- Email: [email protected]
Systemic Treatment for Breast Cancer: Chemotherapy and Biotherapy Agents
Accepted Manuscript Systemic Treatment for Breast Cancer: Chemotherapy and Biotherapy Agents Laura Bourdeanu, PhD, RN, Ellen A. Liu, MSN, CNP PII:
S0749-2081(15)00019-4
DOI:
10.1016/j.soncn.2015.02.003
Reference:
YSONU 50683
To appear in:
Seminars in Oncology Nursing
Please cite this article as: Bourdeanu L, Liu EA, Systemic Treatment for Breast Cancer: Chemotherapy and Biotherapy Agents, Seminars in Oncology Nursing (2015), doi: 10.1016/j.soncn.2015.02.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Laura Bourdeanu, PhD, RN Online Faculty at Excelsior College Albany, NY
Aurora, CO
Nurse Practitioner
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Ellen A. Liu, MSN, CNP
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Online Faculty at American Sentinel University
City of Hope Medical Center
Corresponding Author: Laura Bourdeanu, PhD 2260 South Xanadu Way, Suite 310
[email protected]
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860-558-2403
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Aurora, CO 80014
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Duarte CA
1
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Abstract Objectives: To describe current systemic chemotherapy and biotherapy breast cancer treatments in order to better inform clinical nursing practice.
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Data sources: Cumulative Index to Nursing & Allied Health Literature (CINAHLl), Medline, Academic Research Periodicals, PubMed Clinical Queries, CANCERLIT, and EBM Reviews – Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews
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(CDSR).
Conclusion: Systemic therapeutic options for patients with breast cancer can be complex and
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varied. Furthermore, the guidelines for the treatment of breast cancer are frequently changing as new chemotherapies and biotherapies are being developed.
Implications for Nursing Practice: Nursing clinical practice has to remain current in order to accommodate new treatments and the side effect profiles. This knowledge is essential to
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providing evidence-based care for breast cancer patients receiving these treatments. Key Words: chemotherapy, biotherapy, adjuvant, metastatic, chemotherapy in elderly, brain
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metastasis
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Breast cancer treatment depends on multiple prognostic factors and often involves a combination of local interventions (e.g. surgery, radiation therapy) and systemic treatments (e.g. chemotherapy, hormone therapy and/or targeted therapy).1 Decision making for which types of
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systemic treatments are necessary include biologic features of the tumor, specifically the
estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status, and the extent of disease considering presence or absence of metastatic disease
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to axillary lymph nodes, and presence or absence of detectable distant metastatic disease.2 This article will provide an overview of common systemic treatments for breast cancer using
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chemotherapy and biotherapy in the neoadjuvant (before surgery) or adjuvant (after surgery) settings.
Neoadjuvant Therapy
Neoadjuvant therapy has become a well-established approach to the treatment of locally
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advanced or some early breast cancers. Originally neoadjuvant therapy was used in locally advanced inoperable disease in order to minimize the disease burden and achieve surgical resection.3 Neoadjuvant therapy was then studied in women with early-stage breast cancer in
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order to improve surgical outcomes .4 Neoadjuvant therapy was thought to improve the overall survival with earlier initiation of systemic therapy in patients at risk of distant recurrence.
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However, the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B18 trial revealed that when compared to adjuvant therapy, neoadjuvant chemotherapy did not improve disease-free or overall survival.5 Currently, neoadjuvant therapy is used to downstage tumors in order to improve surgical outcomes or facilitate breast-conserving surgery.5 It also allows the clinician to evaluate whether the therapy is locally effective or to discontinue ineffective treatment.5
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Neoadjuvant therapy is recommended for women with clinical stage IIA, B, and stage III disease, and in women who wish to undergo breast-conserving therapy but have large tumors in comparison to the size of their breast .4, 6 Chemotherapy and biotherapy regimens recommended
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in the neoadjuvant setting are similar to adjuvant therapy. Multiple regimens exist for women who are HER2 negative and positive with various chemotherapy options (Table 1). Following the completion of neoadjuvant therapy the patient will typically undergo surgery to remove the
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primary tumor and determine if further treatment is warranted.3 Once surgical and radiation
initiate anti-hormonal therapy.6 Nursing Considerations
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therapy (if indicated) interventions are completed, patients with ER or PR-positive disease will
Nurses must take an active role in performing pre-treatment assessments in neoadjuvant chemotherapy candidates . Patient education should focus on the need for neoadjuvant
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chemotherapy with emphasis on tumor characteristics, stage of disease, and personal risk factors. Advanced practice nurses should ensure the neoadjuvant chemotherapy recommendations and education are consistent, and precisely document the tumor size and its response to
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chemotherapy.
Adjuvant Therapy
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Adjuvant therapies generally consist of polychemotherapy, biotherapy and/or endocrine
therapy for all patients with early breast cancer regardless of their age at the time of diagnosis7. When recommending and designing individual adjuvant therapy, the oncology provider team should consider and balance the risk of disease recurrence, benefit and toxicity of the therapy, and existing or potential comorbidities. The lymph node status is one of the most important variables in consideration for all treatments.1, 8 If axillary lymph nodes are positive for disease,
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the patient is a candidate for chemotherapy. In patients with negative lymph node involvement, further consideration of the tumor histology and anatomic and pathologic characteristics will guide treatment. Unfavorable prognostic features include estrogen negative tumors,
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intramammary lymph node involvement, angiolymphatic invasion, high nuclear grade, high histologic grade, or positive HER2 status.8 The patient’s age, existing comorbidities, tumor size, tumor grade, number of involved axillary lymph nodes, and HER2 tumor status are the most
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predictive factors for future recurrence or death from breast cancer.2
The following lists several pathologic examples for consideration of chemotherapy: 1)
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negative lymph nodes, negative hormone receptors, and tumor greater than 1cm should consider adjuvant chemotherapy;1, 9 2) Negative lymph nodes, positive hormone receptors, tumor 0.6 to 1.0 cm with high nuclear grade or other unfavorable features should receive adjuvant chemotherapy followed by endocrine therapy;9, 10 3) Node negative tumors greater than 0.5cm
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with positive receptor status may benefit from Oncotype DX or MammaPrint, programs that can assist the provider to determine whether chemotherapy will reduce the risk of systemic recurrence or if only hormonal therapy is necessary; 3, 9-10 4) HER2-positive women should
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receive trastuzumab with chemotherapy for all tumors greater than 1cm regardless of nodal status;9 and 5) HER2-positive women with node negative tumors measuring 0.6 to 1.0 cm, or for
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smaller tumors that have 2mm or less axillary node metastases, chemotherapy and biotherapy should be administered.9 Algorithms
Algorithms and computer-based models such as Adjuvant Online have been designed to
take into account all prognostic factors (with the exception of HER2 status) and estimate the 10year disease free and overall survival of a breast cancer patient.11-16 These programs also provide
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the potential benefit of chemotherapy, endocrine therapy alone, and combination of both therapies. The risk of relapse can also be estimated utilizing DNA microarray gene expression profiling technology.12, 16 This technology assists in identifying five subtypes of breast cancer:
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ER+/HER2- (luminal A and B subtypes), ER-/HER2- (basal subtype), HER2+, and tumor with characteristics similar to normal breast tissue.12-16 Anthracycline-containing regimens provide a common adjuvant chemotherapy approach and are preferred in node-positive patients.2, 15 The
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preferred chemotherapy regimens for both HER2 negative or HER2 positive women are outlined
N1 or greater early stage breast cancer.1 Elderly Population
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in Table 1.2-16 The addition of pertuzumab is to be considered for patients with T2 or greater, or
Historically, the management of patients over 65 years of age has been challenging due to a lack of evidence regarding the role of systemic therapy. However, in recent years studies have
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found that older women can benefit as much from systemic therapy as younger women, although they have an increased risk of toxicities. Decisions regarding systemic therapy in the elderly are made based on tumor biology and biological age, rather than chronological age, as well as the
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conditions associated with advanced age.2 In deciding treatment for elderly patients with breast cancer, most importantly life expectancy must be considered in the treatment decision. For
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patients with limited life expectancy, systemic chemotherapy may not be of any benefit irrespective of tumor type and stage of disease.17 The National Comprehensive Cancer Network (NCCN) guidelines18 indicate that prior to
considering systemic treatment for an elderly patient the healthcare provider must determine the following: 1) comparison of moderate or high risk of dying versus risk of suffering from cancer symptoms with consideration of overall life expectancy, 2) decision making capacity and their
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goals are consistent with wanting anti-cancer therapy,or 3) there is minimal risk for adverse outcomes of cancer therapy.18 Elderly patients should be considered for chemotherapy or biotherapy much like the younger patients in the neoadjuvant, adjuvant or metastatic setting.18
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However, since the elderly are more likely to experience severe treatment toxicities, their risk for toxicities should be assessed using tools such as Comprehensive Geriatric Assessment Tool,
Group Chemo Toxicity Calculator.18, 19, 20,21 Nursing Considerations
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Chemotherapy Risk Assessment Scale for High-Aged Patients score, Cancer and Aging Research
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Nurses play a crucial role in ensuring that patients receive their adjuvant chemotherapy at full dose and on schedule to achieve the best possible outcome from their treatment. Nurses should educate patients before the administration of the therapy on the dose, frequency, and potential side effects of each chemotherapy and biotherapy drug. Patients should be aware of the
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treatment regimen they are receiving, laboratory monitoring, and the necessity of keeping their clinic visits. When the treatment includes oral medications, nurses must ensure patient understanding of the oral agent and self-care measures. Patients should be educated on the
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correct dose and administration schedule of the drug, the toxicity profile of the oral agent, and early recognition and reporting of the side effects, as well as the importance of not missing a
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dose or doubling a doses to make up for a missed dose. Metastatic Breast Cancer
Metastatic breast cancer is unlikely to be cured; however substantial advances have
enabled meaningful improvements in survival and quality of life. Treatment selection for metastatic breast cancer is based on multiple factors, including hormone receptor or HER2 overexpression, treatment history, comorbidities, performance status, and patient preferences.19
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Although some patients may benefit from loco-regional therapy, most patients receive systemic therapy consisting or chemotherapy, hormone therapy, and/or biologic therapies in combination with supportive care when appropriate.22,23
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In women with hormone-negative metastatic disease, chemotherapy is indicated as initial therapy. Similarly women with hormone-negative disease and patients with hormone-positive disease who failed hormonal therapies may benefit from treatment.24 In the metastatic setting
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sequential single-agent therapy or combination therapy are viable strategies.25 The preferred single agents recommended by NCCN include anthracyclines (doxorubicin), taxanes,
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antimetabolites, and other microtubules inhibitors.25 Healthcare providers may also use alkylating agents, anthracyclines (epirubicin), and microtubule inhibitors.25 The treatments can also be administered in combinations of chemotherapy and biotherapy.25 For HER2 positive disease the preferred first-line agents include
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trastuzumab/pertuzumab with a chemotherapeutic agent, however, trastuzumab as a single agent may also be used.25 For patients previously exposed to trastuzumab, ado-trastuzumab emtansine (T-TM1) is recommended, although other regimens are acceptable such as
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lapatinib/capecitabine, trastuzumab/capecitabine, trastuzumab/lapatinib, and trastuzumab/other agents.25 There are no clear guidelines indicating which agent or combination should be used
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first; this is generally decided by the healthcare provider. It is important to mention that patients who received doxorubicin in the adjuvant setting will not be a candidate for doxorubicin in the metastatic setting due to the cumulative dose ceiling. Concurrent use of anthracyclines, trastuzumab, and pertuzumab is not recommended as it may increase the risk of cardiac toxicity.24 Cardiac function is assessed with two-dimensional cardiac echocardiograms and
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consultation with cardiology. Patients who have metastases that involve the bones also receive bisphosphonates to reduce the risk of fractures.1, 26 Nursing Considerations
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The numerous available systemic therapies, routes, schedules, and side effect profiles can be confusing and overwhelming to patients. Nurses must communicate the treatment regimens and side effect profiles with the patients in order to facilitate adherence to treatment, as well as
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promote self-care measures. Helping patients understand the rationale behind the treatment recommendations may reduce distress during treatment and promote compliance. Advance
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practice nurses play a pivotal role in assessing the disease response to treatment, cardiac status, bone loss, and treatment side effects. Patients should be provided education about proper management of treatment side effects, and changes in dosing in the presence of abnormal liver and/or renal function.
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Central Nervous System Metastases
The incidence of brain metastases in breast cancer patients has increased over the last several years, presumably due to better advances in systemic treatment with the addition of
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targeted agents and better diagnostic screening tools.27 Up to 30% of patients with metastatic disease will develop central nervous system metastasis (CNS) as brain metastases or
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leptomeningeal carcinomatosis.28 With supportive care alone patients die within 3 to 6 months, but with treatment they can live up to 24 months.29 Treatment options for brain metastases include whole brain radiotherapy, surgery, gamma knife radiosurgery, linac-based radiosurgery, and stereotactic radiotherapy.29 Chemotherapy has traditionally played a limited role in the treatment of brain metastases secondary to breast cancer due to the fact that most agents cannot cross the blood-brain barrier.
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Currently there are no FDA-approved chemotherapies or biotherapies for the treatment of brain metastasis from breast cancer, However there is emerging evidence of potential regimens. Capecitebine in combination with lapatinib has been shown to have activity in brain metastases
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from breast cancer.30 Bevacizumab, a monoclonal antibody was found to be effective for
progressive brain metastases when combined with paclitaxel.31 For patients with HER2 positive disease, there has been improved survival in patients who received trastuzumab or lapatinib.32,33
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Patients treated with sequential combination of trastuzumab and lapatinib/capecitabine
experience significantly longer survival when compared to patients treated with trastuzumab
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based treatments alone.34 Although well-designed prospective clinical trials are urgently needed, current data suggests that lapatinib and trastuzumab could be potentially active drugs for managing brain metastases in HER2-positive breast cancer. Traditional regimens such as cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), anthracycline-based regimens have
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reported efficacy in case series.35, 36
Leptomeningeal disease occurs in 3%-5% of patients with metastatic breast cancer, and although there is no standard of care for leptomeningeal disease, radiation therapy and
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chemotherapy may be considered. Depending on the functional status of the patient, the healthcare provider may consider IV chemotherapy with high-dose methotrexate, intrathecal
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chemotherapy with liposomal cytarabine, methotrexate or thiotepa.35 Intrathecal trastuzumab is currently being investigated in prospective trials as a result of several case reports of patients showing the effectiveness of intrathecal trastuzumab in stabilizing the disease.36, 37 Nursing Considerations
Patient education in this setting is important as most patients experience fear and anxiety about prognosis and quality of life related to brain metastases. Nurses have the opportunity to
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educate patients about the incidence, presentation, related symptoms, treatment strategies, and prognosis. The advanced practice nurse should assess and manage the side effects of treatment, as well as monitor treatment effectiveness. Complete neurologic assessment with each visit, as
intracranial pressure in these patients. Future Directions
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well as period imaging studies as clinically indicated are important due to the risk of increased
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Enhanced understanding and identification of molecular subtypes of breast cancer, and the driving genetic alterations and signaling pathways have led to the clinical development of
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several novel targeted agents. Agents such as tyrosine kinase inhibitors, inhibitors of intracellular signaling pathways, angiogenesis inhibitors, poly (ADP-ribose) polymerase inhibitors for BRCSdeficient tumors, rapamycin analogs, and agents that interfere with DNA repair have shown remarkable clinical activity.6, 19-25, 27-36 Several of these agents are already a part of standard of
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care for patients with breast cancer, and others are being further investigated due to indications of clinical response in early clinical trials. As a result of these targeted therapies health care providers will have the ability to match each patient with the right therapy.
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Conclusion
Chemotherapy and biotherapy are pivotal components in the treatment of patients with
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breast cancer, with patients receiving multiple types of chemotherapy and biotherapy throughout the course of their disease. The guidelines for the treatment of breast cancer are frequently changing as new chemotherapies and biotherapies are being developed. Nursing clinical practice must accommodate the new treatments and the side effect profiles to best care for patients. References 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64: 929. 11
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2. Gradishar WJ, Anderson BO, Blair SL, et al. Breast cancer version 3.2014. J Natl Compr Canc Netw. 2014;12:542-90. 3. Govender P. An approach to the management of locally advanced breast cancer: part 1. S Afr Med J. 2014;104:384. 4. Thompson AM, Moulder-Thompson SL. Neoadjuvant treatment of breast cancer. Ann Oncol, 2012;23 Suppl 10: x231-6. 5. Gampenrieder SP, Rinnerthaler G, Greil R. Neoadjuvant chemotherapy and targeted therapy in breast cancer: past, present, and future. J Oncol. 2013; 2013:732047. 6. National Comprehensive Cancer Network. Guidelines for patients v. 2014. Accessed September 9, 2014: http://www.nccn.org/patients/guidelines/stage_iii_breast/index.html#26 7. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Peto R, Davies C, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432-44. 8. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687-717. 9. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 2003;100:8418-23. 10. Paik S, Tang G, Shak S, et a. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:372634. 11. Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol. 2005;23:2716-25. 12. Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol. 2001; 19:980-91. 13. Jeffrey SS, Lonning PE, Hillner BE. Genomics-based prognosis and therapeutic prediction in breast cancer. J Natl Compr Canc Netw. 2005;3:291-300. 14. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869-74. 15. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Canc Res Treat. 2010;120:655-61. 16. Kunz, G., Use of a genomic test (MammaPrint) in daily clinical practice to assist in risk stratification of young breast cancer patients. Arch Gynecol Obstet, 2011. 283(3): p. 597602. 17. Barginear MF, Muss H, Kimmick G, et al. Breast cancer and aging: results of the U13 conference breast cancer panel. Breast Canr Res Treat. 2014; Jul;146(1):1-6. 18. National Comprehensive Cancer Network. Senior Adult Oncology, v. 2014. Accessed September 6, 2014:http://www.nccn.org/professionals/physician_gls/PDF/senior.pdf 19. Hurria, A, Gupta,S, Zauderer, M, et al. Developing a cancer-specific geriatric assessment: A feasibility study. Cancer. 2005; 104: 1998-2005. 12
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20. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer. 2012 Jul 1;118(13):3377-86. doi: 10.1002/cncr.26646. Epub 2011 Nov 9. 21. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study [published online August 1, 2011]. J Clin Oncol. 2011;29(25):3457–3465 22. Pagani O, Senkus E, Wood W, et al. International guidelines for management of metastatic breast cancer: can metastatic breast cancer be cured? J Natl Cancer Inst. 2010; 102:456-63. 23. Harbeck N, Marschner N, Untch M, et al. Second International Consensus Conference on Advanced Breast Cancer (ABC2), Lisbon, 11/09/2013: the German Perspective. Breast Care. 2014;9(1):52-9. 24. Wilcken N, Dear R. Chemotherapy in metastatic breast cancer: a summary of all randomised trials reported 2000-2007. Eur J Cancer. 2008;44:2218-25. 25. Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Breast. 2014;23:489-502. 26. Mathew A, Brufsky A. Bisphosphonates in breast cancer. Int J Cancer. 2014;2014:00-00. [Epub ahead of print]. 27. Gil-Gil MJ, Martinez-Garcia M, Sierra A, et al. Breast cancer brain metastases: a review of the literature and a current multidisciplinary management guideline. Clin Transl Oncol. 2014;16:436-46. 28. Lin NU, Amiri-Kordestani L, Palmieri D, Liewehr DJ, Steeg PS. CNS metastases in breast cancer: old challenge, new frontiers. Clin Cancer Res. 2013;19:6404-18. 29. Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14:64-71. 30. Sim HW, Morris PG, Patil S, Khasraw M. Brain metastases in breast cancer. Expert Rev Anticancer Ther. 2014;14(2):173-83. 31. Bartsch R, Berghoff A, Pluschnig U, et al. Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases. Br J Cancer. 2012;106:25-31. 32. Bachelot, T., Romieu G, Campone M, et al., Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14(1):64-71. 33. Metro G, Foglietta J, Russillo M, et al. Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine. Ann Oncol. 2011;22:625-30. 34. Lassman AB, Abrey LE, Shah GD, et al. Systemic high-dose intravenous methotrexate for central nervous system metastases. J Neurooncol. 2006;78(3):255-60. 35. Scott BJ, Kesari S. Leptomeningeal metastases in breast cancer. Am J Cancer Res. 2013; 3(2): 117–126. 36. Zagouri F, Sergentanis TN, Bartsch R, et al. Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis. Breast Cancer Res Treat. 2013;139(1):13-22. 13
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Table 1. Treatment options for adjuvant and neoadjuvant chemotherapy 2-16 Treatment Options
Her2Neu Positive
AC (Four 21-day cycles) then
Doxorubicin/cyclophosphamide
paclitaxel (Twelve 7-day
(four 14-day cycles) then
cycles) with trastuzumab
paclitaxel (four 14-day cycles)
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(Weekly during paclitaxel then
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First-Line
Her2Neu Negative
year)
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every 7 or 21 daysto complete 1
AC (Four 21-day cycles) then
Doxorubicin/cyclophosphamide
paclitaxel (Four 21-day cycles)
(four 14-day cycles) then
with pertuzumab (Weekly
paclitaxel (twelve 7-day cycles)
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during paclitaxel) and
trastuzumab (Weekly during paclitaxel then every 21 days to
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complete 1 year)
Doxorubicin/cyclophosphamide
Docetaxel/ cyclophosphamide
(four 14-day cycles) then
(four 21-day cycles)
paclitaxel (four 14-day cycles) with trastuzumab (Weekly during paclitaxel then every 21 days to complete 1 year) TCH (Six 21-day cycles) with
Doxorubicin/cyclophosphamide
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weekly trastuzumab, then
(four 14-day cycles)
trastuzumab every 21 days to complete 1 year FAC (Six 21-day cycles) or
docetaxel (Four 21-day cycles)
CAF (Six 28-day cycles)
during docetaxel cycles then
year)
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every 21 days to complete 1
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with trastuzumab (Weekly
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AC (Four 21-day cycles) then
AC (Four 21-day cycles) then
CEF (six 28-day cycles) or
docetaxel (Four 21-day cycles)
FEC (Six 28-day cycles)
with pertuzumab (On day 1
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during docetaxel cycles) and
trastuzumab (On day 1 during docetaxel cycles then every 21
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days to complete 1 year)
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FEC (Three 21-day cycles) then CMF (Six 28-day cycles) docetaxel (Three 21-day cycles) with pertuzumab (On day 1 during docetaxel cycles) and trastuzumab (On day 1 during docetaxel cycles then every 21 days to complete 1 year)
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FEC (Three 21-day cycles) then
AC (Four 21-day cycles) then docetaxel (Four 21-day cycles)
paclitaxel (three 21-day cycles)
during docetaxel cycles) and trastuzumab (On day 1 during
days to complete 1 year)
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docetaxel cycles then every 21
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with pertuzumab (on day 1
AC (Four 21-day cycles) then
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docetaxel (twelve 7-day cycles)
EC (Eight 21-day cycles) FAC (Six 21-day cycles) then paclitaxel (twelve 7-day cycles)
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FEC or CEF (Four 21-day cycles) then paclitaxel (Eight 7day cycles) FEC or CEF (Three 21-day cycles) then docetaxel (Three 21-day cycles) TAC (Six 21-day cycles)
Abbreviations AC- doxorubicin+cyclophosphamide TC- docetaxel+cyclophosphamide CAF-cyclophosphamide+doxorubicin+fluorouracil CEF -cyclophosphamide+epirubicin+fluorouracil CMF-cyclophosphamide+methotrexate+fluorouracil EC-epirubicin+cyclophosphmide 16
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AC C
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SC
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FAC-fluorouracil+doxorubicin+cyclophosphamide FEC-fluorouracil_epirubicin+cyclophosphamide TAC-docetaxel+doxorubicin+cyclophosphamide TCH- docetaxel+carboplatin+trasutuzumab
17
S0749-2081(15)00019-4
DOI:
10.1016/j.soncn.2015.02.003
Reference:
YSONU 50683
To appear in:
Seminars in Oncology Nursing
Please cite this article as: Bourdeanu L, Liu EA, Systemic Treatment for Breast Cancer: Chemotherapy and Biotherapy Agents, Seminars in Oncology Nursing (2015), doi: 10.1016/j.soncn.2015.02.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Laura Bourdeanu, PhD, RN Online Faculty at Excelsior College Albany, NY
Aurora, CO
Nurse Practitioner
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Ellen A. Liu, MSN, CNP
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Online Faculty at American Sentinel University
City of Hope Medical Center
Corresponding Author: Laura Bourdeanu, PhD 2260 South Xanadu Way, Suite 310
[email protected]
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860-558-2403
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Aurora, CO 80014
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Duarte CA
1
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Abstract Objectives: To describe current systemic chemotherapy and biotherapy breast cancer treatments in order to better inform clinical nursing practice.
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Data sources: Cumulative Index to Nursing & Allied Health Literature (CINAHLl), Medline, Academic Research Periodicals, PubMed Clinical Queries, CANCERLIT, and EBM Reviews – Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews
SC
(CDSR).
Conclusion: Systemic therapeutic options for patients with breast cancer can be complex and
M AN U
varied. Furthermore, the guidelines for the treatment of breast cancer are frequently changing as new chemotherapies and biotherapies are being developed.
Implications for Nursing Practice: Nursing clinical practice has to remain current in order to accommodate new treatments and the side effect profiles. This knowledge is essential to
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providing evidence-based care for breast cancer patients receiving these treatments. Key Words: chemotherapy, biotherapy, adjuvant, metastatic, chemotherapy in elderly, brain
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EP
metastasis
2
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Breast cancer treatment depends on multiple prognostic factors and often involves a combination of local interventions (e.g. surgery, radiation therapy) and systemic treatments (e.g. chemotherapy, hormone therapy and/or targeted therapy).1 Decision making for which types of
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systemic treatments are necessary include biologic features of the tumor, specifically the
estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status, and the extent of disease considering presence or absence of metastatic disease
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to axillary lymph nodes, and presence or absence of detectable distant metastatic disease.2 This article will provide an overview of common systemic treatments for breast cancer using
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chemotherapy and biotherapy in the neoadjuvant (before surgery) or adjuvant (after surgery) settings.
Neoadjuvant Therapy
Neoadjuvant therapy has become a well-established approach to the treatment of locally
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advanced or some early breast cancers. Originally neoadjuvant therapy was used in locally advanced inoperable disease in order to minimize the disease burden and achieve surgical resection.3 Neoadjuvant therapy was then studied in women with early-stage breast cancer in
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order to improve surgical outcomes .4 Neoadjuvant therapy was thought to improve the overall survival with earlier initiation of systemic therapy in patients at risk of distant recurrence.
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However, the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B18 trial revealed that when compared to adjuvant therapy, neoadjuvant chemotherapy did not improve disease-free or overall survival.5 Currently, neoadjuvant therapy is used to downstage tumors in order to improve surgical outcomes or facilitate breast-conserving surgery.5 It also allows the clinician to evaluate whether the therapy is locally effective or to discontinue ineffective treatment.5
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Neoadjuvant therapy is recommended for women with clinical stage IIA, B, and stage III disease, and in women who wish to undergo breast-conserving therapy but have large tumors in comparison to the size of their breast .4, 6 Chemotherapy and biotherapy regimens recommended
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in the neoadjuvant setting are similar to adjuvant therapy. Multiple regimens exist for women who are HER2 negative and positive with various chemotherapy options (Table 1). Following the completion of neoadjuvant therapy the patient will typically undergo surgery to remove the
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primary tumor and determine if further treatment is warranted.3 Once surgical and radiation
initiate anti-hormonal therapy.6 Nursing Considerations
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therapy (if indicated) interventions are completed, patients with ER or PR-positive disease will
Nurses must take an active role in performing pre-treatment assessments in neoadjuvant chemotherapy candidates . Patient education should focus on the need for neoadjuvant
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chemotherapy with emphasis on tumor characteristics, stage of disease, and personal risk factors. Advanced practice nurses should ensure the neoadjuvant chemotherapy recommendations and education are consistent, and precisely document the tumor size and its response to
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chemotherapy.
Adjuvant Therapy
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Adjuvant therapies generally consist of polychemotherapy, biotherapy and/or endocrine
therapy for all patients with early breast cancer regardless of their age at the time of diagnosis7. When recommending and designing individual adjuvant therapy, the oncology provider team should consider and balance the risk of disease recurrence, benefit and toxicity of the therapy, and existing or potential comorbidities. The lymph node status is one of the most important variables in consideration for all treatments.1, 8 If axillary lymph nodes are positive for disease,
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the patient is a candidate for chemotherapy. In patients with negative lymph node involvement, further consideration of the tumor histology and anatomic and pathologic characteristics will guide treatment. Unfavorable prognostic features include estrogen negative tumors,
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intramammary lymph node involvement, angiolymphatic invasion, high nuclear grade, high histologic grade, or positive HER2 status.8 The patient’s age, existing comorbidities, tumor size, tumor grade, number of involved axillary lymph nodes, and HER2 tumor status are the most
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predictive factors for future recurrence or death from breast cancer.2
The following lists several pathologic examples for consideration of chemotherapy: 1)
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negative lymph nodes, negative hormone receptors, and tumor greater than 1cm should consider adjuvant chemotherapy;1, 9 2) Negative lymph nodes, positive hormone receptors, tumor 0.6 to 1.0 cm with high nuclear grade or other unfavorable features should receive adjuvant chemotherapy followed by endocrine therapy;9, 10 3) Node negative tumors greater than 0.5cm
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with positive receptor status may benefit from Oncotype DX or MammaPrint, programs that can assist the provider to determine whether chemotherapy will reduce the risk of systemic recurrence or if only hormonal therapy is necessary; 3, 9-10 4) HER2-positive women should
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receive trastuzumab with chemotherapy for all tumors greater than 1cm regardless of nodal status;9 and 5) HER2-positive women with node negative tumors measuring 0.6 to 1.0 cm, or for
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smaller tumors that have 2mm or less axillary node metastases, chemotherapy and biotherapy should be administered.9 Algorithms
Algorithms and computer-based models such as Adjuvant Online have been designed to
take into account all prognostic factors (with the exception of HER2 status) and estimate the 10year disease free and overall survival of a breast cancer patient.11-16 These programs also provide
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the potential benefit of chemotherapy, endocrine therapy alone, and combination of both therapies. The risk of relapse can also be estimated utilizing DNA microarray gene expression profiling technology.12, 16 This technology assists in identifying five subtypes of breast cancer:
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ER+/HER2- (luminal A and B subtypes), ER-/HER2- (basal subtype), HER2+, and tumor with characteristics similar to normal breast tissue.12-16 Anthracycline-containing regimens provide a common adjuvant chemotherapy approach and are preferred in node-positive patients.2, 15 The
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preferred chemotherapy regimens for both HER2 negative or HER2 positive women are outlined
N1 or greater early stage breast cancer.1 Elderly Population
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in Table 1.2-16 The addition of pertuzumab is to be considered for patients with T2 or greater, or
Historically, the management of patients over 65 years of age has been challenging due to a lack of evidence regarding the role of systemic therapy. However, in recent years studies have
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found that older women can benefit as much from systemic therapy as younger women, although they have an increased risk of toxicities. Decisions regarding systemic therapy in the elderly are made based on tumor biology and biological age, rather than chronological age, as well as the
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conditions associated with advanced age.2 In deciding treatment for elderly patients with breast cancer, most importantly life expectancy must be considered in the treatment decision. For
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patients with limited life expectancy, systemic chemotherapy may not be of any benefit irrespective of tumor type and stage of disease.17 The National Comprehensive Cancer Network (NCCN) guidelines18 indicate that prior to
considering systemic treatment for an elderly patient the healthcare provider must determine the following: 1) comparison of moderate or high risk of dying versus risk of suffering from cancer symptoms with consideration of overall life expectancy, 2) decision making capacity and their
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goals are consistent with wanting anti-cancer therapy,or 3) there is minimal risk for adverse outcomes of cancer therapy.18 Elderly patients should be considered for chemotherapy or biotherapy much like the younger patients in the neoadjuvant, adjuvant or metastatic setting.18
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However, since the elderly are more likely to experience severe treatment toxicities, their risk for toxicities should be assessed using tools such as Comprehensive Geriatric Assessment Tool,
Group Chemo Toxicity Calculator.18, 19, 20,21 Nursing Considerations
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Chemotherapy Risk Assessment Scale for High-Aged Patients score, Cancer and Aging Research
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Nurses play a crucial role in ensuring that patients receive their adjuvant chemotherapy at full dose and on schedule to achieve the best possible outcome from their treatment. Nurses should educate patients before the administration of the therapy on the dose, frequency, and potential side effects of each chemotherapy and biotherapy drug. Patients should be aware of the
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treatment regimen they are receiving, laboratory monitoring, and the necessity of keeping their clinic visits. When the treatment includes oral medications, nurses must ensure patient understanding of the oral agent and self-care measures. Patients should be educated on the
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correct dose and administration schedule of the drug, the toxicity profile of the oral agent, and early recognition and reporting of the side effects, as well as the importance of not missing a
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dose or doubling a doses to make up for a missed dose. Metastatic Breast Cancer
Metastatic breast cancer is unlikely to be cured; however substantial advances have
enabled meaningful improvements in survival and quality of life. Treatment selection for metastatic breast cancer is based on multiple factors, including hormone receptor or HER2 overexpression, treatment history, comorbidities, performance status, and patient preferences.19
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Although some patients may benefit from loco-regional therapy, most patients receive systemic therapy consisting or chemotherapy, hormone therapy, and/or biologic therapies in combination with supportive care when appropriate.22,23
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In women with hormone-negative metastatic disease, chemotherapy is indicated as initial therapy. Similarly women with hormone-negative disease and patients with hormone-positive disease who failed hormonal therapies may benefit from treatment.24 In the metastatic setting
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sequential single-agent therapy or combination therapy are viable strategies.25 The preferred single agents recommended by NCCN include anthracyclines (doxorubicin), taxanes,
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antimetabolites, and other microtubules inhibitors.25 Healthcare providers may also use alkylating agents, anthracyclines (epirubicin), and microtubule inhibitors.25 The treatments can also be administered in combinations of chemotherapy and biotherapy.25 For HER2 positive disease the preferred first-line agents include
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trastuzumab/pertuzumab with a chemotherapeutic agent, however, trastuzumab as a single agent may also be used.25 For patients previously exposed to trastuzumab, ado-trastuzumab emtansine (T-TM1) is recommended, although other regimens are acceptable such as
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lapatinib/capecitabine, trastuzumab/capecitabine, trastuzumab/lapatinib, and trastuzumab/other agents.25 There are no clear guidelines indicating which agent or combination should be used
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first; this is generally decided by the healthcare provider. It is important to mention that patients who received doxorubicin in the adjuvant setting will not be a candidate for doxorubicin in the metastatic setting due to the cumulative dose ceiling. Concurrent use of anthracyclines, trastuzumab, and pertuzumab is not recommended as it may increase the risk of cardiac toxicity.24 Cardiac function is assessed with two-dimensional cardiac echocardiograms and
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consultation with cardiology. Patients who have metastases that involve the bones also receive bisphosphonates to reduce the risk of fractures.1, 26 Nursing Considerations
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The numerous available systemic therapies, routes, schedules, and side effect profiles can be confusing and overwhelming to patients. Nurses must communicate the treatment regimens and side effect profiles with the patients in order to facilitate adherence to treatment, as well as
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promote self-care measures. Helping patients understand the rationale behind the treatment recommendations may reduce distress during treatment and promote compliance. Advance
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practice nurses play a pivotal role in assessing the disease response to treatment, cardiac status, bone loss, and treatment side effects. Patients should be provided education about proper management of treatment side effects, and changes in dosing in the presence of abnormal liver and/or renal function.
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Central Nervous System Metastases
The incidence of brain metastases in breast cancer patients has increased over the last several years, presumably due to better advances in systemic treatment with the addition of
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targeted agents and better diagnostic screening tools.27 Up to 30% of patients with metastatic disease will develop central nervous system metastasis (CNS) as brain metastases or
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leptomeningeal carcinomatosis.28 With supportive care alone patients die within 3 to 6 months, but with treatment they can live up to 24 months.29 Treatment options for brain metastases include whole brain radiotherapy, surgery, gamma knife radiosurgery, linac-based radiosurgery, and stereotactic radiotherapy.29 Chemotherapy has traditionally played a limited role in the treatment of brain metastases secondary to breast cancer due to the fact that most agents cannot cross the blood-brain barrier.
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Currently there are no FDA-approved chemotherapies or biotherapies for the treatment of brain metastasis from breast cancer, However there is emerging evidence of potential regimens. Capecitebine in combination with lapatinib has been shown to have activity in brain metastases
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from breast cancer.30 Bevacizumab, a monoclonal antibody was found to be effective for
progressive brain metastases when combined with paclitaxel.31 For patients with HER2 positive disease, there has been improved survival in patients who received trastuzumab or lapatinib.32,33
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Patients treated with sequential combination of trastuzumab and lapatinib/capecitabine
experience significantly longer survival when compared to patients treated with trastuzumab
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based treatments alone.34 Although well-designed prospective clinical trials are urgently needed, current data suggests that lapatinib and trastuzumab could be potentially active drugs for managing brain metastases in HER2-positive breast cancer. Traditional regimens such as cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), anthracycline-based regimens have
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reported efficacy in case series.35, 36
Leptomeningeal disease occurs in 3%-5% of patients with metastatic breast cancer, and although there is no standard of care for leptomeningeal disease, radiation therapy and
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chemotherapy may be considered. Depending on the functional status of the patient, the healthcare provider may consider IV chemotherapy with high-dose methotrexate, intrathecal
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chemotherapy with liposomal cytarabine, methotrexate or thiotepa.35 Intrathecal trastuzumab is currently being investigated in prospective trials as a result of several case reports of patients showing the effectiveness of intrathecal trastuzumab in stabilizing the disease.36, 37 Nursing Considerations
Patient education in this setting is important as most patients experience fear and anxiety about prognosis and quality of life related to brain metastases. Nurses have the opportunity to
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educate patients about the incidence, presentation, related symptoms, treatment strategies, and prognosis. The advanced practice nurse should assess and manage the side effects of treatment, as well as monitor treatment effectiveness. Complete neurologic assessment with each visit, as
intracranial pressure in these patients. Future Directions
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well as period imaging studies as clinically indicated are important due to the risk of increased
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Enhanced understanding and identification of molecular subtypes of breast cancer, and the driving genetic alterations and signaling pathways have led to the clinical development of
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several novel targeted agents. Agents such as tyrosine kinase inhibitors, inhibitors of intracellular signaling pathways, angiogenesis inhibitors, poly (ADP-ribose) polymerase inhibitors for BRCSdeficient tumors, rapamycin analogs, and agents that interfere with DNA repair have shown remarkable clinical activity.6, 19-25, 27-36 Several of these agents are already a part of standard of
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care for patients with breast cancer, and others are being further investigated due to indications of clinical response in early clinical trials. As a result of these targeted therapies health care providers will have the ability to match each patient with the right therapy.
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Conclusion
Chemotherapy and biotherapy are pivotal components in the treatment of patients with
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breast cancer, with patients receiving multiple types of chemotherapy and biotherapy throughout the course of their disease. The guidelines for the treatment of breast cancer are frequently changing as new chemotherapies and biotherapies are being developed. Nursing clinical practice must accommodate the new treatments and the side effect profiles to best care for patients. References 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64: 929. 11
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2. Gradishar WJ, Anderson BO, Blair SL, et al. Breast cancer version 3.2014. J Natl Compr Canc Netw. 2014;12:542-90. 3. Govender P. An approach to the management of locally advanced breast cancer: part 1. S Afr Med J. 2014;104:384. 4. Thompson AM, Moulder-Thompson SL. Neoadjuvant treatment of breast cancer. Ann Oncol, 2012;23 Suppl 10: x231-6. 5. Gampenrieder SP, Rinnerthaler G, Greil R. Neoadjuvant chemotherapy and targeted therapy in breast cancer: past, present, and future. J Oncol. 2013; 2013:732047. 6. National Comprehensive Cancer Network. Guidelines for patients v. 2014. Accessed September 9, 2014: http://www.nccn.org/patients/guidelines/stage_iii_breast/index.html#26 7. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Peto R, Davies C, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:432-44. 8. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687-717. 9. Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 2003;100:8418-23. 10. Paik S, Tang G, Shak S, et a. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:372634. 11. Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol. 2005;23:2716-25. 12. Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol. 2001; 19:980-91. 13. Jeffrey SS, Lonning PE, Hillner BE. Genomics-based prognosis and therapeutic prediction in breast cancer. J Natl Compr Canc Netw. 2005;3:291-300. 14. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869-74. 15. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Canc Res Treat. 2010;120:655-61. 16. Kunz, G., Use of a genomic test (MammaPrint) in daily clinical practice to assist in risk stratification of young breast cancer patients. Arch Gynecol Obstet, 2011. 283(3): p. 597602. 17. Barginear MF, Muss H, Kimmick G, et al. Breast cancer and aging: results of the U13 conference breast cancer panel. Breast Canr Res Treat. 2014; Jul;146(1):1-6. 18. National Comprehensive Cancer Network. Senior Adult Oncology, v. 2014. Accessed September 6, 2014:http://www.nccn.org/professionals/physician_gls/PDF/senior.pdf 19. Hurria, A, Gupta,S, Zauderer, M, et al. Developing a cancer-specific geriatric assessment: A feasibility study. Cancer. 2005; 104: 1998-2005. 12
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20. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer. 2012 Jul 1;118(13):3377-86. doi: 10.1002/cncr.26646. Epub 2011 Nov 9. 21. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study [published online August 1, 2011]. J Clin Oncol. 2011;29(25):3457–3465 22. Pagani O, Senkus E, Wood W, et al. International guidelines for management of metastatic breast cancer: can metastatic breast cancer be cured? J Natl Cancer Inst. 2010; 102:456-63. 23. Harbeck N, Marschner N, Untch M, et al. Second International Consensus Conference on Advanced Breast Cancer (ABC2), Lisbon, 11/09/2013: the German Perspective. Breast Care. 2014;9(1):52-9. 24. Wilcken N, Dear R. Chemotherapy in metastatic breast cancer: a summary of all randomised trials reported 2000-2007. Eur J Cancer. 2008;44:2218-25. 25. Cardoso F, Costa A, Norton L, et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Breast. 2014;23:489-502. 26. Mathew A, Brufsky A. Bisphosphonates in breast cancer. Int J Cancer. 2014;2014:00-00. [Epub ahead of print]. 27. Gil-Gil MJ, Martinez-Garcia M, Sierra A, et al. Breast cancer brain metastases: a review of the literature and a current multidisciplinary management guideline. Clin Transl Oncol. 2014;16:436-46. 28. Lin NU, Amiri-Kordestani L, Palmieri D, Liewehr DJ, Steeg PS. CNS metastases in breast cancer: old challenge, new frontiers. Clin Cancer Res. 2013;19:6404-18. 29. Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14:64-71. 30. Sim HW, Morris PG, Patil S, Khasraw M. Brain metastases in breast cancer. Expert Rev Anticancer Ther. 2014;14(2):173-83. 31. Bartsch R, Berghoff A, Pluschnig U, et al. Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases. Br J Cancer. 2012;106:25-31. 32. Bachelot, T., Romieu G, Campone M, et al., Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14(1):64-71. 33. Metro G, Foglietta J, Russillo M, et al. Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine. Ann Oncol. 2011;22:625-30. 34. Lassman AB, Abrey LE, Shah GD, et al. Systemic high-dose intravenous methotrexate for central nervous system metastases. J Neurooncol. 2006;78(3):255-60. 35. Scott BJ, Kesari S. Leptomeningeal metastases in breast cancer. Am J Cancer Res. 2013; 3(2): 117–126. 36. Zagouri F, Sergentanis TN, Bartsch R, et al. Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis. Breast Cancer Res Treat. 2013;139(1):13-22. 13
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Table 1. Treatment options for adjuvant and neoadjuvant chemotherapy 2-16 Treatment Options
Her2Neu Positive
AC (Four 21-day cycles) then
Doxorubicin/cyclophosphamide
paclitaxel (Twelve 7-day
(four 14-day cycles) then
cycles) with trastuzumab
paclitaxel (four 14-day cycles)
SC
(Weekly during paclitaxel then
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First-Line
Her2Neu Negative
year)
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every 7 or 21 daysto complete 1
AC (Four 21-day cycles) then
Doxorubicin/cyclophosphamide
paclitaxel (Four 21-day cycles)
(four 14-day cycles) then
with pertuzumab (Weekly
paclitaxel (twelve 7-day cycles)
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during paclitaxel) and
trastuzumab (Weekly during paclitaxel then every 21 days to
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complete 1 year)
Doxorubicin/cyclophosphamide
Docetaxel/ cyclophosphamide
(four 14-day cycles) then
(four 21-day cycles)
paclitaxel (four 14-day cycles) with trastuzumab (Weekly during paclitaxel then every 21 days to complete 1 year) TCH (Six 21-day cycles) with
Doxorubicin/cyclophosphamide
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weekly trastuzumab, then
(four 14-day cycles)
trastuzumab every 21 days to complete 1 year FAC (Six 21-day cycles) or
docetaxel (Four 21-day cycles)
CAF (Six 28-day cycles)
during docetaxel cycles then
year)
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every 21 days to complete 1
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with trastuzumab (Weekly
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AC (Four 21-day cycles) then
AC (Four 21-day cycles) then
CEF (six 28-day cycles) or
docetaxel (Four 21-day cycles)
FEC (Six 28-day cycles)
with pertuzumab (On day 1
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during docetaxel cycles) and
trastuzumab (On day 1 during docetaxel cycles then every 21
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days to complete 1 year)
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FEC (Three 21-day cycles) then CMF (Six 28-day cycles) docetaxel (Three 21-day cycles) with pertuzumab (On day 1 during docetaxel cycles) and trastuzumab (On day 1 during docetaxel cycles then every 21 days to complete 1 year)
15
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FEC (Three 21-day cycles) then
AC (Four 21-day cycles) then docetaxel (Four 21-day cycles)
paclitaxel (three 21-day cycles)
during docetaxel cycles) and trastuzumab (On day 1 during
days to complete 1 year)
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docetaxel cycles then every 21
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with pertuzumab (on day 1
AC (Four 21-day cycles) then
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docetaxel (twelve 7-day cycles)
EC (Eight 21-day cycles) FAC (Six 21-day cycles) then paclitaxel (twelve 7-day cycles)
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FEC or CEF (Four 21-day cycles) then paclitaxel (Eight 7day cycles) FEC or CEF (Three 21-day cycles) then docetaxel (Three 21-day cycles) TAC (Six 21-day cycles)
Abbreviations AC- doxorubicin+cyclophosphamide TC- docetaxel+cyclophosphamide CAF-cyclophosphamide+doxorubicin+fluorouracil CEF -cyclophosphamide+epirubicin+fluorouracil CMF-cyclophosphamide+methotrexate+fluorouracil EC-epirubicin+cyclophosphmide 16
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AC C
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SC
RI PT
FAC-fluorouracil+doxorubicin+cyclophosphamide FEC-fluorouracil_epirubicin+cyclophosphamide TAC-docetaxel+doxorubicin+cyclophosphamide TCH- docetaxel+carboplatin+trasutuzumab
17