Follow-up Issues for Early Stage Breast Cancer: The Role of Surveillance and Long-Term Care

Transcription

1 Follow-up Issues for Early Stage Breast Cancer: The Role of Surveillance and Long-Term Care Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education University of California San Francisco Comprehensive Cancer Center

2 A Growing and Important Issue >200,000 new cases of invasive breast cancer per year in U.S. Additional >50,000 cases of DCIS The majority of patients will have early stage disease Treatment continues to improve ~80% of women diagnosed with breast cancer will be survivors This is a huge and increasing population How do we best serve the almost 3 million survivors?

3 Understanding Appropriate Follow-up is Important Overuse of medical resources for follow-up appears common in long-term survivors (Hensley et al, BCRT; 2005) Follow-up should be performed to detect problems that can be treated with curative intent, or controlled for long duration

4 What are the Goals of Follow-up Care? Monitor and treat symptoms Related to completed and ongoing treatment Related to disease diagnosis Psychosocial Fertility Diagnosis of recurrence New primary cancers Screen for genetic risk Locoregional recurrence Distant metastases Facilitate reporting of symptoms

5 Who Should be Referred for Genetic Counseling? Age < 50 at diagnosis; TNBC age < 60 History of bilateral breast cancer Ashkenazi Jewish heritage, age < 50 History of ovarian cancer Family history of: First or second degree relative with bilateral breast cancer First degree relative with breast cancer < age 50 First or second degree relative with ovarian cancer Male relative with breast cancer Adapted from NCCN and PSTF guidelines

6 Screening for New Cancers Mammography Lack of high level evidence to support an impact on DFS or OS (Grunfeld et al, Breast,2002;11:228, Esserman and Thompson, JAMA 2009) Ongoing controversy: mammography is best at detecting low risk disease Observational studies suggest that the method of detection does not influence survival Decreased specificity and sensitivity in the irradiated breast 62% of women in one series did not have a follow-up mammogram in the first year following diagnosis (Mandelblatt et al JCO,2006;24:77)

7 Recommendations Mammography First post treatment within first year (no earlier than 6 months after RT), then yearly if stable Breast self-exam Monthly Clinical breast exam Every 3-6 months for the first 3 years Every 6-12 months for the next 2 years Then annually MRI Decision should be based on an individual basis considering: Genetic risk factors Young age, dense breasts Mammographically occult tumors Khatcheressian JL, et al, JCO 31:961-5, 2013

8 Relative Risk of CL BC Based on Familial Risk: Swedish Registry Parameter N RR (95% CI) Reference rate All women, no FH or CL BC 90, Familial risk, all women 7, ( ) Familial risk, no CL BC 6, ( ) Risk for CL breast, all women 5, ( ) Risk for CL breast, no family history 4, ( ) Risk for CL breast, with family history ( ) NOTE: Data were adjusted for age, parity, and age at first birth. Boldface indicates that RR was statistically >1.00 (Hemminki et al, 2007 Cancer Res;67:868)

9 Detection of Locoregional Recurrences Meta-analysis of 12 studies 378 isolated LRR in 5,045 patients (7.5%) 58% diagnosed during routine visits or with routine tests 40% had no symptoms No data on survival or QOL Based on type of surgery 158/1,948 (8%) with mastectomy 47% (75) asymptomatic at routine FU 152/1,648 (9%) with breast conservation 36% (54) asymptomatic at routine FU de Bock et al; JCO 22:4010, 2004

10 What is the Role of Follow-up in Detecting Local Recurrence? Netherlands Cancer Registry random sampling in first 5 years of FU Studied mode of relapse FU with multiple medical disciplines increased the number of visits 9 recommended 14 and 18 visits for 2 and 3 disciplines To detect one locoregional recurrence or second primary breast cancer 1,349 PEs vs 262 mammograms and/or MRI tests Imaging is important, PEs are not Geurts et al, BCRT 2012

11 Detection of Early Recurrences Hypotheses: 1. Aggressive follow-up detects recurrences at an earlier stage 2. Early treatment of recurrences offers a better chance of cure, longer survival or improvement in QOL. However, data suggest that this is not the case

12 Detection of Early Recurrences Justifications: Early detection results in more effective treatment Patients are reassured does this improve quality of life? Investigational endpoint Monitor effectiveness of adjuvant therapy Disadvantages: Aggressive screening results in overtreatment of early disease Routine testing creates anxiety and need for additional tests Increased costs to patients without benefit

13 What is the Value of Intensive Diagnostic Followup? GIVIO study, JAMA 1994:271; Italian sites 1320 women < 70 yo, stage I-III breast cancer Treatment defined by nodal status Randomization Intensive follow-up with PE and LFTs (q 3m x 8 then q 6m), CXR (q 6m x 4), bone scan and liver US (q 12m) Control PE (q 3 m x 8 then q 6m), additional tests dictated by symptoms Both had annual mammograms Primary endpoints Overall survival Health Related quality of life

14 GIVIO Trial: Results Impact of Follow-up Testing 71 mo F/U Deaths (%) Med.Time to Met (mo) Intensive 132 (20) Control 122 (18) Distant mets Asymptomatic in 31% intensive, 21% control 69-79% presented with symptoms No difference in: Overall survival Quality of life

15 What is the Value of Intensive Diagnostic Followup (2)? Roselli Del Turco, JAMA 1994;271: women from 12 Italian sites Randomized: Intensive: MD visit, mammogram, CXR, bone scan q 6 mo Control: MD visit, mammogram Primary endpoint 5 year survival Results More thoracic and bone mets detected in intensive arm (112 v 70), no impact on survival #Distant Recurrences (%) Mortality (%) Intensive 164 (26.4) 18.6 Control 125 (20.1) 19.5

16 Primary Care vs Oncologist Observed for 4.5 yrs after diagnosis Primary endpoint: Recurrence-Related Serious Clinical Events (SCEs) Secondary endpoint: health-related QOL Family Practice Cancer Center Recurrences 54 (11.2%) 64 (13.2%) Deaths 29 (6.1%) 30 (6.2%) SCEs 17 (3.5%) 18 (3.7%) No difference in health-related QOL Grunfeld E et al. JCO 2006, JCO 2011

17 What is the Role of Tumor Associated Antigens? CEA, CA 15-3, CA Elevated in 30 65% of distant recurrences with lead time of about 4-6 months Measured every 2-3 months: Chan DW, JCO 1997

18 The Case Against! Patient outcomes are not improved by routine measurement of tumor antigens to detect early recurrence Average 5-month lead-time in diagnosis does not change treatment or outcome At least 2 clinical guideline expert panels independently recommend against routine monitoring Additional expense, reimbursement may be a challenge in some settings Generates patient anxiety and need for additional follow-up and testing

19 Consensus Recommendations for Follow-up Annual mammography (at least 6 months after breast radiation Other routine cancer screening Regular clinic visits for H and P Every 3-6 months for 3 years, every 6 months for 2 years, then yearly Health care maintenance Bone and cardiovascular health No routine testing (labs, tumor markers or imaging). Testing as indicated by clinical findings. Resources: NCCN.org ASCO guidelines, 2012 (ASCO.org/guidelines/breastfollowup) American Cancer Society

20 Monitoring and Treatment Symptom Hot flashes Sexual dysfunction (libido, dyspareunia) Weight gain Depression, fatigue Cognitive dysfunction Osteopenia/porosis Cardiovascular disease Thrombosis Secondary malignancies Management options SSRIs, SSNRIs, gabapentin Vaginal moisturizer, vaginal estrogen (on tamoxifen) or introitus Exercise (Daley et al, JCO 2007;25:1713), Diet Counseling, treat underlying cause, time Tools for improving function Calcium/vit D, weight bearing exercise, anti-osteoclast agents Monitor lipid panel, evaluate symptoms Family and personal history Screening, evaluate symptoms Hayes, NEJM 2007;356:2505

21 USPSTF Draft Recommendations 2013 National Lung Screening Trial 53, 454 patients at high risk for lung cancer At least 30 pack/years, age Three annual screenings with: Low dose CT or CXR Results High adherence (>90%) Rate of positive tests CT: 24.2% CXR: 6.9% False positives in 96% (CT) and 95% (CXR) Screening with CT resulted in a 20% relative reduction in mortality Annual low-dose chest CT screening recommended ages with at least 30 pack-years current or former smoker (within 15 years)

22 CIRCULATING TUMOR CELLS Transition state to metastasis? Minimal residual disease Accessible tumor cells for biomarker development Danila D C et al. Clin Cancer Res 2011;17:

23 Pooled Analysis of Prognostic Impact of Disseminated Tumor Cells in Bone Marrow: 10 yr Survival of 4703 Breast Cancer Patients Pooled analysis from 9 centers Prevalence of disseminated tumor cells (DTC) in bone marrow (BM) Breast Cancer Stage I-III Pts. No OMC in BM 3,265 (69%) OMC in BM 1,438 (31%) Braun et al, Cancer Investig 2009

24 Subgroups Cancer-specific survival Chemotherapy only 1,596 patients DTC-Prevalence 38% MR 2.34 (95%CI; ); p<0.001 Endocrine Treatment only 1,499 patients DTC-Prevalence 30% MR 2.05 (95%CI; ); p<0.001 T1N0, no systemic adjuvant treatment 1,499 patients DTC-Prevalence 38% MR 1.61 (95%CI; ); p=0.001 Prognotic value independent of tumor size, grading, receptor status with HR 3.83 (95% CI )

25 Conclusions DTC are a strong prognosticator for all endpoints Indicate early and multiple distant mets Strong prognosticator in all subgroups Value in T1N0 suggests role in cancer progression Consider DTC as a stratification factor in clinical trials? As a surrogate marker of therapeutic efficacy? What is the role of DTC in breast cancer progression? Most patients with CTC did not display overt metastasis Need predictors of behavior of DTCs Ongoing trials Denosumab (anti-rank ligand antibody)

26 Promoting a Healthy Lifestyle in Cancer Survivors: ACS Guidelines for Cancer Prevention Be as lean as possible throughout life (without being underweight). Balance caloric intake with physical activity. Avoid excessive weight gain throughout the lifecycle. Achieve and maintain a healthy weight if currently overweight or obese. Adopt a physically active lifestyle. Adults: at least 30 minutes of moderate-to-vigorous physical activity, on 5 or more days of the week minutes of intentional physical activity preferable. Consume a healthy diet, with an emphasis on plant sources. Choose foods and beverages in amounts that help achieve and maintain a healthy weight. Eat five or more servings of a variety of vegetables and fruits each day, choose whole grains in preference to processed Limit consumption of processed and red meats. If you drink alcoholic beverages, limit consumption. Drink no more than one drink per day for women or two per day for men.

27 Give all patients ASCO follow-up guidelines and document it! Cancer.net Discuss diet and exercise

28 Summary Follow-up for women with a history of early stage breast cancer should include breast imaging and periodic H/P Early follow-up important role for medical and psychologic reasons and to facilitate adherence Frequency of visits should be minimized Early detection of second primary cancers and perhaps LRR is beneficial Frequency of visits should be individualized Duplication should be avoided

29 Summary (2) Routine laboratory and imaging studies have not changed survival Very early detection of occult disease, new therapies could possibly change our approach Individualize approach in very high risk patients Cost effective follow-up strategies need to be developed and implemented Computerized input of symptom data with telephone follow-up Routine follow-up with nurse practioner/physician assistants Identification of patients at risk, and early intervention of high risk groups, is currently being studied