united dark blue A Supplement to A UBM Medica Publication® OCTOBER 2010 VOL 24 • NO 11 • SUPPLEMENT NO 4 Improving Outcomes in Early-Stage Breast Cancer Expert Reviewers Stefan Glück, md, phd Sylvester Professor of Medicine Division of Hematology/Oncology Department of Medicine Sylvester Comprehensive Cancer Center University of Miami Miami, Florida Terry Mamounas, md, mph, facs Professor of Surgery Northeastern Ohio Universities College of Medicine Medical Director Aultman Cancer Center Canton, Ohio Medical Writer Jennifer Klem, phd 1.0 1.0 Category 1 credit 1.5 Category 1 credits For ONCOLOGY on the Web, visit www.cancernetwork.com Improving Outcomes in Early-Stage Breast Cancer Expert Reviewers Stefan Glück, MD, PhD Terry Mamounas, MD, MPH, FACS Sylvester Professor of Medicine Professor of Surgery Division of Hematology/Oncology Northeastern Ohio Universities Department of Medicine College of Medicine Sylvester Comprehensive Cancer Center Medical Director University of Miami Aultman Cancer Center Miami, Florida Canton, Ohio Medical Writer Jennifer Klem, PhD Klem Medical Communications, LLC Coppell, Texas Supported by an educational grant from Genentech, Inc. and Pfizer Inc. PROGRAM OVERVIEW • Conduct an informed and interactive clinical consulta- Program Title tion for each patient with ESBC, including discussion of multiple alternative treatment options, and provide The Criteria for Improving Outcomes in Early-Stage opportunities for the patient to request prognosis Breast Cancer: Guidelines, Individualized Treatment, information and second opinions and Enhanced Communication. • Implement a checklist-based system for transferring Statement of Need case-specific data to primary care physicians and patients to improve long-term survivorship care of Breast cancer is the most prevalent type of cancer ESBC patients among women in the United States. It is the second leading cause of cancer-related deaths in this popula- • Summarize recent clinical findings of hormone therapy tion, despite the fact that the majority of women with and chemotherapy regimens for ESBC, interpret how newly diagnosed breast cancer have early-stage they may benefit patients with hormone-sensitive breast cancer (ESBC), which has a favorable prog- breast cancer, and select appropriate patients to enroll nosis. Nonetheless, specific practice patterns in the in active clinical trials for treatment of ESBC treatment of ESBC prevent optimal clinical outcome Accreditation and Designation for some patients. Established national guidelines for the surgical and adjuvant treatment of ESBC are fre- Physicians quently not followed, with particular patient subpopula- This activity has been planned and implemented in ac- tions disproportionately affected by these disparities cordance with the Essential Areas and policies of the in care. Furthermore, a plethora of evidence indicates Accreditation Council for Continuing Medical Education not only that doctor-patient communication is crucial (ACCME) through the joint sponsorship of the University to patient satisfaction and outcomes, but also that this of Kentucky College of Medicine and The Center for type of communication is often inadequate in meeting Medical Knowledge. The University of Kentucky Col- the needs of the patient. Finally, in recent years a new lege of Medicine is accredited by the ACCME to provide set of unmet needs has been acknowledged – that of continuing medical education for physicians. the breast cancer survivor, specifically with respect to smoothing the transition to management by a primary The University of Kentucky College of Medicine des- care provider. ignates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should This monograph will present current guidelines with only claim credit commensurate with the extent of their discussion focused on circumstances and reasons participation in the activity. for nonadherence as well as proposed strategies for increasing the use of guideline-recommended care for The University of Kentucky College of Medicine presents these patients. Additionally, the importance of and strat- this activity for educational purposes only. Participants egies for improvement of doctor-patient communication, are expected to utilize their own expertise and judgment the needs of breast cancer survivors, and the value of while engaged in the practice of medicine. The content staying up-to-date of current and emerging data in the of the presentations is provided solely by presenters field of ESBC will be explored. who have been selected for presentations because of recognized expertise in their field. Target Audience Physicians Assistants This is a 1-hour activity accredited for oncologists, AAPA accepts AMA PRA Category 1 Credits™ from physician assistants, nurse practitioners, nurses, and organizations accredited by the ACCME. pharmacists. Nurse Practitioners Learning Objectives AANP accepts AMA PRA Category 1 Credits™ from Upon completion of this activity, participants should organizations accredited by the ACCME. be able to: Nurses • Implement current evidence-based guidelines for TCL Institute, LLC is a provider approved by the California breast-conserving surgery, lymph node dissection, Board of Registered Nursing, Provider Number 15225, for radiation therapy, and radical mastectomy into your 1.2 contact hours. RNs outside of California must verify practice, specifically taking into consideration the with their licensing agency for approval of this course. preferred first-line course and need for individualized treatment of patients with ESBC Pharmacists • Design and employ individualized surgical, adjuvant, The University of Kentucky College of and endocrine therapy regimens for patients with Pharmacy is accredited by the Accredi- postmenopausal, hormone receptor–positive ESBC, tation Council for Pharmacy Education and incorporate ongoing discussions with patients (ACPE) as a provider of continuing phar- regarding the importance of compliance throughout macy education. the prescribed course of treatment SUPPLEMENT • OCTOBER 2010 • ONCOLOGY 3 PROGRAM OVERVIEW (continued) 1. Complete the activity in its entirety Pharmacists (continued) 2. After the activity, go to www.CECentral.com/getcredit 3. Enter activity code XEN10095 This knowledge-based activity has been assigned ACPE #022-999-10-071-H04-P and will award up to 1.0 contact 4. Select the type of credit you wish to claim hour (0.1 CEU) of continuing pharmacy education credit 5. Log in or register for a free account in states that recognize ACPE providers. 6. Complete the evaluation Statements of credit will indicate hours and CEUs based on 7. Get credit. A printable certificate will be available. participation and will be issued online at the conclusion of Nurses ONLY the activity. Successful completion includes completing the activity, its accompanying evaluation and posttest (score Nurses only should log onto http://www.TotalMedEd.com/ 70% or higher) and requesting credit online at conclusion links/9044GMonograph/index.html and complete the on- of the activity.The College complies with the Accreditation line evaluation to receive credit. A printable certificate will Standards for Continuing Pharmacy Education. be available upon completion of the activity evaluation. Disclosures Disclosure of Unlabeled or Investigational Drugs All planners, speakers, authors, reviewers, and staff This educational activity may contain discussion of members involved with content development for con- published and/or investigational uses of agents that are tinuing education activities sponsored by the University not indicated by the FDA. The opinions expressed in the of Kentucky Colleges of Medicine and Pharmacy are educational activity are those of the faculty. Please refer expected to disclose any real or perceived conflict of to the official prescribing information for each product for interest related to the content of the activity. Detailed discussion of approved indications, contraindications, and disclosures will be included in participant materials or warnings. Further, attendees/participants should appraise given prior to the start of the activity. the information presented critically and are encouraged to Accordingly: consult appropriate resources for any product or device mentioned in this program. Dr. Stefan Glück reported that he is a consultant to, a speaker for, and receives research support from Genen- Disclaimer tech, Inc.; Hoffman-La Roche Inc.; Genomic Health, Inc.; The content and views presented in this educational activ- sanofi-aventis U.S. LLC; Novartis Corporation; Pfizer ity are those of the authors and do not necessarily reflect Inc.; GlaxoSmithKline; and Abraxis BioScience, LLC. those of the University of Kentucky Colleges of Medicine Dr. Terry Mamounas reported that he is a consultant to and Pharmacy; the Center for Medical Knowledge; Genen- and speaker for sanofi-aventis U.S. LLC and Genomic tech, Inc.; or Pfizer Inc. This material is prepared based Health, Inc. He also reported that he is a consultant upon a review of multiple sources of information, but it to Genentech, Inc.; Novartis Corporation; and Bayer is not exhaustive of the subject matter. Therefore, health Corporation. care professionals and other individuals should review and consider other publications and materials on the The University of Kentucky Colleges of Medicine and subject matter before relying solely upon the information Pharmacy staff and The Center for Medical Knowledge contained within this educational activity. staff that were involved in the development of this activ- ity have no financial relationship with any commercial This activity has been planned and produced by the interests that are relevant to this activity. University of Kentucky Colleges of Medicine and Phar- macy and The Center for Medical Knowledge strictly as a To resolve identified conflicts of interest, the educational nonpromotional continuing medical education activity.The content was fully peer-reviewed by a physician who has University of Kentucky is an equal opportunity university. nothing to disclose. The resulting certified activity was found to provide educational content that is current, Support Statement evidence-based, and commercially balanced. This activity is supported by an educational grant from Instruction on How to Receive Credit Genentech, Inc. and Pfizer Inc. In order to receive credit, participants must review the CME information (accreditation, learning objectives, faculty disclosures, etc) and complete the activity in its entirety. Cosponsored by the University of Kentucky Colleges of Medicine and Pharmacy and The Center for Medical Physicians, Physician Assistants, Knowledge. Nurse Practitioners, and Pharmacists The method of participation for physicians, physician assistants, nurse practitioners, and pharmacist is as follows: 4 ONCOLOGY • VOLUME 24 • NUMBER 4 • SUPPLEMENT expert reviewers stefan glück, md, phd Improving Outcomes in Early-Stage Breast Cancer Sylvester Professor of Medicine Division of Hematology/Oncology Department of Medicine Sylvester Comprehensive Cancer Center University of Miami Miami, Florida ABSTRACT Early-stage breast cancer is a prevalent malignancy that continues terry mamounas, md, mph, to cause a significant number of cancer-related deaths each year. Cur- facs rent evidence points to suboptimal care in patients with early-stage Professor of Surgery Northeastern Ohio Universities breast cancer, especially with regard to physician use of guideline- College of Medicine recommended care. Such appropriate treatment regimens as breast- Medical Director conserving therapy and adjuvant therapy (including radiation therapy, Aultman Cancer Center chemotherapy, and hormonal therapy) are underutilized in this patient Canton, Ohio population. Critical steps toward optimizing the appropriate treatment of early-stage breast cancer and providing the most significant benefits for medical writer patients include increasing awareness of potential barriers and develop- jennifer klem, phd ing strategies to overcome them. Improved communication, increased Klem Medical Communications, llc proactive behavior in terms of emerging data, and promotion of clinical Coppell, Texas trial participation may additionally improve outcomes in this patient population. This review incorporates pertinent oncology literature in a comprehensive overview of early-stage breast cancer treatment, I t is estimated that more than including a review of existing guidelines, race and age disparities, and 207,000 women will be diagnosed communication strategies for oncologists. The focus is on appropriate, with breast cancer in 2010; the evidence-based treatment of this patient population. majority of these women will have early-stage disease. Breast cancer survival has increased dramatically since 1975, from a 5-year survival important. Each treatment modality undergone axillary lymph node dis- rate of 75.5% for all patients com- used in the management of ESBC section (ALND). Thus, treatment bined to a rate of 90.6% in 2002. has numerous associated morbidities: of ESBC should be based on a careful  This improvement in survival is some unique to a particular modal- risk/benefit analysis. This monograph also manifested in decreased breast ity and some overlapping with other will explore ways to improve the out- cancer mortality rates across all age modalities. For instance, radiation comes of women with ESBC. groups, although the largest magni- therapy can increase the risk of cardiac tude of benefit appears in patients dysfunction, lung dysfunction, and Treatment for ESBC: over 70 years old. While survival secondary cancers. Chemotherapy Guidelines and Adherence is highly favorable overall for patients and other systemic therapies may put with early-stage disease, it decreases patients at risk for both permanent side Need for Any Type of Adjuvant dramatically within this category by effects (infertility, cardiac dysfunc- Therapy stage, from a 5-year relative survival tion) and transient side effects (cog- According to breast cancer treat- of 100% for stage I disease to only nitive impairment, nausea, fatigue, ment guidelines developed by the 67% for stage IIIA disease. hair loss).[7-10] Hormonal therapy National Comprehensive Cancer Although survival is the most can lead to bone loss, hot flashes, and Network (NCCN), adjuvant therapy— crucial outcome for patients with arthralgia. Even surgical proce- which may include chemotherapy, early-stage breast cancer (ESBC), dures can have long-term implica- hormonal therapy, targeted therapy, because many patients have excellent tions for a patient’s health, as in the and/or radiation therapy—should be long-term outcomes, minimizing mor- case of lymphedema and decreased used for women over 70 years old bidity from treatment is also highly arm function in patients who have who have lymph node involvement or SUPPLEMENT • OCTOBER 2010 • ONCOLOGY 5 tumors greater than 1 cm in diameter. adjuvant therapy, were less likely to majority of women with stage I and II  However, compliance with these know that adjuvant therapy improved breast cancer, and that it is preferable guidelines is poor; a recent study of survival. Moreover, they had greater because it provides survival that is 354 patients from 6 surgical oncology mistrust of the medical system and less equivalent to total mastectomy and ax- practices in the northeastern United self-efficacy. illary dissection while preserving the States with stage 0, stage I, or stage While this study identified some breast. Similarly, the 2010 NCCN IIA/node-negative disease reported potential patient-centered explana- guidelines state that BCT consisting that 40% did not receive guideline- tions for underutilization of adjuvant of lumpectomy, ALND, and whole- recommended care, which included therapy, another study conducted by breast irradiation is equivalent to surgery, radiation therapy, and hor- Bickell and colleagues focused on mastectomy with axillary dissection as monal therapy. While this lack of the surgeon’s perspective. This study primary breast treatment for the major- compliance can represent either under- surveyed breast cancer surgeons ity of women with stage I and II breast or overutilization of therapy, evidence who treated 119 women who did cancers. This statement is based suggests that adjuvant therapy is more not receive guideline-recommended on numerous studies demonstrating often underutilized. Investigators from adjuvant therapy. Investigators that BCT produces equivalent survival Mount Sinai School of Medicine ex- reported a nearly equal distribution to that of mastectomy (Table 1). BCT amined the treatment of 723 women among the top three reasons for un- has increased over time, but stage II with ESBC treated surgically at four derutilization: (1) the perceived risks, patients lag behind stage I patients in Mount Sinai hospitals and found that as judged by the surgeon, exceeded utilization rates. between 18% and 33% of those pa- the expected benefits, (2) the patient The National Cancer Institute tients who could have benefited from refused treatment despite surgeon (NCI) recently reported data sug- adjuvant therapy did not receive it (the recommendation, and (3) the patient gesting that BCS is underutilized, omitted therapies included radiation did not receive surgeon-recommended with 35% of patients with stage I therapy after breast-conserving sur- care for an unknown reason (termed or II disease receiving mastectomy. gery [BCS], adjuvant chemotherapy, system failures). The authors provided  Predictors for underutilization and hormonal therapy). evidence that these system failures of BCS that have been identified by In a study of 258 women with were likely often due to suboptimal a number of investigators are listed ESBC who underwent surgery but did interactions between a patient’s sur- in Table 2.[26-30] These predictors not receive guideline-recommended geon and her medical oncologist, as are varied, with some being associ- adjuvant therapy (radiation therapy, when patients were referred to an ated with patient/tumor characteristics chemotherapy, or hormonal therapy, oncology clinic rather than a specific (lower socioeconomic status, larger where appropriate), the same group of oncologist’s office. tumor size), some associated with investigators surveyed these patients characteristics of the surgeon (male regarding their care, knowledge, medi- Breast-Conserving Therapy gender, surgical training outside the cal mistrust, and physician communi- (BCS With Radiation Therapy) United States), and others associated cation in an attempt to define reasons In 1990, the National Institutes with a variety of factors (lower BCS for this underutilization of care. of Health (NIH) released guidelines reimbursement, residence outside a They reported that untreated women, stating that breast-conserving therapy metropolitan area). compared to those who received (BCT) is appropriate treatment for the Despite research showing that radi- ation therapy following BCS reduces local recurrence rates and increases Table 1 survival, the NCI has reported that Clinical Trials Showing Equivalent Overall Survival Between radiation therapy is omitted from BCT Breast-Conserving Therapy and Mastectomy in Patients With in one-third of women receiving BCS. Early-Stage Breast Cancer  Predictors for omission of radia- tion therapy include older age, tumor Author, OS Results: Year N Length of OS BCT vs Mastectomy P Value size greater than 2 cm, negative nodes, treatment by surgical oncologist, and Arriagada, 179 15 yr RR: 1.41 .19 1996 residence in the western United States. [26,29,32] It should be mentioned that van Dongen, 868 10 yr 65% vs 66% .11 2000 omission of radiation therapy may not be considered underutilization for pa- Fisher, 1851 20 yr RR: 0.97 .74 tients older than 70 with hormone re- 2002 ceptor (HR)-positive disease who are Veronesi, 701 20 yr 41.7% vs 41.2% 1.0 being treated with hormonal therapy; 2002 recent data have demonstrated that Poggi, 237 18.4 yr 54% vs 58% .67 outcomes in this patient population 2003 did not improve with the addition of OS = overall survival; RR = relative risk. radiation therapy to BCS. 6 ONCOLOGY • VOLUME 24 • NUMBER 4 • SUPPLEMENT Lymph Node Dissection Table 2 Two different national guide- Characteristics Associated With Decreased Rates of lines—from the NCCN and the Breast-Conserving Surgery (BCS) American Society of Clinical Oncol- ogy (ASCO)—support the use of Patient/Tumor Characteristic Author, Year sentinel lymph node biopsy (SLNB) Age ≥ 70 yr Siesling, 2007; for patients with clinically node- Hershman, 2009; negative breast cancer.[13,34] A Smith, 2009 small randomized study of patients Lower socioeconomic status Hershman, 2009; with negative sentinel lymph nodes Smith, 2009 provided early support for this ap- Lower education level Smith, 2009 proach; the study found that SLNB Tumor size 2–5 cm Siesling, 2007; was associated with equivalent breast Morrow, 2001 cancer–related events (P = .52) and Tumors with an extensive intraductal component Morrow, 2001 a trend toward increased survival Positive nodes Siesling, 2007; (P = .15) compared with ALND. Smith, 2009 Sentinel lymph node biopsy has sev- Surgeon Characteristic Author, Year eral advantages over ALND, including decreases in lymphedema, sensory Male gender Hershman, 2009; loss, drain usage, length of hospital Mandelblatt, 2001 stay, and time to resumption of nor- Surgical training outside US Hershman, 2009 mal daily activities; and increases in Educated prior to 1975 Hershman, 2009 patient-recorded quality-of-life (QOL) Lack of belief in patient participation in treatment Mandelblatt, 2001 and arm function scores. The decisions NCCN guidelines also support SLNB Other Characteristic Author, Year for clinically positive lymph nodes if they are found to be negative by Lower BCS reimbursement Mandelblatt, 2001 fine needle aspiration or core biopsy Geographical region, outside northeastern US Morrow, 2001; prior to surgery. Acceptance of Smith, 2009 SLNB is high, and SLNB alone for Population density, outside metropolitan area Smith, 2009 patients with negative sentinel nodes Practices with low volume of breast cancer cases Mandelblatt, 2001 is currently the accepted standard of care. Recent data from two indepen- 1 cm; the guidelines also state that While it is true that adjuvant dent studies presented at the 2010 chemotherapy should be considered chemotherapy improves the overall ASCO annual meeting confirmed for women with lymph node–nega- survival of patients with ESBC, not all that, compared to SLNB, ALND did tive, HR-negative tumors between 0.6 patients in this population benefit from not improve outcome in patients with and 1.0 cm in size. Each of the it. Adjuvant chemotherapy can come clinically node-negative disease, re- NCCN’s seven preferred combination at a high cost with respect to financial gardless of whether the disease was adjuvant chemotherapy regimens con- resources and acute and chronic side sentinel node–negative or sentinel tain an anthracycline (doxorubicin), a effects. Therefore, it is desirable to node–positive.[36,37] However, re- taxane (docetaxel), or both. The limit adjuvant chemotherapy to only sults from the study examining node- Early Breast Cancer Trialists’ Collab- those patients most likely to derive negative disease must be interpreted orative Group has performed several benefit. Within the past decade, ge- with caution, as it did not reach its ac- meta-analyses showing that combina- nomic profiling tools designed to help crual goal and was thus underpowered. tion chemotherapy reduces the risk of identify such patients have become death from breast cancer in women available. The most widely used of Chemotherapy with ESBC, and three of their publica- these tools in the United States is the The 2000 NIH consensus state- tions have reported that this survival 21-gene recurrence score assay, which ment recommends chemotherapy for advantage is present largely regardless has been developed for patients with women with node-positive tumors or of HR status or nodal status.[39-41] HR-positive, human epidermal growth with node-negative tumors larger than Despite the overwhelming evi- factor receptor 2 (HER2)-negative, 1 cm, regardless of HR status. dence that adjuvant chemotherapy has node-negative disease. Using Largely similar are the 2010 NCCN a survival advantage in patients with the reverse-transcriptase polymerase breast cancer guidelines, which sup- ESBC, some studies have shown that it chain reaction profiles of 16 tumor- port the use of adjuvant chemotherapy is underutilized in ESBC populations, associated genes and 5 housekeep- for women with lymph node–positive regardless of these disease character- ing genes, a recurrence score can disease or with lymph node–nega- istics: node-negative, node-positive, be calculated that classifies patients tive, HR-negative tumors larger than HR-negative, HR-positive.[14,42,43] into 3 categories: low, intermediate, SUPPLEMENT • OCTOBER 2010 • ONCOLOGY 7 and high risk for recurrence when taking AIs have an increased risk of examined exemestane (Aromasin) as treated with tamoxifen. Patients with arthralgia, myalgia, and bone loss. up-front therapy vs sequential therapy a low recurrence score are unlikely to  The life-threatening nature of the of tamoxifen followed by exemestane. benefit from chemotherapy and, thus, increased risk of tamoxifen-specific  Jones and colleagues reported may reasonably avoid an expensive, toxicities creates a safety profile for that, after a median follow-up of potentially toxic treatment. tamoxifen that is less favorable than 5 years, both regimens produced It is currently unclear whether that of the AIs. similar DFS, overall survival (OS), patients with an intermediate recur- A number of randomized clinical and recurrence rates, showing that ex- rence score derive substantial benefit trials have reported positive results emestane used as up-front or sequen- from chemotherapy, but TAI- with the three commercially available tial therapy provides similar results LORx (Trial Assessing Individual- AIs. Three different approaches to hor- to tamoxifen in women with ESBC. ized Options for Treatment for Breast monal therapy have been examined: The third up-front therapy trial, Cancer), an international randomized (1) up-front therapy, in which an AI is BIG (Breast International Group) trial, seeks to address this issue. compared to tamoxifen, (2) sequential 1-98, was designed to compare 5-year This trial will complete accrual later therapy, in which the AI is given 2 to treatment with letrozole (Femara) to in 2010. 3 years after completion of tamoxifen tamoxifen. The initial design was treatment, and (3) extended adjuvant one of up-front therapy, with patients Hormonal Therapy therapy, in which an AI is given to receive either letrozole or tamoxi- Tamoxifen was the first hormonal 5 years after completion of tamoxifen fen. But because positive results agent to demonstrate a survival ad- treatment. were being published with sequential vantage in the adjuvant setting. The first clinical trial to report fa- therapy, the trial was amended to More recently, the third-generation vorable results with up-front therapy include two additional arms: 2 years aromatase inhibitors (AIs) were in- was the ATAC (Arimidex, Tamoxi- of tamoxifen followed by 3 years of vestigated as potential therapies to fen, Alone and in Combination) trial, letrozole and 2 years of letrozole fol- improve outcomes in postmenopausal which demonstrated that anastrozole lowed by 3 years of tamoxifen. women with ESBC.[48-55] As a class, (Arimidex) produced superior disease- Up-front therapy results showed the AIs have a safety profile that is dis- free survival (DFS) compared with that patients receiving letrozole tinct from that of tamoxifen. Whereas tamoxifen. The TEAM (Tamoxi- showed a significant 19% improve- patients taking tamoxifen have an fen Exemestane Adjuvant Multi- ment in DFS (hazard ratio, 0.81; increased risk of endometrial cancer national) trial was an international P = .003) and a reduced risk of dis- and thromboembolic disease, patients study of nearly 10,000 patients that tant recurrence (hazard ratio, 0.73; P = .001) compared with those receiv- ing tamoxifen. When examining the Table 3 sequential therapy arms of the BIG Barriers to Adherence to Oral Hormonal Therapies—and 1-98 trial, both had similar DFS rates Strategies to Overcome These after 5 years, with 87.6% for letrozole Barriers to Adherence Strategies to Overcome Barriers followed by tamoxifen and 86.2% Lack of tangible benefit Discuss studies showing the benefit of adjuvant for tamoxifen followed by letrozole, endocrine therapy and neither was superior to letrozole Lack of understanding of the monotherapy. Switching from le- importance of adherence trozole to tamoxifen after 2 to 3 years Length of treatment had no impact on patient outcomes, with the letrozole monotherapy arm Side effects of medication Review potential side effects and develop and the letrozole → tamoxifen arm management strategies, as needed both having similar DFS and OS rates Busy schedule (not enough Encourage mail-order prescription refills at 5 years. This indicates that pa- time to refill prescriptions) tients who are intolerant of letrozole Cost Discuss strategies to decrease costs and save time or who have developed bone loss in (mail-order refills, discount drug programs) the first 2 to 3 years should be able to Patient dissatisfaction with Augment patient-provider communication by having switch to tamoxifen without compro- treating physician the nurse solicit questions that may be intimidating mising outcome. or embarrassing The IES (Intergroup Exemestane General barriers Identify potential barriers; provide written information Study) trial, which took a sequential about the therapy; provide patient with professional approach to therapy by randomly contact information; schedule regular follow-up; assigning patients to receive either provide a list of relevant organizations and support 5 years of tamoxifen or to 2 to 3 years groups; explore specific needs/characteristics of the patient of tamoxifen followed by 2 to 3 years of exemestane, showed that patients Data from Miaskowski et al, Moore, and Kirk and Hudis. who switched from tamoxifen to 8 ONCOLOGY • VOLUME 24 • NUMBER 4 • SUPPLEMENT exemestane after 2 to 3 years had Table 4 improved DFS compared with those Survivorship Issues Specific to Patients With Breast Cancer who received 5 years of tamoxifen.  The next two sequential therapy Need for continuing medical evaluation trials—ARNO (Arimidex-Nolvadex) Local complications of therapy (eg, lymphedema, pain, numbness) 95 and The Austrian Breast and Late complications of chemotherapy (eg, secondary leukemia, cardiac impairment, Colorectal Cancer Study Group Trial osteoporosis) 8—were similar to the IES trial in Gynecologic and reproductive issues (eg, infertility, amenorrhea, increased risk of design but examined the use of an- endometrial cancer) astrozole instead of exemestane. Management of menopausal symptoms Because they were nearly identical in design and inclusion criteria, the two Discussion of hormone-replacement therapy trials were analyzed together. Results Psychosocial issues (eg, anxiety, mood disorders, sexual dysfunction) showed a significant improvement in Changes in lifestyle (eg, weight gain, exercise) event-free survival with anastrozole Adapted from Burstein and Winer. (hazard ratio, 0.60; P = .0009). MA.17, an extended therapy trial, provided evidence that DFS was pro- gesterone receptor–positive invasive tics (eg, busy schedule that makes it longed when patients received 5 years breast cancers regardless of patient challenging to refill prescriptions).[62- of letrozole after 5 years of tamoxifen. age, lymph node status, or plans for 64] These barriers can potentially be  Mamounas and colleagues con- adjuvant chemotherapy. Despite overcome by employing the strategies ducted the National Surgical Adjuvant these broad guidelines, adjuvant in Table 3. For instance, with patients Breast and Bowel Project (NSABP) hormonal therapy is underutilized in who do not appreciate the benefit of B-33 trial to similarly test exemestane women with HR-positive ESBC, with adjuvant hormonal therapy, studies as extended adjuvant therapy. approximately 30% of patients not re- showing the benefit of adjuvant en- In this trial, postmenopausal breast ceiving hormonal therapy, regardless docrine therapy should be discussed. cancer patients who were disease- of nodal status. General strategies to increase adher- free after 5 years of tamoxifen were Several studies have shown that ad- ence, such as scheduling regular randomly assigned to receive either herence to hormonal therapy by wom- follow-up, may also be used.[62,63] 5 years of exemestane (25 mg daily) en with ESBC is low. For instance, or 5 years of placebo. Because of the Chlebowski and Geller reported that Trastuzumab Therapy positive results from the MA.17 trial, 23% to 28% of women who were Four large randomized trials the NSABP trial was terminated and enrolled in adjuvant breast cancer examining adjuvant trastuzumab unblinded after approximately half of clinical trials prematurely discontin- (Herceptin) therapy nearly simultane- the patients had been accrued. Despite ued hormonal therapy (tamoxifen or ously demonstrated that the addition of this reduction in power, results showed AIs) after at least 4 years of follow-up. trastuzumab to adjuvant chemotherapy a borderline significant improvement  Charlson and colleagues reported produced a dramatic DFS and overall in 4-year DFS in patients receiving a similar percentage (23%) of older survival advantage in patients with exemestane (91% vs 89%; relative patients prematurely discontinuing HER2-positive ESBC.[65-67] Reduc- risk [RR], 0.68; P = .07) as well as adjuvant hormonal therapy. tion in the risk of DFS events ranged a significant improvement in 4-year Finally, in a study of almost 1,500 from 36% to 52% and reduction in relapse-free survival (96% vs 94%; insured, low-income women, 36% did the risk of death with trastuzumab RR, 0.44; P = .004). not even fill their prescription for hor- ranged from 33% to 41%. As a re- The use of AIs rather than tamoxi- monal therapy, and 20% of those who sult, practice was quickly changed to fen is supported primarily by their did were nonpersistent (had a greater include adjuvant trastuzumab for more favorable safety profile and than 90-day gap in prescription refills). patients with HER2-positive, stage I their ability to reduce the risk of re-  Not surprisingly, nonadherence or greater disease; the US Food currence, rather than by an ability to to adjuvant hormonal therapy has a and Drug Administration (FDA) ap- improve OS. Moreover, this choice of negative impact on survival. proved adjuvant use of trastuzumab hormonal therapy is only available to A number of barriers to adherence in November 2006. Physician postmenopausal women; tamoxifen to oral hormonal therapies have been adherence to HER2 testing is high, is the only option for premenopausal identified (Table 3) and include issues with a recent study reporting 98.1% women because AIs do not sufficiently specific to therapy (eg, side effects, block ovarian production of estrogen. cost, and length of treatment), patient As a result of the above stud- attitudes (eg, patient dissatisfaction Address all correspondence to: ies of hormonal agents, the NCCN with the treating physician, lack of TCL Institute, LLC 104 Towerview Court recommends that hormonal therapy appreciation of benefit, and lack of Cary, NC 27513 should be considered for patients appreciation of the importance of 919-467-0006 x 233 with estrogen receptor– and/or pro- adherence), and patient characteris- email@example.com SUPPLEMENT • OCTOBER 2010 • ONCOLOGY 9 adherence in 322 patients for whom Racial Disparities Racial disparities in the treatment HER2 testing was indicated (breast In the United States, the incidence of ESBC are not only con ned to the cancers that are stage 1 or higher). of breast cancer in Caucasians exceeds African American population. In a  In this study, trastuzumab use that in African Americans and other cross-sectional study of 677 women was appropriately administered in 51 ethnicities; however, breast cancer with ESBC treated in New York, of 52 patients, with 1 patient having mortality is higher in African Ameri- Bickell and colleagues found that race no documentation of HER2 overex- cans than in Caucasians (Figure 1). played a statistically signi cant role pression. However, of the 45 patients Although a number of factors may in the underutilization of appropriate with stage 2 or higher HER2-positive contribute to this disparity in mortal- adjuvant therapy, with Caucasians breast cancer, 13% did not receive ity, including differences in breast can- having the least underuse (16%), trastuzumab. The reasons for this cer screening, tumor biology, genetic followed by Hispanics (23%) and underutilization of trastuzumab were predisposition, demographics, and African Americans (34%). His- not explored in this study. However, comorbidities, substantial evidence panics are more likely to be diagnosed because trastuzumab increases the risk exists that treatment differences across at later stages than Caucasians, even of cardiotoxicity, cardiovascular races account for at least some of the after poverty level is accounted for. morbidity is one valid reason to avoid observed disparity.  Furthermore, Hispanic patients trastuzumab, particularly in patients Several independent studies ex- with ESBC had the lowest rates of with increased cardiovascular risk. amined two large US databases (Sur- de nitive local therapy of all races in In the pivotal adjuvant trastuzumab veillance, Epidemiology, and End an analysis of SEER data from over trials, the incidence of class III or IV Results [SEER] and National Cancer 375,000 women. congestive heart failure or death from Database) to identify treatment dif- Sometimes, treatment disparities cardiac causes in the trastuzumab arm ferences between African American may affect QOL more than survival, was 4.1% in the NSABP B-31 trial and Caucasian women.[73-75] While as in the case of Asian American and 2.9% in the North Central Cancer no disparity in the rate of BCS was women and their mastectomy rate. Treatment Group N9831 trial. observed, African Americans Asian Americans have higher rates Examination of cardiac dysfunction were reported to be 24% less likely of mastectomy than other races. Im- reported in the N9831 trial revealed to receive radiation therapy follow- portant factors that contribute to this that older age, lower baseline left ing BCS and to have lower odds of increased rate include fear, cultural ventricular ejection fraction, and receiving definitive locoregional beliefs, smaller breast size, and pa- antihypertensive medications are risk therapy, adjuvant hormonal therapy, tient attitudes toward preserving the factors for trastuzumab-associated and adjuvant chemotherapy.[74,75] breast. A study of 93 patients who cardiac dysfunction. underwent either BCT Despite the risk of cardio- or mastectomy revealed toxicity, it is widely ac- a modest but signi cant 100 cepted that the bene ts of improvement in QOL trastuzumab outweigh the with BCT compared with 90 risks for most patients. mastectomy. 80 Disparities in the Age Disparities Care of Patient 70 It is well established Subsets that older women with 60 breast cancer are treated In the above section, less aggressively and Percent different areas of treat- 50 with less adherence to ment nonadherence were treatment guidelines than discussed in the context of 40 are younger women. For the general ESBC popu- instance, SEER data lation. However, non- 30 showed that increasing adherence is not evenly All Races age was significantly distributed across the 20 associated with decreas- Black US patient population; ing BCS rates, with 48% 10 White rather, certain subgroups of patients older than receive less guideline- 50 years receiving BCS, 0 recommended care than r o r r r r r r r r r a r but only 35% of patients Ze 1 yea 2 yea 3 yea 4 yea 5 yea 6 yea 7 yea 8 yea 9 yea 0 ye other subgroups. The me 1 older than 80 years re- Ti following discussion will Survival Interval ceiving the same treat- focus on US treatment ment. Similarly, disparities with respect to Figure 1: Racial disparities in breast cancer survival. From numerous studies have race and age. National Cancer Institute. concluded that older age 10 ONCOLOGY • VOLUME 24 • NUMBER 4 • SUPPLEMENT (aged ≥ 70-80 years) is a predictor of less frequent utilization of radiation 1.0 Ratio of annual recurrence rates therapy following BCS than is seen with younger patients.[26,29,32] 0.8 < 40 years SEER data also showed that older 40-49 years women (aged ≥ 80 years) were less 0.6 50-59 years likely to undergo lymph node dissec- 60-69 years tion as part of their BCT than younger 0.4 < 69 years women. Finally, elderly patients (aged ≥ 70 years) with nodal involve- 0.2 ment or HR-negative tumors were less likely to receive adjuvant che- 0.0 motherapy than younger controls. Recurrence rate Mortality rate While it is clear that older patients with ESBC are treated differently than Figure 2: Effect of age on the efficacy of combination chemotherapy in patients their younger cohorts, the question is with early-stage breast cancer. Reprinted from Early Breast Cancer Trialists’ whether this is appropriate. There is a Collaborative Group. With permission from Elsevier. paucity of national guidelines on the topic of treating older patients with be treated differently with respect to more intense chemotherapy produced breast cancer, primarily because so lymph node assessment. superior outcomes. Patients on few elderly patients enroll in clinical Finally, the NCCN guidelines de- capecitabine had an almost two-fold trials, making conclusions about their cline to make de nitive chemotherapy increase in the risk of death compared responses to treatment challenging. recommendations for patients older with the patients on combination che- For instance, the NCCN does not make than 70 years due to insuf cient data. motherapy (P = .02). Older patients speci c recommendations regarding  In fact, a meta-analysis conducted are most often inappropriately under- the use of BCS in elderly patients by the EBCTCG found that the ef- treated, primarily because of bias on and suggests that radiation therapy cacy of combination chemotherapy the part of one or more parties—phy- is not always necessary for women in patients with ESBC declines with sicians, patients, or family members. aged 70 years or older. Yood and age (Figure 2). It is possible that less aggressive colleagues, however, demonstrated Older patients with breast cancer management of breast cancer in older that older women receiving BCT with have an increased likelihood of having patients is only infrequently the result radiation therapy had similar mortality more favorable biologic tumor char- of medical complications. Thus, older rates to those receiving mastectomy, acteristics than younger patients, patients should be treated according to whereas those receiving BCS alone which can translate into older patients guidelines whenever possible, as long (without radiation therapy) were twice with ESBC being treated less aggres- as such treatment does not exacerbate as likely to die as those receiving sively. Similarly, comorbidities (eg, existing comorbidities and does not mastectomy. However, the NCCN hypertension, heart-related conditions, cause signi cant side effects. recommendation that radiation ther- arthritis, and gastrointestinal prob- apy may be omitted in women aged lems) increase with age, making it Doctor-Patient Communication 70 years or older who have HR-posi- more challenging to provide adjuvant tive, node-negative T1 tumors is therapy to this patient population. In The importance of doctor-patient supported by recent data presented at fact, comorbidities, including heart communication is often ignored in the ASCO 2010; these data showed that failure and diabetes, are not only literature and in practice, but it has an patients aged 70 years or older with associated with the underuse of ad- enormous impact on patient care. For HR-positive disease who were treated juvant therapy; they also have a instance, a retrospective study of near- with BCS with tamoxifen had approxi- signi cant negative effect on survival. ly 10,000 elderly women with breast mately the same survival whether or [86,87] However, it is not an accepted cancer showed that consulting with a not radiation therapy was added. fact that older patients with ESBC medical oncologist prior to surgery The NCCN guidelines also state derive less benefit from adjuvant increased the likelihood of receiving that both ALND and SLNB are op- therapy than younger patients, with guidelines-recommended care. tional in elderly patients due to the ab- the possible exception of combition Another study of patients with breast sence of de nitive data demonstrating chemotherapy. When comparing cancer, speci cally node-negative, superior survival with the use of these adjuvant combination chemotherapy HR-positive disease, demonstrated procedures; however, recent data to single-agent capecitabine (Xeloda) that patients with more favorable show that older patients (aged 55 years in women aged 65 years or older, ratings of provider communication or older) with small tumors are not less Muss and colleagues determined that, were more likely to receive adjuvant likely to have positive sentinel lymph although moderate-to-severe toxici- chemotherapy. nodes than a younger cohort, sug- ties were elevated in the combination However, the challenges involved gesting that older patients should not chemotherapy arm (64% vs 33%), the in establishing effective doctor-pa- SUPPLEMENT • OCTOBER 2010 • ONCOLOGY 11 tient communication are substantial. Keating and colleagues reported that tions, and encouraging patient partici- Results of a survey of over 1,100 78% of over 2,000 patients surveyed pation in decision making.[94-96] women with ESBC and their surgeons had experienced at least one of the demonstrated that patients and their following problems with their physi- Breast Cancer Survivorship surgeons disagreed about whether both cian, which caused them to consider BCS and mastectomy were discussed changing physicians: (1) not giving Cancer survivorship is a relatively as treatment options, with patients in understandable answers to questions, new area of research and care that ac- one-third of the cases reporting that (2) not taking enough time to answer knowledges that the needs of patients both options had not been discussed questions, and (3) not giving enough with cancer diagnoses do not stop while their surgeons asserted that they medical information. after active treatment is terminated. had. Another study illustrated Although physicians are often not  According to the Institute of the dissatisfaction sometimes expe- adequately trained in communication Medicine (IOM), cancer survivorship rienced by patients: in this survey of skills, several groups have studied care is a distinct phase of care that has over 600 patients with breast cancer, strategies for improving doctor-patient been neglected in such diverse areas 30% rated their physicians 5 or less communication. These include in- as advocacy, education, clinical prac- on a scale from 1 (poor) to 10 (good) creasing affective, or emotional, par- tice, and research. In the 2006 seminal with respect to the completeness of ticipation with the patient, attending report on survivorship, From Cancer information they received about their to both verbal and nonverbal patient Patient to Cancer Survivor: Lost in disease and treatment. Moreover, cues, encouraging patients to ask ques- Transition, the IOM proposed four essential components of patient-cen- Table 5 tered survivorship care: (1) preven- Phase III Trials Currently Recruiting Patients With Early-Stage tion of recurrent and new cancers and Breast Cancer other late effects; (2) surveillance for cancer spread, recurrence, or second 1. Radiation therapy trials cancers, and assessment of medical • Intraoperative vs postoperative radiation therapy (ClinicalTrials.gov identifier: and psychosocial late effects; (3) in- NCT00983684) tervention for consequences of cancer • Intensity-modulated radiation therapy vs partial organ radiation therapy (ClinicalTrials.gov identifier: NCT01185132) and its treatment; and (4) coordination • Three intensity-modulated radiation therapy schedules following BCS between specialists and primary care (ClinicalTrials.gov identifiers: NCT00818051; NCT00337064; NCT00909909) providers (PCPs) to ensure that all of • Conventional radiation therapy vs tomotherapy (ClinicalTrials.gov identifier: the survivors’ health needs are met. NCT00459628) Burstein and Winer have also identi- • Whole breast irradiation vs partial breast irradiation (ClinicalTrials.gov identifier: fied a number of specific breast cancer NCT00892814) survivorship issues (Table 4), 2. Hormonal therapy trials many of which can be categorized • Intermittent vs continuous use of letrozole (ClinicalTrials.gov identifier: under one of the four IOM essential NCT00553410) components of survivorship care • Letrozole after tamoxifen (ClinicalTrials.gov identifier: NCT01064635) mentioned above; however, novel • Anastrozole with and without fulvestrant (Faslodex) (ClinicalTrials.gov identifier: areas of need identified by these au- NCT00570323) thors include psychosocial issues (eg, 3. HER2-directed therapy trials anxiety, mood disorders, and sexual dysfunction) and changes in lifestyle • Neratinib (anti-HER2 tyrosine kinase inhibitor) vs placebo (ClinicalTrials.gov identifier: NCT00878709) (eg, weight gain and the need for • Lapatinib (Tykerb) vs trastuzumab (ClinicalTrials.gov identifier: NCT01137994) increased exercise). • Lapatinib with trastuzumab (ClinicalTrials.gov identifier: NCT00470704) Central to providing comprehen- • Trastuzumab with and without bevacizumab (Avastin) (ClinicalTrials.gov sive survivorship care are cancer identifier: NCT00625898) treatment summaries and survivor- 4. Trials focusing on other therapies ship care plans. Although prepar- ing a concise summary of previous • Denosumab (Prolia; anti–receptor activator of nuclear factor κB ligand treatment may appear to be a trivial [RANKL] antibody) as adjuvant treatment in high-risk early breast cancer (ClinicalTrials.gov identifier: NCT01077154) and uncomplicated matter, the fre- • Bevacizumab with combination chemotherapy (ClinicalTrials.gov identifier: quent separation of the various breast NCT00679029) cancer treatments in time, space, and • Ixabepilone (Ixempra) vs paclitaxel for triple-negative disease (ClinicalTrials.gov health care systems makes the likeli- identifier: NCT00789581) hood of mistakes and oversight high. • Adjuvant sequential vs combination chemotherapy (ClinicalTrials.gov identifier: Thus, such a summary should be NCT00670878) prepared to facilitate communication • Bisphosphonates as adjuvant therapy (ClinicalTrials.gov identifiers: among providers. Survivorship care NCT00332709; NCT00196872) plans are also created to facilitate c 12 ONCOLOGY • VOLUME 24 • NUMBER 4 • SUPPLEMENT the coordination of care with other ularly relevant to patients with ESBC mendations, with respect to BCT, physicians (eg, internal medicine because the vast majority of them will hormonal therapy, and chemotherapy. specialists, PCPs, gynecologists) who spend many years as cancer survivors Moreover, particular subpopulations can provide successful ongoing care as a result of their favorable progno- of patients are disproportionately for breast cancer patients. These plans ses. In addition, they receive a wide affected by these disparities in care. must address not only immediate range of different therapies, includ- Other areas of physician behavior that posttreatment and long-term effects ing surgical resection/reconstruction, can create barriers to appropriate pa- of cancer treatment, but also the ongo- hormonal therapy, chemotherapy, tient management include unsatisfac- ing psychosocial burden of a cancer and radiation therapy, so they may be tory doctor-patient communication, a diagnosis, and the potential for late dealing with a multitude of chronic lack of proactive behavior regarding sequelae of treatment. Survivorship or late effects of therapy. Thus, this emerging data, including the promo- care plans, which are a relatively new population of patients stands to derive tion of clinical trial participation, and concept, have yet to be widely used great benefit from improvements in inadequate care of patients after they in practice. survivorship care. have reached the survivorship stage, The need for improved survivor- which can be decades-long for many ship care is great, as attested by pa- Ongoing Clinical Trials and patients with ESBC. Finally, because tients and physicians alike. A 2007 Emerging Data these patients often receive oral agents survey of PCPs revealed that confi- (eg, tamoxifen, AIs) as part of their dence in caring for cancer survivors Staying abreast of emerging data treatment, patient adherence is also is not high; only 49% of respondents and ongoing clinical trials is crucial an obstacle to optimal care. As these were comfortable having responsibil- to providing optimal care to patients issues are brought to the forefront of ity for surveillance of breast cancer with ESBC. Practice-changing results physicians’ awareness and strategies recurrence and even fewer (41%) are frequently unveiled at annual are developed to minimize problems were confident that they were follow- oncology conferences, such as those in each area, patients with ESBC will ing standard surveillance guidelines of ASCO, the European Society reap the benefits through improve- for breast cancer recurrence. of Medical Oncology, and the San ments in clinical outcomes. The same survey reported that 57% Antonio Breast Cancer Symposium. of PCPs rated the current transfer Even physicians who cannot attend of care from oncologists as fair or these conferences can learn what was References poor. 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As our readers must surely appreciate, our editorial advisors, consultants, and reviewers cannot diagnose or prescribe for a particular patient without actually seeing the patient. Thus, the general comments in this journal are based on the clinical experience of the authors, reviewers, and consultants and should not be construed as a formal consultation or specific recommendation for a particular patient. The authors, editors, and publisher take extreme care to be certain that drugs and dosage recommenda- tions are precise and accurate. However, typographical errors can occur. Therefore, be sure to double-check all dosage schedules in articles against the manufacturer’s package information data. Also, dosages and methods of administration of pharmaceutical products mentioned by authors may not necessarily be the same as those listed in the package insert and may not be approved by the US Food and Drug Administra- tion. Such dosages and delivery methods may reflect the clinical experience of the author or authors and/or may reflect the experience of other clinical investigators. Readers are advised to consult the manufacturer’s current package labeling for accepted indications, absolute dosage recommendations, and other information pertinent to the safe and effective use of the product described. This supplement and associated publication costs were funded by Genentech, Inc. and Pfizer Inc.
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