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Epirubicin and Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Therapy for Early Breast Cancer
Frequency and Cost of Chemotherapy-Related Serious Adverse Effects in a Population Sample of Women With Breast Cancer Hassett MJ, O’Malley AJ, Pakes JR, et al J Natl Cancer Inst 98:1108-1117, 2006 Adjuvant hormonal therapy and chemotherapy are the primary contributors to the 25% to 30% decline in mortality rates in middleaged women with breast cancer in the 1990s. This is due, in part, to evidence from randomized trials being rapidly adopted by cancer providers into routine care. In other words, the efficacy of adjuvant therapies in the clinical trial setting successfully transferred to effectiveness in routine care. A benefit-risk discussion must occur between patient and provider about the short- and long-term toxicities and mortality rates associated with adjuvant chemotherapy. The relative frequencies of grade 3 or 4 toxicities observed in clinical trials are a commonly used source of such information when the toxicities are quantitatively measured. The key issue that Hassett and colleagues addressed was whether the toxicities reported in routine practice (effectiveness) were similar to or different from the clinical trial estimates (efficacy). This careful report used a unique database that is increasingly being used by health services researchers. This database is an aggregation of medical claims from America’s largest corporations that self-insure employees and their dependents. This large cohort, while not a full representation of the cross-section of patients, had unique strengths: a geographically diverse population still in the work force (age >65 years) and a broad range of health care plans contracted to oversee the delivered health care. More than 12,000 women from 1998 to 2002 were carefully evaluated. The number of hospitalizations and emergency room visits associated with the period that women were eligible for receiving adjuvant chemotherapy after primary surgical therapy was recorded. The authors then carefully matched patients undergoing chemotherapy (based on their drug and procedure claims) to women not undergoing chemotherapy using propensity scores. The results were striking: hospitalizations in the year after breast cancer diagnoses were 8.4% for fever, 5.5% for neutropenia or thrombocytopenia, 2.5% for dehydration, and 2.4% for other gastrointestinal toxicities. About 40% of the hospitalizations were attributed to chemotherapy toxicity, and the remainder was due to surgery-related toxicities. The financial costs of these adverse effects averaged an additional $1,271 per patient undergoing chemotherapy, and the average amount spent by patients experiencing complications due to chemotherapy was about $14,000. No deaths were reported. Fortunately, 92% of these women did not have a major comorbidity using established administrative coding indicators. So how does one explain these high rates? As the authors’ suggested, these rates may appear high due to under-reporting issues in clinical trials and under-appreciation for the relatively healthy volunteer effect of trial participants.
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These findings suggest that in routine care, more frequent use of assorted supportive care measures and reductions of dosages are needed. Specifically, the oncology community may be under-using various antiemetics, under-using or failing to reduce the doses of white blood cell growth factors, and/or under-using erythropoiesisstimulating agents. As chemotherapy is being given for smaller and smaller absolute benefits, determining ways to avoid these high-frequency, common toxicities warrants ongoing attention and discussion. B. E. Hillner, MD
Randomized, Placebo-Controlled Trial of Saforis for Prevention and Treatment of Oral Mucositis in Breast Cancer Patients Receiving Anthracycline-Based Chemotherapy Peterson DE, Jones JB, Petit RG Cancer 109:322-331, 2007 This study provides data demonstrating that a novel glutamine formulation decreases chemotherapy-induced oral mucositis. The benefit associated with this product, as opposed to that of previously studied glutamine products, appears to be related to the markedly improved local absorption of glutamine into oral mucosal cells. Although the mucositis reduction seen in this trial is far short of ideal, this formulated glutamine product does appear to be a real step in the right direction. Hopefully, future studies will test the potential efficacy of this product with other chemotherapy regimens. Potentially, this compound will lead to additional benefit over that seen with oral cryotherapy alone for patients receiving fluorouracilbased chemotherapy regimens. Additionally, future studies will hopefully test the utility of this product in alleviating radiationinduced mucositis. C. L. Loprinzi, MD
Epirubicin and Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Therapy for Early Breast Cancer Poole CJ, Earl HM, Hiller L, et al N Engl J Med 355:1851-1862, 2006 Poole and colleagues reported the results of 2 large randomized phase III European trials that were designed during the height of the investigation on the role of anthracyclines as adjuvant therapy for early-stage breast cancer. The National Epirubicin Adjuvant Trial (NEAT) enrolled patients in England, and the BR9601 trial enrolled patients in Scotland. Both studies were designed to compare 4 cycles of epirubicin plus 4 cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) to 6 (NEAT) or 8 (BR9601) cycles of CMF alone. The primary endpoints of both trials were overall and relapse-free survival. In NEAT, the standard regimen of CMF was administered, while a modified version of CMF (all drugs given intravenously every 3 weeks) was used in the BR9601 trial. Conducted between 1996 and 2001, these studies consistently showed an improvement in both relapse-free and overall survival at
2 and 5 years in the epirubicin plus CMF arm, with an absolute improvement in overall survival of 7% at 5 years. Treatment was an independent prognostic variable associated with improved relapsefree and overall survival, falling behind nodal status, tumor grade, and tumor size as the most important factors. The increase in adverse events associated with the addition of epirubicin to CMF did not compromise treatment delivery, and the addition of epirubicin was associated with only a short-term reduction in quality of life compared to CMF alone. This study adds to the body of literature confirming the importance of anthracyclines in the armamentarium of adjuvant therapy for early-stage breast cancer. Despite the slightly different regimens of the 2 studies, the results consistently showed an improvement in survival, which is attributed to the addition of epirubicin. However, the absolute superiority of anthracycline-based regimens over CMF has been inconsistent, with conflicting results among investigated regimens. The National Surgical Adjuvant Breast and Bowel Project B-15 trial showed that the use of every-3-week doxorubicin and cyclophosphamide was equivalent to CMF with respect to survival measure and resulted in better tolerance and delivery of therapy.1 The National Cancer Institute of Canada Clinical Trials Group Mammary.5 (MA.5) trial compared cyclophosphamide, epirubicin, and fluorouracil (CEF) to CMF in premenopausal women with node-positive disease and found an improvement in relapse-free and overall survival in the CEF arm despite a lower dose intensity due to toxicity.2 Cyclophosphamide, epirubicin, and fluorouracil remained superior in terms of relapse-free and overall survival after a median follow-up of 10 years, although further correlative studies demonstrated that this benefit was confined to women with HER2amplified breast cancers.3,4 The Oxford meta-analysis that involved 14,000 women enrolled in trials comparing anthracycline- versus CMF-based regimens showed a moderate but significant advantage for anthracycline-based therapy, with an absolute improvement in survival of 4% at 10 years. This benefit was equivalent across age groups, with older women achieving similar superior survival as younger women.5 As a result of these studies, anthracycline-based therapy has become the standard of care in early-stage breast cancer. The importance of amplification of HER2 and topoisomerase II-alpha (topo2-alpha) in determining anthracycline sensitivity is being evaluated in both NEAT and the BR9601 trial. This analysis stems from a growing body of evidence that HER2 amplification and topo2-alpha gene aberration may predispose patients with breast cancer to anthracycline sensitivity. In the MA.5 trial, correlative studies evaluating the impact of HER2 amplification on the likelihood of response to CEF versus CMF demonstrated that the increase in benefit of CEF was confined to patients whose tumors overexpressed HER2. In women who did not have overexpression of HER2, there was no significant difference between treatment with CMF and CEF.4 The association between HER2 overexpression and anthracycline sensitivity may be related to topo2-alpha, a nuclear DNA-binding enzyme encoded on chromosome 17 near the HER2/neu oncogene. The gene topo2-alpha is the target of anthracyclines and is coamplified with HER2 in 44% of breast cancers, whereas 42% of breast cancers have deletions of this gene.6,7 In many adjuvant studies evaluating the efficacy of anthracycline-
based regimens, expression of topo2-alpha correlated with sensitivity to the anthracyline-based regimen, with overexpression resulting in a greater benefit from anthracyclines than those with normal expression.6,8-10 Although many of these analyses are exploratory, the roles of topo2-alpha and HER2 as predictive markers for benefit from anthracycline-based therapy is intriguing. The role of HER2 overexpression and topo2-alpha expression will be explored in the NEAT and BR9601 studies and may provide the largest cohort of women in which this concept is evaluated. Poole and colleagues have contributed to the growing evidence of the efficacy of anthracycline-based therapy in early-stage breast cancer. These studies have shown that the addition of epirubicin results in a statistically significant improvement in relapse-free and overall survival, which is attributed to the addition of epirubicin. However, given the evidence supporting the role of taxanes in nodepositive patients and the length of therapy required for epirubicin plus CMF, alternative therapies remain more attractive options for patients with early-stage breast cancer. The planned analysis of HER2/neu and topo2-alpha remains an intriguing component of this study. C. S. Denlinger, MD L. J. Goldstein, MD
References 1. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with six months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483-1496, 1990. 2. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol 16:2651-2658, 1998. 3. Levine MN, Pritchard KI, Bramwell VH, et al: A randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: Update of National Cancer Institute of Canada Clinical Trials Group Trial MA.5. J Clin Oncol 23:5166-5170, 2005. 4. Pritchard KI, Shepherd LE, O’Malley FP, et al: HER2 and responsiveness of breast cancer to adjuvant therapy. N Engl J Med 354:2103-2111, 2006. 5. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 365:1687-1717, 2005.
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6. MacGrogen G, Rudolph P, de Mascarel I, et al: DNA topoisomerase II alpha expression and the response to primary chemotherapy in breast cancer. Br J Cancer 89:666-671, 2003. 7. Jarvinen TA, Tanner M, Rantanen V, et al: Amplification and deletion of topoisomerase II alpha associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer. Am J Pathol 156:839-847, 2000. 8. Di Leo A, Gancberg D, Larsimont D, et al: HER-2 amplification and topoisomerase II alpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res 8:1107-1116, 2002. 9. O’Malley FP, Chia S, Tu D, et al: Topoisomerase II alpha protein overexpression has predictive utility in a randomized trial
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comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTA MA.5) (abstract 38). Presented at the 29th Annual San Antonio Breast Cancer Symposium. Available at http://www.abstract2view .com/sabcs06/view.php?nu+SABCS06L_712. Accessed May 8, 2007. 10. Gunnarsdottir K, Jensen MB, Zahrieh D, et al: CEF is superior to CMF for tumors with topoisomerase II alpha gene alterations: A STEPP (subpopulation treatment effect pattern plot) analysis on Danish breast cancer cooperative group study 89D (abstract 1023). Presented at the 29th Annual San Antonio Breast Cancer Symposium. Available at http://www.abstract 2view.com/sabcs06/view.php?nu+SABCS06L_296. Accessed May 8, 2007.
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Breast Diseases: A Year Book Quarterly Vol 18 No 3 2007
These findings suggest that in routine care, more frequent use of assorted supportive care measures and reductions of dosages are needed. Specifically, the oncology community may be under-using various antiemetics, under-using or failing to reduce the doses of white blood cell growth factors, and/or under-using erythropoiesisstimulating agents. As chemotherapy is being given for smaller and smaller absolute benefits, determining ways to avoid these high-frequency, common toxicities warrants ongoing attention and discussion. B. E. Hillner, MD
Randomized, Placebo-Controlled Trial of Saforis for Prevention and Treatment of Oral Mucositis in Breast Cancer Patients Receiving Anthracycline-Based Chemotherapy Peterson DE, Jones JB, Petit RG Cancer 109:322-331, 2007 This study provides data demonstrating that a novel glutamine formulation decreases chemotherapy-induced oral mucositis. The benefit associated with this product, as opposed to that of previously studied glutamine products, appears to be related to the markedly improved local absorption of glutamine into oral mucosal cells. Although the mucositis reduction seen in this trial is far short of ideal, this formulated glutamine product does appear to be a real step in the right direction. Hopefully, future studies will test the potential efficacy of this product with other chemotherapy regimens. Potentially, this compound will lead to additional benefit over that seen with oral cryotherapy alone for patients receiving fluorouracilbased chemotherapy regimens. Additionally, future studies will hopefully test the utility of this product in alleviating radiationinduced mucositis. C. L. Loprinzi, MD
Epirubicin and Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Therapy for Early Breast Cancer Poole CJ, Earl HM, Hiller L, et al N Engl J Med 355:1851-1862, 2006 Poole and colleagues reported the results of 2 large randomized phase III European trials that were designed during the height of the investigation on the role of anthracyclines as adjuvant therapy for early-stage breast cancer. The National Epirubicin Adjuvant Trial (NEAT) enrolled patients in England, and the BR9601 trial enrolled patients in Scotland. Both studies were designed to compare 4 cycles of epirubicin plus 4 cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) to 6 (NEAT) or 8 (BR9601) cycles of CMF alone. The primary endpoints of both trials were overall and relapse-free survival. In NEAT, the standard regimen of CMF was administered, while a modified version of CMF (all drugs given intravenously every 3 weeks) was used in the BR9601 trial. Conducted between 1996 and 2001, these studies consistently showed an improvement in both relapse-free and overall survival at
2 and 5 years in the epirubicin plus CMF arm, with an absolute improvement in overall survival of 7% at 5 years. Treatment was an independent prognostic variable associated with improved relapsefree and overall survival, falling behind nodal status, tumor grade, and tumor size as the most important factors. The increase in adverse events associated with the addition of epirubicin to CMF did not compromise treatment delivery, and the addition of epirubicin was associated with only a short-term reduction in quality of life compared to CMF alone. This study adds to the body of literature confirming the importance of anthracyclines in the armamentarium of adjuvant therapy for early-stage breast cancer. Despite the slightly different regimens of the 2 studies, the results consistently showed an improvement in survival, which is attributed to the addition of epirubicin. However, the absolute superiority of anthracycline-based regimens over CMF has been inconsistent, with conflicting results among investigated regimens. The National Surgical Adjuvant Breast and Bowel Project B-15 trial showed that the use of every-3-week doxorubicin and cyclophosphamide was equivalent to CMF with respect to survival measure and resulted in better tolerance and delivery of therapy.1 The National Cancer Institute of Canada Clinical Trials Group Mammary.5 (MA.5) trial compared cyclophosphamide, epirubicin, and fluorouracil (CEF) to CMF in premenopausal women with node-positive disease and found an improvement in relapse-free and overall survival in the CEF arm despite a lower dose intensity due to toxicity.2 Cyclophosphamide, epirubicin, and fluorouracil remained superior in terms of relapse-free and overall survival after a median follow-up of 10 years, although further correlative studies demonstrated that this benefit was confined to women with HER2amplified breast cancers.3,4 The Oxford meta-analysis that involved 14,000 women enrolled in trials comparing anthracycline- versus CMF-based regimens showed a moderate but significant advantage for anthracycline-based therapy, with an absolute improvement in survival of 4% at 10 years. This benefit was equivalent across age groups, with older women achieving similar superior survival as younger women.5 As a result of these studies, anthracycline-based therapy has become the standard of care in early-stage breast cancer. The importance of amplification of HER2 and topoisomerase II-alpha (topo2-alpha) in determining anthracycline sensitivity is being evaluated in both NEAT and the BR9601 trial. This analysis stems from a growing body of evidence that HER2 amplification and topo2-alpha gene aberration may predispose patients with breast cancer to anthracycline sensitivity. In the MA.5 trial, correlative studies evaluating the impact of HER2 amplification on the likelihood of response to CEF versus CMF demonstrated that the increase in benefit of CEF was confined to patients whose tumors overexpressed HER2. In women who did not have overexpression of HER2, there was no significant difference between treatment with CMF and CEF.4 The association between HER2 overexpression and anthracycline sensitivity may be related to topo2-alpha, a nuclear DNA-binding enzyme encoded on chromosome 17 near the HER2/neu oncogene. The gene topo2-alpha is the target of anthracyclines and is coamplified with HER2 in 44% of breast cancers, whereas 42% of breast cancers have deletions of this gene.6,7 In many adjuvant studies evaluating the efficacy of anthracycline-
based regimens, expression of topo2-alpha correlated with sensitivity to the anthracyline-based regimen, with overexpression resulting in a greater benefit from anthracyclines than those with normal expression.6,8-10 Although many of these analyses are exploratory, the roles of topo2-alpha and HER2 as predictive markers for benefit from anthracycline-based therapy is intriguing. The role of HER2 overexpression and topo2-alpha expression will be explored in the NEAT and BR9601 studies and may provide the largest cohort of women in which this concept is evaluated. Poole and colleagues have contributed to the growing evidence of the efficacy of anthracycline-based therapy in early-stage breast cancer. These studies have shown that the addition of epirubicin results in a statistically significant improvement in relapse-free and overall survival, which is attributed to the addition of epirubicin. However, given the evidence supporting the role of taxanes in nodepositive patients and the length of therapy required for epirubicin plus CMF, alternative therapies remain more attractive options for patients with early-stage breast cancer. The planned analysis of HER2/neu and topo2-alpha remains an intriguing component of this study. C. S. Denlinger, MD L. J. Goldstein, MD
References 1. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with six months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483-1496, 1990. 2. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol 16:2651-2658, 1998. 3. Levine MN, Pritchard KI, Bramwell VH, et al: A randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: Update of National Cancer Institute of Canada Clinical Trials Group Trial MA.5. J Clin Oncol 23:5166-5170, 2005. 4. Pritchard KI, Shepherd LE, O’Malley FP, et al: HER2 and responsiveness of breast cancer to adjuvant therapy. N Engl J Med 354:2103-2111, 2006. 5. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 365:1687-1717, 2005.
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6. MacGrogen G, Rudolph P, de Mascarel I, et al: DNA topoisomerase II alpha expression and the response to primary chemotherapy in breast cancer. Br J Cancer 89:666-671, 2003. 7. Jarvinen TA, Tanner M, Rantanen V, et al: Amplification and deletion of topoisomerase II alpha associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer. Am J Pathol 156:839-847, 2000. 8. Di Leo A, Gancberg D, Larsimont D, et al: HER-2 amplification and topoisomerase II alpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res 8:1107-1116, 2002. 9. O’Malley FP, Chia S, Tu D, et al: Topoisomerase II alpha protein overexpression has predictive utility in a randomized trial
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Breast Diseases: A Year Book Quarterly Vol 18 No 3 2007
comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTA MA.5) (abstract 38). Presented at the 29th Annual San Antonio Breast Cancer Symposium. Available at http://www.abstract2view .com/sabcs06/view.php?nu+SABCS06L_712. Accessed May 8, 2007. 10. Gunnarsdottir K, Jensen MB, Zahrieh D, et al: CEF is superior to CMF for tumors with topoisomerase II alpha gene alterations: A STEPP (subpopulation treatment effect pattern plot) analysis on Danish breast cancer cooperative group study 89D (abstract 1023). Presented at the 29th Annual San Antonio Breast Cancer Symposium. Available at http://www.abstract 2view.com/sabcs06/view.php?nu+SABCS06L_296. Accessed May 8, 2007.