, if anemia is severe, blood transfusions Neutropenia Discontinue or modify chemotherapy Administer granulocyte colony-stimulating factors (e.g., filgrastim, pegfilgrastim) Pain Administer immediate-release oral or injectable opioid analgesics Administer transdermal fentanyl or extended-release oral or injectable opioid analgesics Nausea and vomiting Administer rectal suppositories containing phenothiazines (e.g., prochlorperazine) or antihistamines (e.g., trimethobenzamide) or recommend marijuana use Administer oral or injectable 5-HT3 receptor antagonist or the oral NK1 receptor antagonists aprepitant Management Approach Symptom or Type of Toxicity 1978 Present a 5-HT3 = type 3 5-hydroxytryptamine; NK1 = neurokinin-1. Alopecia Use wigs Use wigs Anemia Administer blood transfusions Administer erythropoietic agents (e.g., epoetin alfa, darbepoetin alfa) and, if anemia is severe, blood transfusions Neutropenia Discontinue or modify chemotherapy Administer granulocyte colony-stimulating factors (e.g., filgrastim, pegfilgrastim) Pain Administer immediate-release oral or injectable opioid analgesics Administer transdermal fentanyl or extended-release oral or injectable opioid analgesics Nausea and vomiting Administer rectal suppositories containing phenothiazines (e.g., prochlorperazine) or antihistamines (e.g., trimethobenzamide) or recommend marijuana use Administer oral or injectable 5-HT3 receptor antagonist or the oral NK1 receptor antagonists aprepitant Open in new tab In recent years, chemotherapy often has been administered in physician offices. This practice usually is convenient for patients and highly profitable for physicians, despite the need for additional nursing staff to administer the drugs and office staff to order and maintain drug inventories. Changes in Medicare reimbursement Colorectal cancer is primarily a disease of older Americans, many of whom are eligible for Medicare.1 The Medicare Prescription Drug Improvement and Modernization Act (MMA) of 2003 is expected to have a large impact on the management of colorectal cancer. In 2003, the Medicare reimbursement rate for drugs and biologicals was 95% of the average wholesale price (AWP). The typical AWP was roughly threefold higher than the acquisition cost, so reimbursement rates provided a sufficient margin (i.e., the difference between the reimbursement rate and the acquisition cost of the drug) to cover the costs associated with administering medications. These administration costs typically include nurses’ salaries and expenses for equipment, supplies (e.g., intravenous tubing, needles), and overhead (e.g., utilities). When the difference between reimbursement and acquisition cost is great, the cost of administration is less of a concern. The Medicare reimbursement rate decreased to 85% of the AWP in 2004, cutting into the margin. In 2005, health care providers were reimbursed for drugs and biologicals at a rate that was based on the average sales price (ASP) plus 6% of the ASP (i.e., 106% of the ASP).2 The ASP reflects manufacturer rebates, promotions, and discounts (but not 340B pharmaceutical procurement program discounts) based on the volume of use and purchase contract negotiated in a wide variety of practice settings with different patient populations. Market share discounts and bundled product discounts will also affect the ASP. The ASP payment method does not provide a large margin between the reimbursement rate and the acquisition cost of the drug. Use of 106% of the ASP could lead to a net loss if the expenses associated with providing drug therapy exceed the margin. To offset this, the reimbursement for administration of drugs needs to increase significantly to cover the cost of these expenses. Concerns have been raised about the impact of MMA on the profitability and financial viability of private physician office practices where chemotherapy is administered. Medicare deductibles have increased, and the ability of a practice to forgive bad debt from uncollected deductibles might be compromised by the small margin associated with the use of the ASP method for reimbursement.2 In the past physicians were often willing to waive the deductible amount of the drug costs for a patient. However, now that reimbursements are lower, physicians are unlikely to waive patient costs because doing so would cut into the already reduced margins. As a result, the out-of-pocket expenses to patients will be higher. Some specialty pharmacies, especially those that work under a competitive bid model, will require that the deductible be paid in advance of chemotherapy preparation. Unanticipated expenses (e.g., an increase in overhead costs related to an unusually cold winter and increases in heating fuel rates) could force a practice to close. The potential loss of flexibility in treatment locations (i.e., reduced access and convenience) for patients if these private physician office practices close is a concern. Patients might need to travel long distances to receive treatment, as was often the case decades ago. Administrators in hospitals and hospital-based outpatient clinics have concerns about accommodating an increase in patient volume because their financial success hinges on keeping beds and chairs filled with patients and currently they do not have excess capacity. It is customary to overbook patient appointments and rely on a consistent percentage of patients failing to keep their appointments. Administrators are reluctant to risk having empty beds or chairs because each one represents a lost opportunity cost. Current inequities in manufacturers’ discount policies and Medicare reimbursement rates exacerbate the concerns of administrators at hospital outpatient clinics about limited space (i.e., chairs and beds), resources, and profitability. Manufacturers offer higher discounts on drugs to private physicians with office-based practices than to even larger cancer hospitals. This may seem odd but it is a way to assure brand loyalty. These same discounts should be offered to cancer hospitals. Extra reimbursement was provided to physicians in 2005 as part of a 1-year Centers for Medicare & Medicaid Services (CMS) demonstration project designed to assess the quality of care that cancer patients receive in oncology clinics. Additional payment was provided for the assessment of three patient-status factors (nausea/vomiting, fatigue, and pain). The demonstration project was terminated at the end of 2005. A different 1-year demonstration project was proposed in 2006, which allowed an additional 2% reimbursement for hospital pharmacy departments to cover their overhead. Hospital overhead can be higher due to extended hours and days of service, equipment, and supplies to comply with compounded sterile product requirements.3 This extra revenue could have reduced the impact of the ASP reimbursement method. In 2006, CMS decided not to provide the additional 2% for reimbursement. A new demonstration project with additional funding for pharmacists to address medication safety issues related to the use of chemotherapeutic agents may be developed by CMS. Various pharmacy organizations, including the American Society of Health-System Pharmacists, the American College of Clinical Pharmacy, and the Hematology/Oncology Pharmacy Association, are working with CMS to develop this demonstration project. Future challenges In 2006, the Medicare reimbursement rates will be based on 106% of the ASP or a competitive bid process. In the competitive bid process, health care providers will submit bids to CMS for the provision of drug therapy to beneficiaries. Administrators at hospital-based outpatient clinics were required to make a decision about the use of the competitive bid process by March 2006 without knowing whether it would provide a larger profit than 106% of the ASP. Private office-based physician practices may find the competitive bid process impractical and therefore very limited Specialty pharmacies may approach private office-based physicians and offer to maintain an inventory and carry the capital cost (i.e., acquisition cost) of chemotherapeutic agents, and then sell the drugs on a just-in-time consignment basis to the physician. The physician would need to collect a 20% copay from the patient before purchasing the drug from the specialty company. This copay would then need to be sent to the specialty pharmacy before any product would be released. The specialty pharmacy would then bill CMS for the balance of the cost of the drug. Since the copay would have to be collected in advance, it is unlikely that physicians’ offices will pay this fee out of their pocket due to the small margins under which they are now working. Outpatient clinics at public hospitals face a dilemma because they are generally obligated to provide care to patients regardless of a patient’s ability to pay. Private office-based physicians may keep those patients who can afford the copay and refer other patients who are unable to pay to these hospital clinics, thereby shifting the financial burden to the hospital-based clinic. Creating a partnership with the private physician office practice and purchasing these practices are options that may be attractive to administrators at public hospitals who are faced with the financial burden of treating patients who cannot afford treatment by the private physician. Such arrangements might solve the problem of inadequate space for treatment. The ASP method for reimbursement provides incentive to use costly drugs because 6% of an expensive drug is larger than 6% of an inexpensive drug (i.e., reimbursement is greater for expensive drugs than for inexpensive drugs). The lack of incentive to use inexpensive medications (e.g., generic medications) represents a dramatic change for clinicians and administrators in health systems who have been accustomed to choosing the least costly therapeutic option when evidence-based medicine demonstrates that the efficacy and safety of two or more options are comparable. Choosing the more expensive drugs may benefit the physician, yet may increase the cost to the patient. The situation makes it imperative to weigh both the costs and benefits (especially overall survival rates) from various treatment options, including the option of providing only palliative and supportive treatment. Impact on patients The largest impact of MMA may be on patients. The out-of-pocket expenses for patients may be substantial if they are required to pay the 20% copay. Delays in chemotherapy may result from a patient’s inability to pay the copay or scheduling difficulties (i.e., increases in waiting times for appointments) due to a shift of patients from private physician offices to hospital outpatient clinics with insufficient space. Patients may spend a lot of time traveling long distances to receive treatment if it is not available at local physician offices. The choice of treatment approach may be influenced by Medicare reimbursement policies, which may favor generic or older drugs instead of newer agents because of the greater out-of-pocket expenses for patients. Clinicians are required to present patients with treatment options, but liability concerns dictate that the choice among the options ultimately is the patient’s to make. Patient outcomes and quality of life may be compromised because of concerns about the cost of treatment. In the case of MAS, he died shortly after recurrence of his colon cancer with liver metastasis. At the time, the two additional years of life that surgery provided was considered very good. The treatment advances that have been introduced in the past several decades make the prognosis for a patient with colorectal cancer much better than it was for MAS. Conclusion The introduction of new chemotherapeutic agents and supportive therapies over the past 30 years has improved survival in patients with colorectal cancer. The changes in reimbursement for drugs and biologicals associated with MMA may adversely affect the profitability and financial viability of health care providers’ practices. The reimbursement changes also have the potential to adversely affect patient access to care and treatment choices, scheduling, and outcomes for patients with colorectal cancer. A balance is needed so that reimbursement more accurately reflects the true expenses and a reasonable profit to support the continuation of physician office chemotherapy administration. Footnotes Based on the proceedings of a symposium held December 4, 2005, during the ASHP Midyear Clinical Meeting, Las Vegas, NV, and supported by an educational grant from Sanofi-Synthelabo Inc. and Aventis Pharmaceuticals, members of the sanofiaventis group. Dr. Siegel received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Siegel reports that he has no affiliations with or financial interest in a commercial organization that poses a conflict of interest with this article. References 1 American Cancer Society. Colorectal Cancer Facts & Figures—Special Edition 2005. http://www.cancer.org/downloads/STT/CAFF2005CR4PWSecured.pdf (accessed 2006 Jan 14). 2 Centers for Medicare & Medicaid Services. Medicare Part B Drug Average Sales Price. http://www.cms.hhs.gov/McrPartBDrugAvgSalesPrice/ (accessed 2006 Jan 23). 3 United States Pharmacopeia, Inc. U.S. Pharmacopeia 27. Chapter <797>: Pharmaceutical Compounding - Sterile Preparations. Rockville, MD: United States Pharmacopeial Convention; 2004 :2461–77. Copyright © 2006. American Society of Health-System Pharmacists, Inc. All rights reserved.