Systemic Adjuvant therapy guidelines

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by Elshami Elamin, Consultant Oncologist, Wichita, KS

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Systemic Adjuvant therapy guidelines

  1. 1.  Operable disease: › Primary treatment (surgery and RT):  Improves locoregional control  Improves OS  Reduces tumor burden  decreases risk of chemoresistance
  2. 2.  Despitesurgery/RT distant mets remains predominant failure  Metastasis usually associated with node involvement 5
  3. 3.  Pts with ER/PR+ve invasive breast ca should be considered for adj endocrine therapy regardless of age, LN status, or whether or not adj chemo is to be administered. › Possible exception:-  Pts with so favorable prognosis (LN-ve, < 0.5 or 0.6- 1 cm with favorable prognostic features ) where the benefits of adj endocrine therapy are very small. Her2 amplification is a marker of relative endocrine resistance 1/3/2013 7
  4. 4.  Decreases the annual odds of recurrence by 39% and th annual odds of death by 31% 1/3/2013 8
  5. 5.  Extended Trial; following 4.5-6 yrs of Tam  MA-17 (NCIC CTG): Initial adj Trial:  ATAC Sequential Trials; following 2-3 yrs of Tam  Breast International group (BIG) 1-98  Intergroup Exemestane Study (IES)  Austrian Breast and CRC study Group (ABCSG) trial 8  Arimidex Nolvadex (ARNO 95) trial  Italian Tam Anastrozole (ITA) 1/3/2013 9
  6. 6.  Tam X4.5-6y  Letrozole or placebo X5y Letrozole after 4.5-6 yrs of adj Tam  reduces recurrence in both N - & N+ve  reduces contralateral cancer  No diff in OS  Survival advantage in N+ve pts 1/3/2013 10
  7. 7.  100 months follow-up in 5,216 pts: › Arimidex improve Recurrence rates (P=0.003) › No diff in survival (p=0.2) Combined: › No benefits over Tam  Possible deleterious effects from the weak estrogenic effects of Tam in pts with near complete elimination of endogenous estrogen Arimidex vs Tam: › Similar in QoL › 60% vs 50% risk of reduction in contralateral breast ca. › Arimidex:  Lesser effect on endometrial tissue  Greater loss of bone mineral density 1/3/2013 11
  8. 8.  Tam X5y vs Let X5y vs Tam X2y  Let X3y vs Let X2y  Tam X3y  DFS superior in Let arm (P=0.003)  No diff in OS  No diff in overall cardiac AE  However, G3-5 cardiac AE sig higher in Let arm  Overall and G3-5 VTE sig higher in Tam arm  Higher incidence of bone fracture in Let arm 1/3/2013 12
  9. 9.  Tam X5y or switch to Exem after 2-3y of Tam  55.7 months F/U:  Tam/Exem improves DFS (P=0.0001)  Tam/Exem sig improves OS in pts with only ER+ 1/3/2013 13
  10. 10.  Tam X5y or switch to arimidex after 2y of Tam  28 months F/U:  EFS superior in Tam/Arimidex (P=0.0009)  No diff in OS ARNO 95 alone:  58 months F/U:  Tam/Arimidex sig improves both DFS and OS (P=0.045) 1/3/2013 14
  11. 11.  Tam X5 or switch to Anastrozole after 2- 3y of Tam  Hazard rate for relapse strongly favored Tam/Anast (P=0.001) 1/3/2013 15
  12. 12.  Significant improvement in OS (p=0.04) with switch to Arimidex 1/3/2013 16
  13. 13.  The differences in design and pts populations among the studies of A.Is. do not allow for direct comparison of the results of these studies. › Thus, it is unknown whether initial, sequential, or extended use of adj A.Is. is the optimal strategy. › The optimal duration of A.I. is also not known 1/3/2013 17
  14. 14.  Third generation A.Is. (initial, sequential, or extended adj) in postmenopausal receptor positive breast cancer pts; in comparison to Tam; lower:  ipsilateral risk of recurrence  risk of contralateral breast cancer  Risk of mets  Tam should be limited to women who decline or have contrindication to A.Is. No compelling evidence that they are meaningful efficacy or toxicity differences between Anastrozole, Letrozole, and Exemestane 1/3/2013 18
  15. 15. 1/3/2013 19
  16. 16.  Early Breast Cancer Trialists (overview of polychemo): › Anthracycline-based vs CMF  12% further reduction in annual odds of recurrence (P=0.006)  11% further reduction in annual odds of death (P=0.02)  Anthracycline-based regimen is preferred for N+ especially Her2+ 1/3/2013 20
  17. 17.  Anthracycline vs non-Anthracycline:  12% proportional odd risk reduction of recurrence  11% odd risk reduction of death  Absolute gain in survival;  4% in N+ve  1.7% in N-ve Anthracycline benefits the most:  Her2-neu +ve  Topoisomerase lla +ve 21
  18. 18.  Randomized trials: › ACx4 vs CMF  Equivalent RFS and OS
  19. 19.  Two randomized trials in N positive: › CEF-120 vs CMF:  10y RFS 52 vs 45% (P=0.007)  OS 62 vs 58% (P=0.085) › FEC-100vs FEC-50:  5y DFS 66 vs 55% (P=0.03)  OS 76 vs 65% (P=0.007) 2 doses levels of EC vs CMF in N positive:  Higher dose EC equivalent to CMF and superior to moderate dose EC in DFS and OS 1/3/2013 23
  20. 20.  AC +/- sequential Taxol in N+  CALGB 9344 and NSABP B-28 suggest Taxol improved DFS  NSABP B-28 showed Taxol improved OS  Retrospective analysis; greater benefits in ER negative 1/3/2013 25
  21. 21.  Concurrent vs Sequential, (CALGB 9741): › D  T  C vs AC  T q2wks + GCSF or q3wks  No sig diff between concurrent vs sequential  Dose Dense q2wks + GCSF:  26% reduction in hazard of recurrence (P=0.01)  31% reduction in hazard of death (P=0.013) 1/3/2013 26
  22. 22.  TAX316 (Adj TAC vs FAC ) LN +ve:  5y DFS 75 vs 68% (P=0.001)  5y OS 87 vs 81% (P=0.008  TAC  improves DFS; sig  improves OS 27
  23. 23.  TAC vs AT vs AC  Taxotere › 73 months F/U:  AC  T has sig advantage in DFS (P=0.006) Not in OS when compared with TAC  AC T is better than AT (improves DFS and OS  AT not inferior to TAC 1/3/2013 28
  24. 24. › AC-Tere+/-Herceptin  Herceptin arm reduces risk of relapse by 51%› Taxotere/Carbo + Herceptin  reduces risk of relapse by 39% compared to AC-T  Lower cardiac toxicity› No sig diff in risk of relapse between AC-TH and TCH 29
  25. 25.  FEC x6 vs FECx3  Doce x3 in N+  5y DFS and OS were superior with FEC/Doce However A large randomized study: FEC x4  Doce x4 vs standard Antracycline regimens (FEC or E CMF)  No sig diff in DFS 1/3/2013 30
  26. 26.  AC  Taxol wkly or q3wk vs AC Doce wkly or q3wk › 63.8 m F/U:  Wkly Taxol superior to q3wks Taxol in DFS and OS  3wk Doce superior to 3wk Taxol in DFS not in OS  Based on these and Dose dense trial; The 3wk taxol was removed from NCCN quidelines 1/3/2013 31
  27. 27.  TC vs AC (stage I-III): › 7y F/U:  DFS 81 vs 75% (P=0.033)  OS 87 vs 82% (P=0.032) 1/3/2013 32
  28. 28.  Retrospective studies evaluated effect of chemo on ER +ve undergoing endocrine therapy vs ER negative not undergoing endocine therapy:  Benefits of chemo are sig greater in ER negative disease 1/3/2013 33
  29. 29.  Trastuzumab is a humanized, monoclonal antibody with specificity for extracellular domain of human epidermal growth factor receptor-2 (Her2-neu) 1/3/2013 34
  30. 30. 1. NSABP-B31: AC [60mg, 600mg] q3wkx4  Taxol 175 q3wkx42. NCCTG-N9831): AC [60mg, 600mg] q3wkx4  Taxol 80 qwkx12 › Herceptin wkly x52 concurrent with Taxol (also given sequential in one arm in NCCTG)  Concurrenr Taxol/Hercp is more effective than the sequential › R+ve received Adj hormone › JOINT ANLYSIS (3968 pts) at 4 yrs F/U:  Hercp reduce risk of recurr by 52% (P=0.0001)  Hercp reduce risk of death by 35% (P=0.0007)  Similar effects on DFS observed when results analyzed seperately  CHF risk increased by 3-4%3. HERA (5,081 pt) [Hercp q3wk x12 or 24m vs observation following standard adj chemo] › Hercp X12m:  sig improve DFS with 46% reduction in recurrence  One yr analysis: No diff in OS but 2 yrs analysis showed OS benefit (P=0.0115)4. BCIRG 006 (ACTere+/-Her vs TCH) › After 36 months F/u:  No sig diff in DFS between ACTH and TCH  ACTH and TCH showed Survival advantage over ACT  Cardiac Toxicity is sig lower in TCH arm5. FinHer trial (Vinorelbine or Doce X3 +/- Herceptin X9wk  FECx3 › 3Yr F/U:  Herceptin reduced risk of recurrence (P=0.01), No diff in OS or cardiac toxicity 1/3/2013 35
  31. 31.  All of the five Herceptin adj trials have demonstrated sig improvements in DFS Joint analysis of NSABP-B31/NCCTG-N9831 and HERA showed sig improvement in OS with the use of Herceptin in high risk Her2 +ve breast cancer The benefit of Herceptin is independent of ER status NCCN:  Recommends Herceptin + Chemo for Her2 +ve tumors >1cm  TCH preferred regimen especially in pts with risk for cardiac toxicity  Consider Herceptin for N-ve 0.6-1 cm tumors 1/3/2013 36
  32. 32.  528 pts with Her2+ve, N+ve: › Herceptin vs observation following completion of adj anthracycline-based chemo +/- Doce:  No sig diff in DFS or OS  Sequential Herceptin and chemo is not effective 1/3/2013 37

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