adjuvant chemotherapy in breast cancer.pptx

adjuvant chemotherapy in breast carcinoma

1. Chemotherapy in Breast Cancer By Dr Gunjan Singhal https://cctansurgery.com.sg/breast-cancer-symptoms-and-early-warning-signs/

2. Adjuvant and Neo-adjuvant Therapies Theories of breast cancer pathogenesis Predicting risk of recurrence Estimating benefit of treatment Tailoring the treatment

3. Breast cancer theories In 1894, Halstead theory: Cancer progressed in a continuous manner Direct extension from primary tumor via lymphatics, to LN and then to distant sites Implication: radical breast Sx Fischer hypothesis: “Breast cancer was a systemic disease in that tumor cells were likely to have been disseminated throughout the body by the time of diagnosis and that more expensive locoregional therapy was unlikely to improve survival".

4. Principles of Chemotherapy Norton and Simon Hypothesis Gompertzian model - Ability to exhibit exponential decay of relative tumor growth rates -> tumor cell growth rates decrease as a function of time Smaller tumors grow faster than larger ones Rate of cell kill by many drugs is proportional to tumor growth rates Tumor given less time to regrow between treatment are more likely to be destroyed High density dosing - improved survival

5. Early administration of Chemotherapy Smaller tumou r Higher Growth Fraction Higher sensitivity to Cth Higher log kill  Better response

6. If an individual drug dose leads to a 2 log kill of cancer cells and reduces the tumor burden from 10 10 to 10 8 cells, the same dose used at a tumor burden of 10 4 cells reduces the tumor mass to 10 2 . Cell kill is therefore proportional, regardless of tumor burden.

7. Skipper’s Law Exponential Tumor Growth: ‘Doubling time of proliferating cancer cells is a constant, forming a straight line on a semilog plot’. A single cell is capable of multiplying & eventually killing the host. Anticancer drugs act with first-order kinetics. Assuming homogeneous sensitivity. Skippers experiment was done in murine leukemia L1210 cell model , in 1964.

8. Breast Cancer responsive to a whole cohort of cytotoxic agents Anthracyclines (e.g. Doxorubicin, Epirubicin, Pegylated Liposomal Doxorubicin) Taxanes (e.g. Paclitaxel, Docetaxel, Nanoparticle Albumin-Bound Paclitaxel) Cyclophosphamide, Gemcitabine Platinum salts (e.g. Cisplatin, Carboplatin) Methotrexate (MTX) 5-Fluorouracil or oral Capecitabine) Choice of the regimen has to balance between oncological outcomes and toxicity profile.  Multidrug Chemotherapy - Standard of Care →  High response, Low toxicity, Less chance of drug resistance.

9. Systemic therapy in Breast Cancer- Goals Adjuvant treatment : - Decrease risk of recurrence - Improve survival Neoadjuvant treatment : - Convert locally advanced, inoperable to operable tumours - Facilitate breast conservation Palliative treatment : - Relieve symptoms - Improve QOL - Prolong survival

10. Role of NACT In OBC: To facilitate breast conservations Patients most likely to be converted to BCT with neoadjuvant chemotherapy are those with: unicentric, higher grade, HER2-positive, or triple-negative cancers. TNBC & Her-2 positive: pCR rates exceed 50% In LABC: Tumor downstaging  improves operability/enables definitive surgery. Opportunity to individualize (tailor) subsequent therapy. Endpoint for NACT: PCR (if good surrogate for oncological outcome) Meta-analysis: PCR substantially improves EFS & OS in individual patients ( esp in her-2 & TNBC); patient with PCR shows better outcome than who does not. But, PCR was not validated as a surrogate endpoint for long term outcome.

11. Adjuvant chemotherapy : How to decide? Step 1:- risk of recurrence?? Step 2:- risk reduction from chemotherapy?? Step 3:- patients comorbidities, tolerance to chemotherapy Step 4:- shared decision regarding role of adj. chemotherapy

12. Factors guiding decision Patient Related Tumour Related Age Comorbid conditions Performance Status Patient preference Risk benefit discussion Treatment affordability Tumour Size Her2-Neu status Lymph node status ER/PR Status Grade of Tumour Genomic expression 

13. Based on St Gallen’s 2017 Classification

14. Adjuvant chemotherapy in breast cancer Polychemotherapy vs no adjuvant therapy Anthracyclines vs no anthracyclines Taxanes vs no taxanes 3 weekly vs dose dense 18

15. Classification of adjuvant chemotherapy regimens:-

16. History of adjuvant chemotherapy B- 01 (1958-1961) - Thiotepa vs Placebo. Short course perioperative. Advantage in premenopausal and > 4 nodes positive. B- 05 (1972- 1975) - L-PAM (L -Phenylalanine mustard, Melphalan) for node positive orally for 2 years. 8% DFS and 5% OS advantage in < 50 yrs at 10 years. Gianni Bonadonna et al (1973-1976)- CMF was evaluated as Adj treatment to radical mastectomy. Relapse in control arm 27 % and experimental arm 5%

17. EBCTCG 2011- Outcome at 10 yr CMF vs no chemo Anthracycline vs no chemo Anthracycline (higher cumulative dose > 240 mg/m2 ) vs CMF Standard dose anthracycline vs CMF has no improvement in risk recurrence, cancer mortality

18. 3-year DFS rates : (62 % vs 63 %; P = 0.5) 3-year OS rates : (83 % vs 82 %; P = 0.8)

19. Conclusions 4 AC = 6 CMF Triple Drug Anthracycline Regimens are superior to CMF in OS Dose of Anthracycline Doxorubicin - 40 to 60 mg/m2 Epirubicin - 75 to 90 mg/m2 Magnitude of Benefit similar across all subgroups

20. ERA OF TAXANES

21. CONCURRENT VS. SEQUENTIAL 34

22. N ew E ngland J ournal of M edicine 2008 Pacli (q3w vs q1w) Doce (q3w vs q1w) 35 dose/cycle Total dose (mg/m2) (mg/m2) 175 700 80 960 100 400 35 420 Pacli vs. Doce

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25. 39 DFS OS

26. POOLED ANALYSIS OF DFS & OS 42 Taxane administration resulted in an absolute 5-year risk reduction of 5 % for DFS and 3 % for OS TC was associated with significant improvement of DFS ( 81 % vs 75% , p=0.033) • TC was also associated with significant improvement of OS ( 87% vs 82% , p=0.032) • TC was superior irrespective of age, HR status , HER-2 status or treatment

27. When to use TC Low risk (Node negative, ER +VE) Contraindication to anthracycline No evidence to say TC better than a combination of anthracycline and taxanes No evidence to say TC better or equal to 6 cycles FAC/FEC

28. Increasing Dose Intensity - Is there a role ? Escalating Doses (did not work in breast cancer ) to shorten the interval between treatment cycles (dose-dense chemotherapy) or to administer individual drugs in sequence (sequential scheduling), which allows higher doses to be used in each cycle than is possible with combined administration of the same drugs (concurrent scheduling)

29. Established role of chemotherapy in adjuvant setting Better results with anthracyclines Establised superiority of sequential taxones based combination Dose dense chemotherapy as an alternative option

30. Conclusion Compared to Anthracycline - Addition of a Taxane reduces Risk of Recurrence Mortality Risk Magnitude of benefit similar across all subgroups Sequential vs Concurrent Better DFS and OS Better Tolerated Weekly Paclitaxel improved DFS and OS compared to other taxane regimens Weekly Paclitaxel and 3 weekly Docetaxel are comparable regimens Consider weekly Paclitaxel in Triple Negative Breast Cancers 4TC > 4 AC = 6 CMF Dose Dense Regimens in the high risk patients

31. Predicting benefit from chemotherapy EBCTCG metanalysis involving taxane -based or anthracycline-based regimens, proportional reductions in risk of recurrence associated with adjuvant chemotherapy were little affected by age, nodal status, tumor diameter or grade, ER expression, or tamoxifen use, and breast cancer mortality was reduced on average by one-third. Several multiparameter gene expression assays have been shown to provide prognostic information in patients with ER-positive breast cancer and also identify which patients derive greatest benefit from adjuvant chemotherapy. Currently available assays include the Oncotype DX®

32. Do all patients require adj CT How to select adj systemic treatment

33. NEOADJUVANT CHEMOTHERAPY Facilitate BCS ( eg where large tumor in small breast) Convert inoperable tumors to operable (T4/ bulky N2/N3) Potential advantage of treating micro-metastatic disease. 55

34. Indication of Neoadjuvant systemic therapy Inoperable disease : Pt with LABC Large tumors (>5 CM) Extensive axillary LN involvement Her 2 positive breast cancer TNBC Inflammatory breast cancer

35. Adjuvant vs Neoadjuvant chemotherapy EBCTCG 2018 Effect of NACT was more in larger tumors (2-4cm) & less significant for smaller tumors (<2cm) Proportional increase in LR did not vary significantly by tumor size or chemotherapy regimen 57

36. 58 Patients who attain pCR defined as ypT0 ypN0 or ypT0/is ypN0 have longer EFS and OS than pt with residual cancer. pCR substantially improved outcome in TNBC and HER 2 positive patients

37. Tailoring the optimal regimen for individual patients Factors considered in selecting patients for adjuvant therapy:- -tumor size -axillary node metastasis -tumor biology (i.e. ER/PR and HER2 expression) -multiparameter gene expression assays) -patient specific factors -age, comorbidities, patient’s preference.

38. Tailoring treatment – tumour biology

39. TNBC

40. TNBC No targeted therapy option Poor prognosis Relapse pattern : - short disease free interval - increase in visceral mets - CNS mets common

41. Management of Non Metastatic TNBC Anthracycline and Taxanes remain the standard of care Dose Dense Chemotherapy improvement in PFS and OS Role of Maintenance ? Capecitabine ? Cyclophosphamide and MTX Role of Addition of Carboplatin

42. Maint CREATE X GEICAM/2003-11_CIBOMA/2004-01 SYSUCC-001  IBCSG 22-00 Patient Population 32% TNBC Those NOT achieving Path CR after NACT TNBC, LN neg-54%, 75% Basal Like TNBC Node Negative-61% 75% TNBC LN – 56 % Previous Anthracycline and Taxane 80% 67% 81% 28% Intervention-Capecitabine 1250 mg/m2 BD D1-14X 6-8 cycles (6 months) 1000mg /m2 BD D1-14q21X 8 cycles (6 months) 650mg/ m2 continuous X 1 year Cyclo 50 mg OD MTX 2.5 mg BD D/1/2 once a wkX1yr DFS %@ 5 yrs 70 vs 56 79 vs 77 (Non basal- 83 vs 73 ) 83 vs 73 ( HR N- 0.37 , N+ 0.82) 79 vs 75 (LN po- 73 vs 65 ) OS % @ 5yrs 78 vs 70 86.2 vs 85.9 (Non basal- 90 vs 80 ) 85 vs 81 Compliance to Treatment Relative Dose Intensity-87% ( 37% completed 8cycles at planned dose) 75% completed all 8 cycles 85% 89 % -C 60% -MTX Toxicity 73% HFS 70% HFS 45% HFS ALT-7%.Leuco-2% AML -2 pts

43. Maintenance Therapy Capecitabine Early Stage , Node Negative ??? – Observe LABC , Residual disease post NACT – Consider Capecitabine Better patient Selection- Biology – Non Basal Subtype Cyclophosphamide + Methotrexate _RCT showed no benefit, More data needed/awaited

44. Platinum Neoadjuvant /Adjuvant Increased pCR Increase in pCR in all subtypes (basal vs Non basal) gBRCA – No additional Benefit of Carboplatin ?? Improving DFS ???

45. Platinum Gepar Sixto CALGB40603 BRIGHTNEss Patient Population Stage II/ III TNBC Stage II /III TNBC Stage II/ III TNBC Control 18 w Pacli 80 mg/m2 Peg Liposomal Doxo20 mg/m2+ Bev Weekly Pacli X 12 ddAC Weekly Pacli X12 AC q 2/3 weekly Intervention-Platinum Carboplatin AUC 1.5w Carboplatin AUC 6 X 4 +/- Bev Carboplatin AUC 6 q 3 X4#+- Veliparib Path CR 57 vs 41 54 vs 41 (carbo v no) 58 vs 31 (carbo vs no) Veli-53 Carboplatin –Basal & Non basal DFS DFS rate -85 vs 73 EFS HR -0.99 OS Compliance to Treatment Dose Discont- 48 vs 39 >2 doses missed 36 vs 16 % Toxicity G3/4 T-14 vs < 1 N-65 vs 27% T 20 vs 4 N 56 vs 22 T-12 N-56

46. KEYNOTE-355: Addition of Pembrolizumab to First-line Chemotherapy in Advanced TNBC Randomized, double-blind, multicenter phase III trial Cortes. ASCO 2020. Abstr 1000. Cortes. Lancet. 2020;396:1817. Slide credit: clinicaloptions.com Adults with previously untreated locally recurrent inoperable or metastatic TNBC; completed curative intent Tx ≥6 mo before first recurrence; no active CNS mets (N = 847) Until progression, toxicity, or completion of 35 cycles of pembrolizumab/placebo Pembrolizumab 200 mg IV Q3W + Chemotherapy† (n = 566) Placebo + Chemotherapy† (n = 281) † Investigator’s choice of chemotherapy: Nab-paclitaxel 100 mg/m 2 IV on Days 1, 8, 15 of 28-day cycle Paclitaxel 90 mg/m 2 IV on Days 1, 8, 15 of 28-day cycle Gem 1000 mg/m 2 + carbo AUC 2 on Days 1, 8 of 21-day cycle Stratified by chemotherapy (taxane vs gem/carbo); PD-L1 tumor expression (CPS ≥1 vs <1*); previous Tx with same class of chemotherapy for EBC (yes vs no) Primary endpoints: PFS and OS (PD-L1 CPS ≥10, PD-L1 CPS ≥1, and ITT) Secondary endpoints: ORR, DoR, DCR, safety 2:1 *PD-L1 expression assessed with 22C3 PD-L1 IHC assay.

47. KEYNOTE-355: PFS in PD-L1 CPS ≥10 Population Slide credit: clinicaloptions.com Cortes. Lancet. 2020;396:1817. n/N Events, % Median PFS, Mo HR (95% CI) P Value (1 Sided) Pembro + CT 136/220 61.8 9.7 0.65 (0.49-0.86) .0012 5.6 Placebo + CT 79/103 76.7 Patients at Risk, n 220 173 122 96 63 52 25 44 37 103 80 41 30 18 15 8 12 8 12 5 7 3 1 65.0% 46.9% 3 6 9 12 15 18 21 24 27 30 33 36 10 20 30 40 50 60 70 80 90 100 Mo Patients (%) 39.1% 23.0% Pembro + CT Placebo + CT

48. Chemotherapy Regimen Selection for Her 2− Subtypes

49. Her 2 positive Ca breast Benefit of Her 2 directed therapy ?? Concurrent v/s sequential Chemotherapy in small tumors De-escalation/ lesser duration trials Role of newer agents :- - Pertuzumab

50. Adjuvant trastuzumab Trial Treatment arm DFS OS HERA Observation 11 yr - 63% 12 yr - 72.9% Seq Trastuzumab x 1 yr 11 yr - 69.3% 79.4% Seq trastuzumab x 2 yr 11 yr - 68.5% 79.5% NCCTG N9831 & NSABP B31 CT 8 yr – 62% 75.2% CT + trastuzumab 8 yr - 73.7% 84% BCIRG 006 AC f/b T 10 yr - 67.9% 85.9% AC f/b T f/b tras 10 yr - 74.6% 83.3 % TCH f/ tras 10 yr - 73% 96%

51. Escalation & de-escalation of adjuvant Anti-Her 2 therapy Trial Treatmet arm DFS PERSEPHONE CT + Trastuzumab for 1 year 4 yr - 89.8% CT + Trastuzumab for 6 months 4 yr - 89.4% Short-Her (phase 3) CT + Trastuzumab for 1 year 5 yr - 87.5% CT + Trastuzumab for 9 weeks 5 yr - 85.4% PHARE (phase 3) CT + Trastuzumab for 1 year 2 yr - 93.8% CT + Trastuzumab for 6 mnths 2 yr - 91.1% Trastuzumab for 1 yr remains the standard of care

52. Metastatic breast cancer

53. Worst prognosis:- -visceral metastases -brain metastases -multiple metastatic sites Improved prognosis:- -better performance status -younger age at diagnosis -bone-only metastatic disease -longer disease-free interval between initial diagnosis & development of metastatic recurrence

54. Chemotherapy in MBC Because single-agent chemotherapy facilitates better understanding of which drugs are contributing to benefit or side effects and is generally associated with less toxicity, it remains the preferred approach. Although anthracycline & taxane -based treatments are generally considered to be among the most active in treatment of metastatic breast cancer, their utility has led to their incorporation into adjuvant chemotherapy regimens. Thus, many women with metastatic breast cancer will already have been treated with anthracyclines and/or taxanes , diminishing the utility of these agents in the palliation of metastatic disease. Capecitabine : in anthracycline- and taxane -resistant breast cancer, improves response and survival as first-line treatment when added to single-agent docetaxel. Gemcitabine similarly yields higher response rates and survival when paired with paclitaxel compared with paclitaxel therapy alone.

55. Systemic Therapy for Nonmetastatic Breast Cancer HR positive / Her2neu negative Subtype

56. TAILORx Trial Assigning Individualized Options for Treatment determining whether chemotherapy is beneficial for women with a mid-range recurrence score of 11 to 25 Prospective trial – 9719 women with HR + ve , (HER2)–negative, axillary node–negative breast cancer. 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger

57. PONDERx Prospective trial – 5018 women with HR+, HER2-ve breast cancer, 1-3 AXLN & a recurrence score of 25 or lower to endocrine therapy only or to chemotherapy plus endocrine ( chemoendocrine ) therapy. Primary objective -effect of chemotherapy on invasive disease–DFS & whether the effect was influenced by the recurrence score. Secondary end points included distant relapse–free survival

58. THANK YOU Dr Tabassum Wadasadawala Dr Krishnanshu Dr Sudha Sinha

59. Despite the associated short- and long-term risks, chemotherapy remains an essential treatment for preventing recurrence in many patients with stage I-III breast cancer. the regimens docetaxel/cyclophosphamide, adriamycin /cyclophosphamide, and cyclophosphamide/ methotrexate/5-fluorouracil are all reasonable choices in lowerrisk patients where chemotherapy benefits are smaller and toxicities are especially important considerations. Chemotherapy regimens containing both anthracycline ( eg , adriamycin ) and taxane (such as adriamycin /cyclophosphamide followed by taxane ) achieve the greatest risk reduction and remain the appropriate choice in highrisk patients. Specifically, the use of anthracycline appears most important in patients with more lymph node involvement and with triple-negative disease.

60. Taxane : Taxane and anthracycline-based chemotherapy superior to CMF-based, nonanthracycline regimens. CALGB 9344 ( 4AC + T > 4AC ): demonstrated that the addition of sequential paclitaxel therapy improved both DFS and OS among women with node-positive breast cancer compared to women receiving 4 cycles of AC. Maximum benefit in TNBC & Her-2 positive HR negative group. Absolute benefit of taxane : approx. 5% DFS & approx. 3% OS at 8 years; across all subgroups Multiple trials including CALGB 9741 : Accelerated, every-2-week treatment ( dose-dense treatment) led to lower risk of recurrence and improved survival [EBCTCG MA 2019: Absolute benefit of dose-dense at 10 years- RFS 4.3%; OS 2.8%]. Should be considere d in high risk. Sparano et al, NEJM 2008 : A randomized comparison of AC followed by either docetaxel or paclitaxel , with taxanes given either every 3 weeks or on a weekly schedule, did not show significant differences between the taxanes with respect to breast cancer recurrence, although weekly paclitaxel was best tolerated (except sensory neuropathy was higher 27% vs 20%) and produced best DFS & OS outcomes. Exploratory analyses- benefit of weekly pacli most pronounced in TNBC group. 3weekly doce was 2 nd best option among the regimens. Swain et al, NEJM, 2010: Sequential therapy with anthracyclines or alkylators followed by taxanes proved superior to concurrent taxane , anthracycline, and alkylator combinations

61. So: women who warrant chemotherapy, sequential anthracycline- and taxane -based treatment remains the “gold standard.” Although multiple possible variations on this regimen exist, the experience to date has not demonstrated that any regimen is better tolerated or more effective than AC for four cycles followed by paclitaxel chemotherapy, with paclitaxel given as either four cycles every 2 weeks or as 12 weeks of weekly therapy. De-escalation in Her-2 negative patients- omitting anthracyclines: In low risk- growing interest in adjuvant chemotherapy regimens that might spare patients exposure to anthracycline-based chemotherapy. Historical options include CMF chemotherapy, which was shown to be equivalent to AC (4AC= 6CMF). US oncology 9735; Joneset et al , JCO, 2009: docetaxel plus cyclophosphamide was superior to AC (each regimen 4 cycles) in a trial of 1,016 women with node-negative disease or one to three positive lymph nodes ( N0/N1 ), establishing docetaxel plus cyclophosphamide as an option for these intermediate-risk patients (4TC> 4AC= 6CMF) - important option in patients with C/I to anthracycline. No evidence that TC Better or equivalent to AC+Taxanes So, Why not in high risk : Anthracyclines in Early Breast Cancer (ABC) study : compared outcomes for women receiving anthracycline-based regimens, such as AC followed by taxane , against docetaxel plus cyclophosphamide therapy in Her-2 negative patients. The anthracycline-based regimens yielded better overall results, particularly in higher risk, node-positive, ER-positive cancers and in triple-negative breast cancers. So, in the high risk patients no evidence to safely omit anthracyclines.

62. FASG05 compared adjuvant fluorouracil (500 mg/m2 ) and cyclophosphamide (500 mg/m2 ) with epirubicin given at 50 mg/m2 (FEC50) or 100 mg/m2 (FEC100) every 21 days for six cycles After 5 years of follow-up, FEC100 showed improved DFS (HR, 0.63; P = 0.02) and OS (HR, 0.45; P = 0.005) compared to FEC50

63. Cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF or FAC) phase 3,RCT(SWOG-8814, INT-0100) Postmenopausal women with HR + ve , node-positive breast cancer primary outcome:- DFS, was longer with (CAF) given every 4 weeks for 6 cycles + 5 years of daily tamoxifen than with tamoxifen alone; DFS was longer with CAF f/b by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT).

64. EBCTCG META ANALYSIS 2012 - Taxanes Trials where same control regimen were used in both the arms (n=11,167) (8 yr outcome) Trials where no. of cycles in control anthracycline regimen was doubled to mirror the addition of cycles of taxens to anthracycline (n=33,084) (5 yr outcome ) Affirms benefit of taxanes when added into adjuvant setting. Benefits were seen independent of age, nodal status, tumor size, tumor grade and ER status

65. Sequential doxorubicin / cyclophosphamide followed by paclitaxel (AC-T) CALGB 9344 RCT that tested, in a 3 x 2 design, the benefit of doxorubicin dose escalation and of sequential addition of 4 cycles of paclitaxel to 4 cycles of adjuvant doxorubicin/cyclophosphamide (AC) in patients with early-stage breast cancer metastatic to axillary lymph nodes. AC plus paclitaxel (ACT) resulted in superior overall and disease-free survival compared with AC

66. Sequential epirubicin f/b CMF National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials Evaluated the efficacy of epirubicin f/b CMF. The BR9601 trial:- modified CMF regimen (cyclophosphamide 750 mg/m2 , methotrexate 50 mg/m2 , and 5-flouorouracil 600 mg/m2 on day 1 every 3 weeks) whereas the NEAT trial used classic CMF. Both trials compared four cycles of epirubicin 100 mg/m2 every 3 weeks followed by four cycles of CMF ( epirubicin -CMF) versus CMF alone (six cycles in NEAT, eight cycles in BR9601). Combined analysis included 2,391 patients. After a median follow-up of 48 months, epirubicin -CMF group was associated with improved DFS

67. Docetaxel plus cyclophosphamide US Oncology Research phase III trial :- 1,016 patients with OBC were assigned :- -four 3-week cycles of AC ( Doxo 60 mg/m2 & cyclophos 600 mg/m2 ) or DC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 ) After a median follow-up of 84 months:- DC was associated with significantly improved DFS

68. Third generation chemotherapy Docetaxel, doxorubicin, and cyclophosphamide (DAC) Sequential FEC- taxane therapy Dose dense sequential doxorubicin/cyclophosphamide paclitaxel (AC-T) Sequential AC-weekly paclitaxel or every 3 week docetaxel

69. Docetaxel, doxorubicin & cyclophosphamide (DAC) The BCIRG 0001 trial :- compared six cycles DAC (docetaxel 75 mg/m2 , doxorubicin 50 mg/m2 , and cyclophosphamide 500 mg/m2 ) with FAC (5-fluorouracil 500 mg/m2 , doxorubicin 50 mg/m2 , and cyclophosphamide 500 mg/m2 ) every 3 weeks as adjuvant treatment for 1,491 women with operable node-positive breast cancer. median f/u-124 months improvements in DFS (HR, 0.80; P = 0.0043) and OS (HR, 0.74; P = 0.002) Benefit in DFS was irrespective of nodal, HR & HER2 status.

70. CALGB 9741; CITRON ET AL, 2003 Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer. Citron ML, et al. J Clin Oncol. 2003 Jun 1;21(11):2226. Total no of patients= 2005. MFU- 36 months. The two axes of the 2 × 2 design of the C9741 trial were “ pure sequential ” A→T→C Vs “ concurrent ” AC→T and “ dose dense ” q2 weeks Vs “ conventional ” q3 weeks. Dose-dense treatment improved the primary end point, DFS (risk ratio [RR] = 0.74; P =.010), and OS (RR = 0.69; P =.013). Four-year DFS was 82% for the dose-dense regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and sequential schedules. Severe neutropenia was less frequent in patients who received the dose-dense regimens.