Welcome to. American College of Surgeons. Clinical Research Program (ACS-CRP) Breast Surgical Trial Webinar

Transcription

1 American College of Surgeons Clinical Research Program Kelly K. Hunt, M.D. Program Director Welcome to American College of Surgeons Clinical Research Program (ACS-CRP) Breast Surgical Trial Webinar Moderator: Judy C Boughey MD, FACS

2 Alliance/ACS Clinical Research Program Improve cancer care outcomes through high-quality health services research that leverages the multidisciplinary collaboration and research infrastructure of the Alliance and its partners to generate new knowledge and facilitate the implementation and dissemination of research findings throughout the oncology community Improve oncological surgical practice through dissemination of best practices and clinical trial findings Increase interaction and integration between the Alliance, the ACS, and the Commission on Cancer

3 An Integrated Model Alliance for Clinical Trials in Oncology ACS CRP American College of Surgeons Cancer Care Delivery Research: Knowledge Generation Standards Committee: Implementation Education Committee: Dissemination Dissemination & Implementation Committee: Engagement

4 Trials Alliance A011202: A Randomized Phase III Trial Comparing Axillary Lymph Node Dissection to Axillary Radiation in Breast Cancer Patients (ct1-3 N1) Who Have Positive Sentinel Lymph Node Disease After Neoadjuvant Chemotherapy. Presenter: Judy C. Boughey, M.D. & Bruce Haffty, M.D. NSABP B-51/RTOG 1304 (NRG 9353): A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy Presenter: Julia White, M.D.

5 A A randomized phase III trial comparing axillary lymph node dissection to axillary radiation in breast cancer patients (ct1-3 N1) who have positive sentinel lymph node disease after receiving neoadjuvant chemotherapy Judy C. Boughey MD, Bruce G. Haffty MD, Thomas Buchholz MD, W. Fraser Symmans MD, Kelly K. Hunt MD, Jane Armer, PhD, RN, Vera Suman PhD

6 Study Objectives Objectives: To evaluate whether radiation to the undissected axilla and regional lymph nodes is not inferior to axillary lymph node dissection with radiation to the regional lymph nodes but not to the dissected axilla in terms of: invasive breast cancer recurrence-free interval (primary) the incidence of invasive loco-regional recurrence (secondary) Other secondary objectives: Examine distribution of Residual Cancer Burden scores in each treatment arm Estimate overall survival in each treatment arm

7 Inclusion Criteria Female or male 18 years old T1-3, N1, M0 clinical stage Axillary FNA or core biopsy documenting nodal disease Invasive breast cancer ER, PR, Her2 testing on breast tumor core biopsy Completed at least 4 cycles of neoadjuvant chemo Her2 positive disease must have received anti-her2 therapy Negative axilla on physical exam after completion of neoadjuvant chemotherapy (NAC) clarified : no bulky adenopathy Surgery performed 56 days after NAC completion

8 Exclusion Criteria Inflammatory breast cancer or any ct4 Clinical N2 or N3 disease at presentation Neoadjuvant endocrine therapy or radiation Previous ipsilateral axillary surgery SLN surgery or excisional biopsy of axilla prior to or during NAC History of or concurrent contralateral invasive breast cancer Pregnant or lactating

9 Schema for patients who pre-register prior to SLN surgery Arm 1 ALND level I and II LNs RT to the breast (BCS) or chest wall (mastectomy) Regional nodal irradiation level III LNs and supraclavicular fossa Arm 2 No ALND RT to the breast (BCS) or chest wall (mastectomy) Regional nodal irradiation to level I, II, III LNs and supraclavicular fossa

10 Schema for patients who pre-register AFTER surgery (where SLN was performed but ALND was not)

11 Arm 1 Treatment of the Axilla ALND level I and II LNs RT to the breast (BCS) or chest wall (mastectomy) Regional nodal irradiation level III LNs and supraclavicular fossa Arm 2 No ALND RT to the breast (BCS) or chest wall (mastectomy) Regional nodal irradiation to level I, II, III LNs and supraclavicular fossa

12 Additional radiation details All patients (mastectomy or BCS) get radiation to: Breast or chest wall Internal mammary Supraclavicular and level 3 nodes Arm 1 receives dissection without radiation to the dissected axilla (unless there is a heavy axillary burden on dissection) Arm 2 receives no dissection with radiation to the level 1 and 2 nodes

13 Radiation for Arm 1

14 Radiation for Arm 2

15 Stratification Factors Tumor subtype: TN vs. Her2+ vs. HR+ & Her2- ct stage: ct1 vs. ct2 vs. ct3 Breast surgery: BCS vs. mastectomy Intending to administer adjuvant chemotherapy: Yes vs. No Removed: Number of positive LNs: 1-2 vs. 3+ as a strat factor

16 Clips in axillary lymph nodes Placement of a clip in the lymph node at diagnosis Allowed / Not required Localization of the clipped lymph node at diagnosis Allowed / Not required If clipped node is localized Evaluate if blue and/or radioactive if yes document and submit as SLN If not submit as localized lymph node and counts as a sentinel node in terms of protocol requirements If clipped node is not localized X-ray specimen to document whether clipped node is excised

17 Breast tumor: Surgical / Pathology aspects Require negative margins (no tumor on ink) around breast primary Sentinel Nodes: Minimum of 1 LN with a metastasis with largest dimension > 0.2 mm identified on intra-operative pathologic assessment. Maximum of 6 LN resected by surgeon Maximum of 8 LN seen by pathologist ALND: Arm 1 pts minimum of 8 LNs for SLN +ALND

18 Sample Size Enrollment: 2918 patients preregistered over 6 years to obtain 1576 patients with positive SLN Follow-up after close of enrollment: 5 years Assume 5 year RFI = 63% for ALND and nodal RT (Arm 2) Non-inferiority HR % power to reject that nodal RT alone (Arm 1) is inferiority to ALND + nodal RT (Arm 2) in terms of RFI

19 Correlative Science Assessment of arm and breast lymphedema (A11202-SII): [Only patients who pre-register prior to surgery] To estimate the incidence of arm lymphedema by treatment arm. To estimate the incidence of breast lymphedema for patients who underwent breast conserving surgery by treatment arm. To assess whether the incidence of arm lymphedema is decreased for those patients who receive radiation therapy alone relative to those who receive both axillary lymph node dissection and radiation therapy.

20 Lymphedema Assessment BMI and bilateral arm circumference measurements Lymphedema Signs/Symptoms Checklist (LBCQ) Breast Lymphedema Symptom Survey (for patients who complete BCT) After pre-registration / before surgery After completion of XRT Every 6 months for 2 years Annually to 5 years

21 Amendment # 7 Allow up to 8 weeks of neoadjuvant endocrine therapy prior to onset of neoadjuvant chemotherapy. Patients may receive adjuvant chemotherapy, novel therapeutics, targeted agents, biologic therapy or vaccine therapy AFTER the completion of RT, at the discretion of the treating physician. Patients may be treated with 3D CRT, IMRT or proton beam.

22 Pre-registration As of Nov Pre-registered = 1943/ (66.6%) Registered = 860/1576 (54.6%) Pre-registering around 60 patients per month (target of 40/month) Registering around 30 patients per month (target of 22/month) Memorial Sloan Kettering Cancer Center 80 M D Anderson Cancer Center 73 Carolinas Medical Center/Levine Cancer 56 Institute Parkland Memorial Hospital 55 University of Kansas Cancer Center 52 Froedtert and the Medical College of 38 Wisconsin William Beaumont Hospital Royal Oak 37 University of Pittsburgh Cancer Institute (UPCI) UT Southwestern/Simmons Cancer Center- Dallas 37 35

23 Pre-reg by Co-operative Group Alliance 1325 NRG 334 SWOG 144 ECOG-ACRIN 96 CCTG 42 NCIC-CTG 2 Total Accrual 1943

24 FAQ Biopsy of intramammary nodes does not fulfill eligibility criteria An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility. Number of positive SLNs does not impact eligibility. Note Study PI and study team are NOT allowed to provide exceptions to anything written in the protocol

25 Questions Judy Boughey (PI) Bruce Haffty (Rad Onc chair) Tracy Rieken (Data Manager) Heather Becker (Protocol Coordinator) Sheri Ramaker (Nursing Contact)

26 Sister Studies ALLIANCE A11202 Schema Clinical T1-3 N1 M0 BC Neoadjuvant Chemotherapy BCT or Mastectomy Sentinel Lymph Node Surgery SLN Negative Randomization SLN Positive NSABP B-51/RTOG 1304 (NRG 9353) Schema Clinical T1-3 N1 M0 BC Axillary nodal involvement (FNA or core needle biopsy) Neoadjuvant chemo (+ Anti-HER-2 therapy for HER-2 neu pts) Definitive surgery with histologic documentation of negative axillary nodes (either by axillary dissection or by SLNB ± axillary dissection Stratification Type of surgery (mastectomy vs lumpectomy) ER status (+ vs -), HER-2 status (+ vs -) pcr in breast (yes vs no) ALND Breast/chest wall and nodal XRT (without RT to dissected axilla) No further axillary surgery. Breast/chest wall and nodal XRT No Regional Nodal XRT with breast XRT if BCS & No chest wall XRT if mastectomy Randomization Regional Nodal XRT with breast XRT if BCS and chest wall XRT if mastectomy

27 NSABP B-51/RTOG 1304 A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy Protocol Co-Chairs: Protocol Officer: Behavioral and Health Outcomes Officer: Protocol Statistician: Behavioral and Health Outcomes Statistician: KEY STUDY PERSONNEL Terry Mamounas, MD, MPH (NSABP) Julia White, MD (RTOG) Thomas Julian, MD Patricia Ganz, MD Joseph Costantino, DrPH Hanna Bandos, PhD

28 Background NC down-stages involved axillary nodes in up to 40%-60% of pts For such patients, there is an active debate on the appropriate use (and extent) of locoregional XRT after mastectomy or BCS Argument for XRT: Presentation with known positive axillary nodes Increased risk for LRR Should receive comprehensive XRT Argument against XRT: Sterilization of involved axillary nodes by NC Lower risk for LRR Need for comprehensive XRT questionable

29 NSABP B-51/RTOG 1304 Clinical T1-3N1M0 BC Axillary Nodal Involvement (FNA or Core) NC (+ Anti-HER-2 Therapy for HER-2 +) Negative Axillary Nodes at Surgery Stratification Type of Surgery (Mastectomy vs. Lumpectomy) ER-Status (+ vs. -), HER-2 Status (+ vs. -) pcr in Breast (yes vs. no) Randomization No Regional Nodal XRT with Breast XRT if BCS and No Chest Wall XRT if Mastectomy Regional Nodal XRT with Breast XRT if BCS and Chest Wall XRT if Mastectomy

30 Primary objective: To evaluate whether the addition of XRT will significantly reduce breast cancer recurrence in node + pts who convert to path node (-) after NC Secondary objectives: Objectives To evaluate whether the addition of XRT will:»prolong overall survival»reduce loco-regional recurrence»reduce distant recurrence»affect cosmetic outcomes of reconstruction»affect QOL after postmastectomy reconstruction»treatment Adequacy: 3DCRT for nodal RT

31 Eligibility Eligible pts must fulfill all of the following criteria: Clinical T 1-3 N 1 M 0 BC at presentation Histologic confirmation of axillary nodal involvement by FNA or CNB Completed at least 8 weeks of NC with an anthracycline and/or taxane-based regimen (+ neoadjuvant anti-her-2 therapy for HER-2 + pts) At the time of surgery, all removed axillary nodes must be histologically free from cancer Known ER/PR and HER-2 neu status from the original CNB before NC

32 B-51: Protocol Status Protocol activation: Study sample size: 1636 Total Accrual as of 9/30/17: 786 (48%) Average monthly accrual*: Quarterly Accrual *Over past 3 months Q2013 1Q2014 3Q2014 1Q2015 3Q2015 1Q2016 3Q2016 1Q2017 3Q2017

33 Recent Amendment The minimum required weeks of NC changed to from 12 to 8 weeks to allow more chemotherapy regimens Protocol no longer indicates a type of anti-her2 therapy for HER2-positive patients Imaging requirements for metastatic workup for Stage II to be performed at the investigator's discretion Interval between last surgery/last chemotherapy treatment and randomization extended from 56 to 70 days to allow additional time to recover from surgery or chemotherapy treatment Radiation plan reviews and credentialing requirements simplified Quality assurance remained the same.

34 B : Q/A Strives for Consistency in Radiotherapy within Each Arm CT based - DVA driven radiation CT Treatment Planning for regional nodal therapy for breast cancer 3DCRT or IMRT ( institution choice) Target volumes and normal structures delineated for planning Radiation plans evaluated by Dose Volume Analysis Planning goal is to meet per protocol or variation acceptable constraints.

35 Radiotherapy QA Review: Targets, OAR and Dose Distribution

36 Questions? Terry Mamounas Julia White Thomas Julian Questions concerning eligibility and clinical aspects of the trial NSABP Operations Center Clinical Coordinating Division Phone: Questions regarding radiation therapy treatment RTOG RT Quality Assurance Phone: