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Download Phase III Randomized Breast Cancer Lymph Node Study Likely to
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Elshami M Elamin, MD Medical Oncologist Central Care Cancer Center www.ccancer.com Wichita, KS - USA LN mets are the most significant prognostic indicator for breast cancer SLN biopsy can be used as an initial evaluation of the axilla in patients with clinically negative axillary nodes. No ALND Negative Stage I-II *SLN candidate SLN mapping Positive Yes ALND SN not identified *SLN involvement identified by H&E. *IHC for equivocal cases only *SLN +ve by routine IHC is not recommended in clinical decision making We all agree: ALND reliably identifies nodal mets ALND maintains regional control Agree Disagree Contribution of local therapy to breast ca survival Diagnostic and/or Therapeutic? LN –ve: 70-90% 5YS 10% chance of death in 10Y LN+ve: 50-70% risk of relapse 35% chance of death in 10Y 1-3 LN+ve: >4 LN+ve: 60-80% 5YS 30-50% 5YS 5 A meta-analysis of breast cancer pts showing that locally controlling breast cancer via ALND improve disease patient survival ALND remain the standard of care for breast cancer pts that have + SLN In the absence of definitive data showing superior survival from ALND. ALND should be considered optional in pts: Favorable tumors Unlike change of adj therapy Elderly Co-morbidities ALND risks: Restricted range of motion Pain discomfort Lymphedema Infection Seroma SLND Candidates: Clinically -ve nodes Solitary T1 or T2 ?? High grade/extensive DCIS No large hematoma or seroma No neoadjuvant chemo SLN can’t be identified or +ve: Formal axillary dissection 9 Lymphatic mapping: Blue dye = 83% success rate Lymphoscintigraphy = 94% Combined = 97% False –ve: 0-11% 10 Minimally invasive way to determine whether the axilla is involved Decision to eliminate nodal dissection in face of a negative SLN is being examined by large clinical trial. If SLN +ve proceed with complete nodal dissection 11 Definition: SLN metastases between 0.2mm and 2.0mm in size. It is considered negative by standard H&E, but positive by CK-IHC staining Clinical significance remains unknown ALND: Yes or No???? Treat as N0 or N1???? Hansen et al JCO 27:4679– 4684: pts with isolated tumor cells (ITCs) and pN0[i+] and pN1mi do not have worse 8-year DFS or OS compared with pN0 pts. Pts with SLN mes >2 mm (pN1) have significantly reduced survival. de Boer et al. NEJM 361:653–663: Pts with ITCs and pN1mi have reduced 5-year DFS NCCN: *SLN involvement identified by H&E. *IHC for equivocal cases only *SLN +ve by routine IHC is not recommended in clinical decision making *Prognostic Advantage *? DFS ALND risks When SLN positive !!! •NO Study conclusively demonstrated: •Survival benefit or •Detriment for omitting ALND SLND accurately identifies nodal metastasis of early breast cancer But it is not clear whether further nodal dissection affects survival The Current Standard •SLND alone: •If SLN is free of cancer •ALND: •If SLN contains cancer Q: Whether ALND affects overall survival in breast cancer with SNL metastasis or whether SNLD alone is sufficient? A: -------------------- Originally presented at the 2010 ASCO Annual Meeting Published on February 9, 2011, JAMA Randomized, multi-center, Phase III noninferiority trial Conducted at 115 sites (May 1999 to Dec 2004) I or IIA (891 pts) No palpable LN Randomized 1:1 SLND ALND or SLND alone Both groups had a lumpectomy and adjuvant systemic treatment Not eligible SLN by IHC > 3 positive SLNs Matted LNs Gross extra nodal disease Neoadjuvant therapy Age, stage of cancer, and tumor size did not vary significantly between the two groups The median number of LN removed in the ALND group was 17 compared with 2 in the SLND group The adjuvant systemic therapies received by both groups were comparable: 96% and 97% of the ALND and SLND patients The majority of pts received whole-breast RT To determine the effects of complete ALND on survival of patients with SLN metastasis of breast cancer OS was the primary end point, with a noninferiority margin of a 1-sided hazard ratio of less than 1.3 indicating that SLND alone is noninferior to ALND. DFS was a secondary end point. 5 year OS 0.7% absolute difference Favoring SLND SLND compared to ALND was not statistically inferior in terms of OS (P=0.008) The 5 YOS rates: 92.5% and 91.8% in the SLND-alone compared to the ALND DFS did not vary between the groups Morbidity: Wound infections Axillary seromas Lymphedema significantly more frequent in the ALND group Total Locoregional recurrence rate at 5 years •2.5% in SLND •3.6% in ALND Further F/U unlikely would result enough additional recurrences to generate aclinically meaningful survival difference The trial results suggest that women may be exposed to morbidity due to ALND with no meaningful improvement in overall survival, including women classified as high-risk (ER/PR -ve) Failure to achieve a target accrual of 1900 pts Potential randomization imbalance that favored the SLND-only cohort Follow-up was approximately 6 yrs and a longerterm follow-up would be beneficial, as earlystage breast cancer can reoccur at 10 to 15 years after diagnosis This data will likely change physician practice for early stage disease Caution: That the study results do not apply to early-stage pts with high risk for reoccurrence: Three or more positive SLN Larger tumors Those who received preoperative chemotherapy The results currently apply only to early stage breast cancer Tumors < 5 cm No clinically evident nodal involvement Lumpectomy/RT No MRM pts included in the study >95% received adj systemic therapy 1-2 positive SLN No extracapsular extension We have concerns about routinely omitting axillary dissection in younger women (under age 50), and cancers with particularly aggressive features, including those considered high grade In some cases, additional information about possible remaining lymph node involvement will be necessary to make decisions about chemotherapy or radiation, and further surgery may still be warranted According to Z0011 The only additional information gained from ALND is the number of involved LN Unlikely to change systemic therapy decison Z0011 results indicate that women with a positive SLN and clinical T1-2 undergoing L/RT systemic therapy do not benefit from ALND in terms of: Local control DFS OS Z0011 vs NSABP B04 Z0011 6 yrs f/u: No survival difference N+ve: 100% 5YS: > 90% First axillary failure in SLND: Only 0.9% Conclusion: High rate of locoregional control even without ALND NSABP B04 25 yrs f/u No survival difference N+ve: 40% 5YS: only 60% First axillary failure: 19% NSABP B04: N-ve pts: rad mastectomy vs total mastectomy + Nodal RT or Delayed Nodal RT for node recurrence Z0011 vs NSABP B04 Changes of breast cancer management during the interval between the 2 studies Improved imaging Detailed pathologic evaluation Improved planning of surgical and radiation approaches More effective systemic therapy The International Breast Cancer Study Group Trial of ALND vs Observation > 50% of pts did not receive breast or axillary RT Women >60 on adj Tamoxifen and No axillary treatment: Axillary recurrence was only 3% OS was 73% (median F/U of 6.6Y) For which pts is the ALND remains the standard of care? Pts with positive SLN and: 1. 2. 3. 4. 5. Mastectomy Lumpectomy without RT Partial breast RT Neoadjuvant therapy Whole breast RT in the prone position (low axilla is not treated) These findings should encourage new and continuing dialogue between physicians and breast cancer patients and their families regarding the most appropriate treatment options available
