Landmark trials in carcinoma breast

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Landmark trials in carcinoma breast

  2. 2. “The farther backward you can look, the farther forward you are likely to see.” ― Winston Churchill “Study the past if you would define the future.” ― Confucius
  5. 5. PRE INDUSTRIAL ERA • HIPPOCRATES- 2400 years back described many forms of cancer and coined the term ‘CANCER’. • 1600 BC, the Edwin Smith Papyrus describes 8 cases of tumors or ulcers of the breast that were treated by cauterization. • GALEN-200 AD classified tumours and considered cancer as a systemic disease related to excess of black bile.
  7. 7. HALSTEDIAN ERA • VALSALVA(1704) ,LEDRAN(1757)& MORGAGNI(1769) –Local lesion capable of cure by operation ,spreads through lymphatics to regional nodes,tends to recur. • WILLIAM HALSTED(1894) popularised radical mastectomy as the treatment of choice for breast cancer ,considered breast cancer strictly as a locoregional disease.
  8. 8. HALSTEDIAN PRINCIPLE • Tumor spreads in an orderdly pattern • Lymphnodes acts as barrier to spread, blood stream is of little significance • More radical the surgery , more the chance of cure • Recurrance & death are due to inadequacy of surgery
  9. 9. FISHER CONCEPT • During the second half of 19th century alternate hypothesis (Fisher Concept)emerged which stressed breast cancer as a systemic disease. • Operable breast cancer is a systemic disease • Blood stream is of considerable importance for tumour dissemination • No orderly spread • Regional lymph nodes are of biological importance
  10. 10. The Contribution of Recent NSABP Clinical Trials of Primary Breast Cancer Therapy to an Understanding of Tumor Biology -An Overview of Findings BERNARD FISHER, MD, CAROL REDMOND, SCD, EDWIN R. FISHER, MD AND PARTICIPATING NSABP INVESTIGATORS* • Disagreement about local-regional management of primary breast cancer is related to differences in • perception of the biology of the disease. Other factors are secondary and obscure the reality that all • treatment must be related to biological considerations; otherwise, the basis for therapy is relegated to • speculation and to personal experience. As a result of extensive laboratory and clinical studies during • the past two decades, there has arisen an altered concept of cancer biology. The National Surgical • Adjuvant Project for Breast and Bowel Cancers (NSABP) has made a major contribution to the change • through findings from a series of prospective randomized clinical trials. That group of American and • Canadian investigators has implemented a series of trials aimed at answering biological as well as clinical • questions. Those studies have not only been concerned with defining proper local-regional treatment but • have also pointed out the need for, and value of, systemic therapy when used in conjunction with • operation. • This report will provide an overview of past and present NSABP contributions and will consider those • findings in relation to observations from other clinical trials of pertinence. It will emphasize that controversies • concerning breast cancer management are related to biological issues that cannot be resolved by • “populism” or appeals to emotion. • Cancer 46:1009-1025, 1980
  11. 11. • Prospective randomised clinical trial has been recognised as a clinical problem solving tool by the middle of 19th century
  12. 12. NSABP B-04 • Between 1971-74, 1765 patients from 34 institutions across USA and Canada participated. • Objective was to find whether reducing the extent of surgery might not compromise outcome. • Two companion trials conducted in parallel –one for those with clincally node negative patients and other for clinically node positive patients. • Radical Mastectomy served as control arm for both.
  13. 13. SCHEMA
  14. 14. RESULTS
  15. 15. • No difference in overall survival among 3 arms in clinically node negative patient.25% for RM arm, 19% for TM/radiation arm, 26% for TM. • P=0.38, Confidence Interval:0.91 to 1.28 • In node positive patients overall survival 14% in each arm. • P=0.72,Confidece Interval :0.87-1.23 • CONCLUSION : MRM = RM (OS,DFS)
  17. 17. NSABP 6 • OBJECTIVE : To find whether LUMPECTOMY & AXILLARY DISSECTION with or without RADIOTHERAPHY is better than TOTAL MASTECTOMY with AXILLARY DISSECTION in early stage breast cancer (stage I & IIwith tumour size < 4 cm,N0/N1)
  18. 18. NSABP 6 • 2163 patients entered the study from 1976- 1984.(354 patients from St.Luke’s hospital excluded)
  19. 19. NSABP 6 • No significant difference in overall survival , disease free survival between three arm .
  20. 20. NSABP 6 • After 25 years of follow- up, the cumulative incidence of a recurrence of tumor in the ipsilateral breast was 39 percent in the group treated with lumpectomy alone and 14 percent in the group treated with lumpectomy and breast irradiation (P<0.001)
  21. 21. MILAN • Int J Radiat Oncol Biol Phys. 1986 May;12(5):717-20. • Local control and survival in early breast cancer: the Milan trial. • Veronesi U, Zucali R, Luini A. • Abstract • From 1973 to 1980, 701 patients with breast cancer measuring less than 2 cm in pathological diameter and with no palpable axillary lymph nodes were randomized to Halsted mastectomy (349) or to "quadrantectomy" with axillary dissection and radiotherapy to the ipsilateral breast tissue (QUART) (352). The two groups were comparable in age distribution, size and site of primary tumor; menopausal status; and frequency of axillary metastases. At 8 years, the disease-free survival was 77% for the Halsted patients and 80% for the "quadrantectomy" patients, while overall survival was 83% and 85%, respectively. Disease-free and overall survival curves show no difference between the two groups. Breast cancer of small size (less than 2 cm) may be safely treated with conservative treatment. Mutilating operations are not justified. • PMID: 3519549 [PubMed - indexed for MEDLINE]
  22. 22. NSABP 6&MILAN: CONCLUSIONS • The NSABP B-06 trial, along with other trials conducted by the Milan group to evaluate quadrantectomy, was instrumental in the establishment of breast conserving surgery plus radiotherapy as the preferred method of local treatment for patients with operable breast cancer.
  24. 24. • Background • Axillary lymph node status is an important prognostic factor in women with early stage breast cancer. • Axillary dissection (AD) and histologic examination of lymph nodes has traditionally been a routine component of surgery for patients with early stage breast cancer. • Benefits of AD include improved local control. In addition, AD provides information that guides prognosis as well as decisions regarding adjuvant treatment. • However, these benefits must be weighed against significant risks of lymphedema, nerve injury, and shoulder dysfunction associated with AD. • Tumor cells generally metastasize from the primary tumor to one or a few sentinel nodes (SN) before involving other lymph nodes. • Sentinel node resection (SNR) is a less invasive method of staging the axilla with less morbidity compared to AD. • In patients with clinically node negative breast cancer, negative SNR can identify patients without axillary nodal involvement, thus obviating the need for a more extensive AD. • NSABP B-32 is a prospective randomized phase III trial designed to determine whether a less invasive SNR provides the same survival and regional control as a more aggressive AD in women with clinically node negative breast cancer.
  25. 25. NSABP B-32 • Methods • 5,611 women with operable, clinically N0, invasive breast cancer were randomized to SNR + AD (Group 1) or to SNR alone with AD only if SNs were positive (Group 2). • 3,989 (71.1%) of 5,611 patients were SN negative, and 3,986 (99.9%) of these SN negative patients had follow- up information. • 1,975 women had SNR + AD (Group 1) and 2,011 women had AD alone (Group 2). • Median time on study was 9.4 years.
  26. 26. NSABP 32
  27. 27. NSABP B-32 • Results • No significant difference in OS between patients who received SNR + AD versus SNR alone (HR: 1.11, p = 0.27) at 10 years. • 10 year Kaplan-Meier (K-M) estimates for OS are 87.8% for SNR alone and 88.9% for SNR + AD. • There continues to be no significant difference in DFS between the two groups (HR: 1.01, p=0.92). • 10 year K-M estimates for DFS were 76.9% for both groups. • There is also no significant difference in distant DFS between the two groups (HR: 1.09, p=0.29). • There was no significant difference in the rates of local-regional recurrence between the two groups (HR: 1.09, p=0.29).
  28. 28. Randomized Multicenter Trial of Sentinel Node Biopsy Versus Standard Axillary Treatment in Operable Breast Cancer: The ALMANAC Trial • Background: Sentinel lymph node biopsy in women with operable breast cancer is routinely used in some countries for staging the axilla despite limited data from randomized trials on morbidity and mortality outcomes. We conducted a multicenter randomized trial to compare quality-of-life outcomes between patients with clinically node-negative invasive breast cancer who received sentinel lymph node biopsy and patients who received standard axillary treatment.
  29. 29. ALMANAC • Methods: The primary outcome measures were arm and shoulder morbidity and quality of life. From November 1999 to October 2003, 1031 patients were randomly assigned to undergo sentinel lymph node biopsy (n = 515) or standard axillary surgery (n = 516). Patients with sentinel lymph node metastases proceeded to delayed axillary clearance or received axillary radiotherapy (depending on the protocol at the treating institution). Intention-to-treat analyses of data at 1, 3, 6, and 12 months after surgery are presented. All statistical tests were two-sided.
  30. 30. ALMANAC • Results: The relative risks of any lymphedema and sensory loss for the sentinel lymph node biopsy group compared with the standard axillary treatment group at 12 months were 0.37 (95% confidence interval [CI] = 0.23 to 0.60; absolute rates: 5% versus 13%) and 0.37 (95% CI = 0.27 to 0.50; absolute rates: 11% versus 31%), respectively. Drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery were statistically significantly lower in the sentinel lymph node biopsy group (all P<.001), and axillary operative time was reduced (P = .055). Overall patient-recorded quality of life and arm functioning scores were statistically significantly better in the sentinel lymph node biopsy group throughout (all P≤.003). These benefits were seen with no increase in anxiety levels in the sentinel lymph node biopsy group (P>.05).
  31. 31. NSABP 32 &ALMANAC • Conclusion: Sentinel lymph node biopsy is associated with reduced arm morbidity and better quality of life than standard axillary treatment and should be the treatment of choice for patients who have early-stage breast cancer with clinically negative nodes.
  32. 32. ACSOG Z011 • Context Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast cancer, but it is not clear whether further nodal dissection affects survival. • Objective To determine the effects of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer.
  33. 33. Date of download: 1/15/2014 Copyright © 2014 American Medical Association. All rights reserved. From: Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node Metastasis: A Randomized Clinical Trial JAMA. 2011;305(6):569-575. doi:10.1001/jama.2011.90 ALND indicates axillary lymph node dissection; SLND, sentinel lymph node dissection. Figure Legend:
  34. 34. • Design, Setting, and Patients The American College of Surgeons Oncology Group Z0011 trial, a phase 3 noninferiority trial conducted at 115 sites and enrolling patients from May 1999 to December 2004. Patients were women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. Targeted enrollment was 1900 women with final analysis after 500 deaths, but the trial closed early because mortality rate was lower than expected.
  35. 35. • Interventions All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN metastases identified by SLND were randomized to undergo ALND or no further axillary treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Systemic therapy was at the discretion of the treating physician. • Main Outcome Measures Overall survival 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. Disease-free survival was a secondary end point.
  36. 36. • Results Clinical and tumor characteristics were similar between 445 patients randomized to ALND and 446 randomized to SLND alone. However, the median number of nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy.
  37. 37. ACSOG Z011 • Conclusion Among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival.
  38. 38. ACSOG Guidelines for Management of Sentinel Lymph Node • BIOPST RESULTS • Negative sentinel node • Positive lymph node at presentation( proven by fnac/core needle biopsy) • 1 0r 2 positive Nodes • 3 or more nodes • GUIDELINES • No further axillary treatment,ALND may be omitted • ALND should be performed • ALND may be ommitted if – 1.primary tumour < 5cm 2.clinically negative axilla 3.will receive whole breast radiation and likely systemic theraphy ALND should be performed
  39. 39. • ACSOG GUIDELINE DONOT APPLY FOR THE FOLLOWING - Those undergoing mastectomy - Those receiving neoadjuvant chemotheraphy - Those receiving partial breast radiation or radiation theraphy in prone position
  41. 41. • WORLD WAR II Aftermath, Goodman & Gillman- 1946 demonstrated the anticancer effects of nitrogen mustard • Sidney Fader -1948- used folic acid to treat leukemia – considered as father of modern chemotheraphy • 1951- Jane wright used MTX to treat breast cancer.ThioTepa,Triethylene Thiophosphyrine were also tried. • Polychemotheraphy developed -1950’s ,based on Goldie codman hypothesis. • CMF was the first used to treat breast cancer by Bonadona
  43. 43. • N Engl J Med. 1976 Feb 19;294(8):405-10. • Combination chemotherapy as an adjuvant treatment in operable breast cancer. • Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini G, Bajetta E, Musumeci R,Veronesi U. • Abstract • Prolonged cyclic combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil was evaluated as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. After 27 months of study, treatment occurred in 24 per cent of 179 control patients and in 5.3 per cent of 207 women given combination chemotherapy (P less than 10(-6)), the advantage appearing statistically significant in all subgroups of patients. Patients with four or more positive axillary nodes had a higher per cent of relapses than those with fewer nodes. The initial new clinical manifestations occurred in distant sites in 81.5 per cent of relapsed patients. Long-term chemotherapy produced an acceptable toxicity, thus allowing the administration of a high percentage of drug dosage. These results should be considered with caution, since, at present, the effect of this therapy on survival and possible long-term side effects remain unknown.
  44. 44. MILAN TRIAL • N Engl J Med. 1976 Feb 19;294(8):405-10. • Combination chemotherapy as an adjuvant treatment in operable breast cancer. • Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini G, Bajetta E, Musumeci R, Veronesi U. • Abstract • Prolonged cyclic combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil was evaluated as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. After 27 months of study, treatment occurred in 24 per cent of 179 control patients and in 5.3 per cent of 207 women given combination chemotherapy (P less than 10(-6)), the advantage appearing statistically significant in all subgroups of patients. Patients with four or more positive axillary nodes had a higher per cent of relapses than those with fewer nodes. The initial new clinical manifestations occurred in distant sites in 81.5 per cent of relapsed patients. Long- term chemotherapy produced an acceptable toxicity, thus allowing the administration of a high percentage of drug dosage. These results should be considered with caution, since, at present, the effect of thistherapy on survival and possible long-term side effects remain unknown.
  45. 45. • Current status of Milan adjuvant chemotherapy trials for node-positive and node-negative breast cancer. • Bonadonna G, Valagussa P, Tancini G, Rossi A, Brambilla C, Zambetti M, Bignami P, Di Fronzo G, Silvestrini R. • Abstract • This report summarizes the most important clinical results achieved at the Milan Cancer Institute through various randomized trials with systemic adjuvant chemotherapy. In the study testing surgery versus surgery plus 12 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in node-positive patients, the reduction in failure rate (34%) significantly favored CMF-treated patients (P less than 0.001). Despite a reduction in the death rate of 23%, the overall survival showed only a trend for CMF compared to surgery alone (P = 0.10). In a second study, the 8-year results confirmed the lack of difference in relapse- free survival and total survival rates between patients who received 12 and 6 cycles of CMF. The third study indicated that at 6 years, postmenopausal women who had 1-3 positive lymph nodes and were treated with full-dose sequential non- cross-resistant combinations had rates of relapse-free survival and total survival that were superior to those previously achieved with CMF in the same menopausal subset. In a limited series of patients with negative axillary nodes as well as negative estrogen receptors, there was clear evidence of very poor prognosis in women given only local-regional therapy, compared to women treated with adjuvant CMF. Within the node-negative subset, the proliferative activity (labeling index) of the primary tumor appears to be a more effective prognostic discriminant than estrogen receptor status. The proportion of primary drug- resistant tumor cells as well as the lack of relative dose intensity in the drug programs tested so far probably represent the two most important causes for the failure of adjuvant chemotherapy.
  46. 46. NSABP 13 • PROTOCOL B-13 A Protocol To Assess Sequential Methotrexate → Fluorouracil In Patients With Primary Breast Cancer And Negative Axillary Nodes Whose Tumors Are Negative For Estrogen Receptors Specific Aims The primary objective of this study is to determine whether the sequential combination M→F is more effective than no treatment with respect to disease-free survival and survival in patients whose tumors are estrogen-receptor-negative. In addition, this study, in conjunction with Protocol B-14, will permit evaluation of treatment failure and survival in untreated patients relative to their ER level.
  47. 47. NSABP 13
  48. 48. NSABP 19 • PROTOCOL B-19 A Clinical Trial to Compare Sequential Methotrexate, 5- Fluorouracil (M→F) with Conventional CMF in Primary Breast Cancer Patients with Negative Nodes and Estrogen- Receptor-Negative Tumors Specific Aims The objective of this study is to determine whether six cycles of conventional cyclophosphamide, methotrexate and 5-fluorouracil (CMF) are as effective with respect to disease-free survival and survival as six cycles of sequential methotrexate and 5-fluorouracil (M→F) followed by leucovorin for negative-node patients whose tumors are estrogen-receptor-negative.
  49. 49. Sequential Methotrexate 5-Fluorouracil (M→F) for the Treatment of Node-Negative Breast Cancer Patients with Estrogen-Receptor-Negative Tumors: Eight-Year Results from NSABP B-13 and First Report of Findings from NSABP B-19 Comparing M→F with Conventional CMF Fisher B, Dignam J, Mamounas EP, Costantino J, Wickerham DL, Redmond C, Wolmark N, Dimitrov N, Bowman D, Glass A, Atkins J, Abramson N, Sutherland C, Aron B, Margolese R, and other contributing NSABP investigators Journal of Clinical Oncology 14:7:1982-1992, 1996 • Methods: A total of 760 patients were randomized to B-13; 1,095 patients with the same eligibility requirements were randomized to B-19. Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were determined using life-table estimates. Results: A significant benefit in overall DFS (74% v 59%; P < .001) was demonstrated at 8 years in all B-13 patients who received M→F (69% v 56% [P = .006] in those ≥50 years). A survival advantage was evident in older patients (89% v 80%; P = .03). In B-19, through 5 years, an overall DFS advantage (82% v 73%; P < .001) and a borderline survival advantage (88% v 85%; P = .06) were evident with CMF. The DFS (84% v 72%; P < .001) and survival (89% v 84%; P = .04) benefits from CMF were greater in women aged F or CMF after lumpectomy and breast irradiation resulted in a low probability of ipsilateral breast tumor recurrence (IBTR). In B-13, the frequency of IBTR was 2.6% following M→F versus 13.4% in women treated by lumpectomy; it was 0.6% following CMF in B-19. Toxicity > or = grade 3 was more frequent among CMF patients in B-19. The age-related difference in CMF benefit was not related to amount of drug received. Conclusion: M→F and CMF are effective for node-negative patients with ER-negative tumors. The incidence of local-regional or distant metastases and IBTR decreased after either therapy. The benefit from either therapy was evident in all patients, but the CMF advantage was greater in those F may be used in patients with medical problems that would preclude CMF administration.
  50. 50. 30 years' follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study BMJ 2005; 330 (Published 27 Jan 2005) • Results After a median follow up of 28.5 years for the initial study, adjuvant CMF was found to reduce the relative risk of relapse significantly (hazard ratio 0.71, 95% confidence interval 0.56 to 0.91, P = 0.005) and death (0.79, 0.63 to 0.98, P = 0.04). Administration of CMF for 12 cycles does not seem superior to a shorter administration of six cycles. In the node negative and oestrogen receptor negative trial, intravenous CMF significantly reduced the relative risk of relapse of disease (0.65, 0.47 to 0.90, P = 0.009) and death (0.65, 0.47 to 0.92, P = 0.01) at a median follow up of 20 years. • Conclusions When delivered optimally, CMF benefits patients at risk of relapse of distant disease without evidence of detrimental effects in any of the examined subgroups.
  52. 52. • Br Med J. 1969 Aug 30;3(5669):503-6. • Clinical evaluation of adriamycin, a new antitumour antibiotic. • Bonadonna G, Monfardini S, De Lena M, Fossati-Bellani F. • Abstract • Adriamycin, a new antitumour antibiotic of the anthracycline group with a structural formula very similar to daunorubicin, has proved to have potent tumour- growth-inhibiting properties, and to be particularly effective in childhood malignancies. Though adriamycin produces a higher percentage of side-effects than daunorubicin-namely, stomatitis and alopecia-a lower dosage may be used for therapy.
  53. 53. NSABP B 15 To determine, in patients with histologically positive axillary nodes who are not classified as tamoxifen-responsive, whether short, intensive adjuvant chemotherapy (AC, with or without interval reinduction with CMF) is as effective as or more effective than "conventional" CMF with respect to disease-free survival and survival.
  54. 54. NSABP 15 • J Clin Oncol. 1990 Sep;8(9):1483-96. • Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. • Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG, et al. • Author information • Abstract • The National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented protocol B-15 to compare 2 months of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and cyclophosphamide (AC) with 6 months of conventional cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with breast cancer nonresponsive to tamoxifen (TAM, T). A second aim was to determine whether AC followed in 6 months by intravenous (IV) CMF was more effective than AC without reinduction therapy. Through 3 years of follow-up, findings from 2,194 patients indicate no significant difference in disease-free survival (DFS, P = .5), distant disease- free survival (DDFS, P = .5) or survival (S, P = .8) among the three groups. Since the outcome from AC and CMF was almost identical, the issue arises concerning which regimen is more appropriate for the treatment of breast cancer patients. AC seems preferable since, following total mastectomy, AC was completed on day 63 versus day 154 for conventional CMF; patients visited health professionals three times as often for conventional CMF as for AC; women on AC received therapy on each of 4 days versus on each of 84 days for conventional CMF; and nausea- control medication was given for about 84 days to conventional CMF patients versus for about 12 days to patients on AC. The difference in the amount of alopecia between the two treatment groups was less than anticipated. While alopecia was almost universally observed following AC therapy, 71% of the CMF patients also had hair loss and, in 41%, the loss was greater than 50%. This study and NSABP B-16, which evaluates the worth of AC therapy in TAM-responsive patients, indicate the merit of 2 months of AC therapy for all positive-node breast cancer patients.
  55. 55. • J Natl Cancer Inst. 2000 Dec 20;92(24):1991-8. • HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. • Paik S, Bryant J, Tan-Chiu E, Yothers G, Park C, Wickerham DL, Wolmark N. • Author information • Abstract • BACKGROUND: • Recent retrospective analyses have suggested that breast cancer patients whose tumors overexpress HER2 derive preferential benefit from treatment with anthracyclines such as doxorubicin. This has led some clinicians to propose that HER2 should be used as a predictive marker in choosing between anthracycline-based regimens and combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). We evaluated this recommendation in a retrospective study of National Surgical Adjuvant Breast and Bowel Project Protocol B-15, in which patients received a combination of doxorubicin and cyclophosphamide (AC), CMF, or AC followed by CMF. We hypothesized that AC would be superior to CMF only in the HER2-positive patients. • METHODS: • Immunohistochemical detection of HER2 was performed on tumor sections from 2034 of 2295 eligible patients. We used statistical analysis to evaluate the interaction between the efficacy of the assigned treatments and HER2 overexpression. All statistical tests were two-sided. • RESULTS: • Tumor sections from 599 patients (29%) stained positive for HER2. AC was superior to CMF in HER2-positive patients only, although differences in outcomes did not reach statistical significance. In the HER2-positive cohort, relative risks of failure (i.e., after AC treatment as compared with CMF treatment) were 0.84 for disease-free survival (DFS) (95% confidence interval [CI] = 0.65--1.07; P =.15), 0.82 for survival (95% CI = 0.63--1.06; P =.14), and 0.80 for recurrence-free survival (RFS) (95% CI = 0.62--1.04; P =.10). Tests for interaction between treatment and HER2 status were suggestive but not statistically significant (P =.19 for DFS, P =.11 for survival, and P =.08 for RFS). • CONCLUSIONS: • These results, together with overview results indicating minor overall superiority for anthracycline-based regimens relative to CMF, indicate a preference for the AC regimen in patients with HER2-positive tumors. Both AC and CMF regimens may be considered for patients with HER2-negative tumors.
  57. 57. © 2005 by American Society of Clinical Oncology Randomized, Controlled Trial of Cyclophosphamide, Methotrexate, and Fluorouracil Versus Cyclophosphamide, Doxorubicin, and Fluorouracil With and Without Tamoxifen for High-Risk, Node- Negative Breast Cancer: Treatment Results of Intergroup Protocol INT-0102
  58. 58. SWOG INT0102 • Abstract • Purpose We evaluated the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) versus cyclophosphamide, doxorubicin, and fluorouracil (CAF) in node-negative breast cancer patients with and without tamoxifen (TAM), overall and by hormone receptor (HR) status. • Patients and Methods Node-negative patients identified by tumor size (> 2 cm), negative HR, or high S-phase fraction (n = 2,690) were randomly assigned to CMF, CAF, CMF + TAM (CMFT), or CAF + TAM (CAFT). Cox regression evaluated overall survival (OS) and disease-free survival (DFS) for CAF versus CMF and TAM versus no TAM separately. Two-sided CIs and one-sided P values for planned comparisons were calculated. • Results Ten-year estimates indicated that CAF was not significantly better than CMF (P = .13) for the primary outcome of DFS (77% v 75%; HR = 1.09; 95% CI, 0.94 to 1.27). CAF had slightly better OS than CMF (85% v 82%, HR = 1.19 for CMF v CAF; 95% CI, 0.99 to 1.43); values were statistically significant in the planned one-sided test (P = .03). Toxicity was greater with CAF and did not increase with TAM. Overall, TAM had no benefit (DFS, P = .16; OS, P = .37), but the TAM effect differed by HR groups. For HR-positive patients, TAM was beneficial (DFS, HR = 1.32 for no TAM v TAM; 95% CI, 1.09 to 1.61; P = .003; OS, HR = 1.26; 95% CI, 0.99 to 1.61; P = .03), but not for HR-negative patients (DFS, HR = 0.81 for no TAMv TAM; 95% CI, 0.64 to 1.03; OS, HR = 0.79; 95% CI, 0.60 to 1.05). • Conclusion CAF did not improve DFS compared with CMF; there was a slight effect on OS. Given greater toxicity, we cannot conclude CAF to be superior to CMF. TAM is effective in HR-positive disease, but not in HR-negative disease.
  64. 64. • Overall, we can conclude that CMF adjuvant chemotherapy is better than no treatment for early- stage breast cancer. For low-risk patients, the above studies conclude that six cycles of oral CMF or four cycles of AC every 3 weeks are equivalent in efficacy. Clinical trials that have incorporated doxorubicin and epirubicin into polychemotherapy regimens (CAF and CEF for six cycles) show a modest but clear benefit for anthracycline-based therapy compared to six cycles of CMF in adjuvant breast cancer. Based on these results, anthracycline therapy with six cycles of CAF or CEF is recommended for higher-risk patients (ie, node-positive patients), and may be used as a benchmark for newer regimens incorporating taxanes and other novel agents. It is important to note that six cycles of CAF/CEF chemotherapy regimens have not been directly compared to four or six cycles of AC in the adjuvant setting. Also, there is no current evidence of excessive cardiac toxicity in women with normal heart function who receive anthracyclines at the cumulative doses utilized in standard adjuvant programs. The trade-off for a small survival benefit with anthracyclines is a different treatment-related toxicity profile including higher incidences of alopecia, vomiting, and cytopenias compared to CMF. With the availability of effective antiemetics (5-HT3 receptor antagonists and NK1 inhibitors) and the use of growth factor support, most of these acute toxicities can be fairly manageable. Data regarding the long-term toxicities of anthracyclines demonstrate a low risk of cardiomyopathy and treatmentrelated leukemia. Overall, we seldom recommend CMF as adjuvant therapy in our practice, and most often recommend anthracycline-based therapy, although we remain very interested in the development of nonanthracycline combinations other than CMF. - See more at: nonanthracycline-adjuvant-therapy-breast-cancer#sthash.J7msq62m.dpuf
  65. 65. TAXANES
  66. 66. CALGB 9344 • 3128 patients with positive LNs were randomized to 3 groups – A(60mg/m2)C x 4 course +/- Taxol (175mg/m2) x 4 courses – A(75mg/m2)C x 4 course +/- Taxol (175mg/m2) x 4 courses – A(90mg/m2)C x 4 course +/- Taxol (175mg/m2) x 4 courses • At 5 years, disease free survival was 69%, 66% and 67 % for patients with different adrimycin dosage • The hazard reduction from adding paclitaxel to AC were 17% for recurrence (p=0.0011) and 18% for death (p=0.0098) JCO 2003;21:976-983
  67. 67. CALGB 9344 Adjuvant Study A = Doxorubicin (doses shown) C = Cyclophosphamide (600 mg/m2) P = Paclitaxel (175 mg/m2 – 3 hour infusion) No P A75 C  4 N=3,170 Node+ Statification: Premenopausal & Postmenopausal P  4 R A N D O M I Z E A90 C  4 A60 C  4 ER+ or PR+ patients received Tamoxifen  5 y
  68. 68. © 2005 by American Society of Clinical Oncology Paclitaxel After Doxorubicin Plus Cyclophosphamide As Adjuvant Chemotherapy for Node-Positive Breast Cancer: Results From NSABP B-28 • Abstract • Purpose The primary aim of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 was to determine whether four cycles of adjuvant paclitaxel (PTX) after four cycles of adjuvant doxorubicin/cyclophosphamide (AC) will prolong disease-free survival (DFS) and overall survival (OS) compared with four cycles of AC alone in patients with resected operable breast cancer and histologically positive axillary nodes. • Patients and Methods Between August 1995 and May 1998, 3,060 patients were randomly assigned (AC, 1,529; AC followed by PTX [AC → PTX], 1,531). Patients ≥ 50 years and those younger than 50 years with estrogen receptor (ER) or progesterone receptor (PR) -positive tumors also received tamoxifen for 5 years, starting with the first dose of AC. Postlumpectomy radiotherapy was mandated. Postmastectomy or regional radiotherapy was prohibited. Median follow-up is 64.6 months. • Results The addition of PTX to AC significantly reduced the hazard for DFS event by 17% (relative risk [RR], 0.83; 95% CI, 0.72 to 0.95; P = .006). Five-year DFS was 76% ± 2% for patients randomly assigned to AC → PTX compared with 72% ± 2% for those randomly assigned to AC. Improvement in OS was small and not statistically significant (RR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Five-year OS was 85% ± 2% for both groups. Subset analysis of the effect of paclitaxel according to hormone receptors or tamoxifen administration did not reveal statistically significant interaction (for DFS, P = .30 and P = .44, respectively). Toxicity with the AC → PTX regimen was acceptable for the adjuvant setting. • Conclusion The addition of PTX to AC resulted in significant improvement in DFS but no significant improvement in OS with acceptable toxicity. No significant interaction between treatment effect and receptor status or tamoxifen administration was observed.
  69. 69. BCIRG 001 • Lancet Oncol. 2013 Jan;14(1):72-80. doi: 10.1016/S1470-2045(12)70525-9. Epub 2012 Dec 12. • Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. • Mackey JR, Martin M, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano MR,Vinholes J, Pinter T, Rodríguez-Lescure A, Colwell B, Whitlock P, Provencher L, Laing K, Walde D, Price C, Hugh JC, Childs BH, Bassi K, Lindsay MA, Wilson V,Rupin M, Houé V, Vogel C; TRIO/BCIRG 001 investigators. • Collaborators (72) • Author information • Abstract • BACKGROUND: • We compared standard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node- positive breast cancer. Here we report the final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety. • METHODS: • BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18-70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with, number NCT00688740. • FINDINGS: • Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90-126), disease-free survival was 62% (95% CI 58-65) for patients in the TAC group and 55% (51-59) for patients in the FAC group (hazard ratio [HR] 0·80, 95% CI 0·68-0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72- 79) for patients in the TAC group and 69% (65-72) for patients in the FAC group (HR 0·74, 0·61-0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3-4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC. • INTERPRETATION: • Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation.
  70. 70. © 2006 by American Society of Clinical Oncology Sequential Adjuvant Epirubicin-Based and Docetaxel Chemotherapy for Node-Positive Breast Cancer Patients: The FNCLCC PACS 01 Trial • Abstract • Purpose The PACS 01 trial compared six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) with a sequential regimen of three cycles of FEC followed by three cycles of docetaxel (FEC-D) as adjuvant treatment for women with node-positive early breast cancer. • Patients and Methods Between June 1997 and March 2000, 1,999 patients with operable node- positive breast cancer were randomly assigned to either FEC every 21 days for six cycles, or three cycles of FEC followed by three cycles of docetaxel, both given every 21 days. Hormone-receptor– positive patients received tamoxifen for 5 years after chemotherapy. The primary end point was 5- year disease-free survival (DFS). • Results Median follow-up was 60 months. Five-year DFS rates were 73.2% with FEC and 78.4% with FEC-D (unadjusted P = .011; adjusted P = .012). Multivariate analysis adjusted for prognostic factors showed an 18% reduction in the relative risk of relapse with FEC-D. Five-year overall survival rates were 86.7% with FEC and 90.7% with FEC-D, demonstrating a 27% reduction in the relative risk of death (unadjusted P = .014; adjusted P = .017). The incidence of grade 3 to 4 neutropenia, the need for hematopoietic growth factor, and incidence of nausea/vomiting were higher with FEC. Docetaxel was associated with more febrile neutropenia in the fourth cycle, stomatitis, edema, and nail disorders. Though rare overall, there were fewer cardiac events after FEC-D (P = .03), attributable mainly to the lower anthracycline cumulative dose. • Conclusion Sequential adjuvant chemotherapy with FEC followed by docetaxel significantly improves disease-free and overall survival in node-positive breast cancer patients and has a favorable safety profile.
  71. 71. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741.• Abstract • PURPOSE: • Using a 2 x 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node-positive breast cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS); to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities. • PATIENTS AND METHODS: • A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A x 4 (doses) --> T x 4 --> C x 4 with doses every 3 weeks, (II) sequential A x 4 --> T x 4 --> C x 4 every 2 weeks with filgrastim, (III) concurrent AC x 4 --> T x 4 every 3 weeks, or (IV) concurrent AC x 4 --> T x 4 every 2 weeks with filgrastim. • RESULTS: • A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced relapse or died, compared with 515 expected treatment failures. 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. There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens. • CONCLUSION: • Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this time. Sequential chemotherapy is as effective as concurrent chemotherapy.
  72. 72. Fluorouracil, Epirubicin, and Cyclophosphamide With Either Docetaxel or Vinorelbine, With or Without Trastuzumab, As Adjuvant Treatments of Breast Cancer: Final Results of the FinHer Trial© 2009 by American Society of Clinical Oncology • Abstract • Purpose Docetaxel has not been compared with vinorelbine as adjuvant treatment of early breast cancer. Efficacy and long-term safety of a short course of adjuvant trastuzumab administered concomitantly with chemotherapy for human epidermal growth factor receptor 2 (HER2) –positive cancer are unknown. • Patients and Methods One thousand ten women with axillary node–positive or high-risk node- negative breast cancer were randomly assigned to receive three cycles of docetaxel or vinorelbine, followed in both groups by three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Women with HER2-positive cancer (n = 232) were further assigned to either receive or not receive trastuzumab for 9 weeks with docetaxel or vinorelbine. The median follow-up time was 62 months after random assignment. • Results Women assigned to docetaxel had better distant disease–free survival (DDFS) than those assigned to vinorelbine (hazard ratio [HR] = 0.66; 95% CI, 0.49 to 0.91; P = .010). In the subgroup of HER2-positive disease, patients treated with trastuzumab tended to have better DDFS than those treated with chemotherapy only (HR = 0.65; 95% CI, 0.38 to 1.12; P = .12; with adjustment for presence of axillary nodal metastases, HR = 0.57; P = .047). In exploratory analyses, docetaxel, trastuzumab, and FEC improved DDFS compared with docetaxel plus FEC (HR = 0.32; P = .029) and vinorelbine, trastuzumab, and FEC (HR = 0.31; P = .020). The median left ventricular ejection fraction of trastuzumab-treated patients remained unaltered during the 5-year follow-up; only one woman treated with trastuzumab was diagnosed with a heart failure. • Conclusion Adjuvant treatment with docetaxel improves DDFS compared with vinorelbine. A brief course of trastuzumab administered concomitantly with docetaxel is safe and effective and warrants further evaluation.
  73. 73. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013 Sep 21;382(9897):1021-8. doi: 10.1016/S0140-6736(13)61094-6. Epub 2013 Jul 18. • Abstract • BACKGROUND: • Trastuzumab has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. The standard of care is 1 year of adjuvant trastuzumab, but the optimum duration of treatment is unknown. We compared 2 years of treatment with trastuzumab with 1 year of treatment, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial. • METHODS: • The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both in 5102 patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. The comparison of 2 years versus 1 year of trastuzumab treatment involved a landmark analysis of 3105 patients who were disease-free 12 months after randomisation to one of the trastuzumab groups, and was planned after observing at least 725 disease-free survival events. The updated intention-to-treat comparison of 1 year trastuzumab treatment versus observation alone in 3399 patients at a median follow-up of 8 years (range 0-10) is also reported. This study is registered with, number NCT00045032. • FINDINGS: • We recorded 367 events of disease-free survival in 1552 patients in the 1 year group and 367 events in 1553 patients in the 2 year group (hazard ratio [HR] 0·99, 95% CI 0·85-1·14, p=0·86). Grade 3-4 adverse events and decreases in left ventricular ejection fraction during treatment were reported more frequently in the 2 year treatment group than in the 1 year group (342 [20·4%] vs 275 [16·3%] grade 3-4 adverse events, and 120 [7·2%] vs 69 [4·1%] decreases in left ventricular ejection fraction, respectively). HRs for a comparison of 1 year of trastuzumab treatment versus observation were 0·76 (95% CI 0·67- 0·86, p<0·0001) for disease-free survival and 0·76 (0·65-0·88, p=0·0005) for overall survival, despite crossover of 884 (52%) patients from the observation group to trastuzumab therapy. • INTERPRETATION: • 2 years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer. 1 year of treatment provides a significant disease-free and overall survival benefit compared with observation and remains the standard of care.
  75. 75. J Clin Oncol. 1997 Jul;15(7):2483-93. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18.
  76. 76. NSABP 18 • Abstract • PURPOSE: • To determine whether preoperative doxorubicin and cyclophosphamide (AC) permits more lumpectomies to be performed and decreases the incidence of positive nodes in women with primary breast cancer. • PATIENTS AND METHODS: • Women (n = 1,523) were randomized to National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18; 759 eligible patients received postoperative AC and 747, preoperative AC. The clinical size of breast and axillary tumors was determined before each of four cycles of AC and before surgery. Tumor response to preoperative therapy was clinically complete (cCR), partial (cPR), stable (cSD), or progressive disease (cPD). Tissue from patients with a cCR was evaluated for a pathologic complete response (pCR). • RESULTS: • Breast tumor size was reduced in 80% of patients after preoperative therapy; 36% had a cCR. Tumor size and clinical nodal status were independent predictors of cCR. Twenty-six percent of women with a cCR had a pCR. Clinical nodal response occurred in 89% of node-positive patients: 73% had a cCR and 44% of those had a pCR. There was a 37% increase in the incidence of pathologically negative nodes. Before randomization, lumpectomy was proposed for 86% of women with tumors < or = 2 cm, 70% with tumors 2.1 to 5.0 cm, and 3% with tumors > or = 5.1 cm. Clinical tumor size and nodal status influenced the physician's decision. Overall, 12% more lumpectomies were performed in the preoperative group; in women with tumors > or = 5.1 cm, there was a 175% increase. • CONCLUSION: • Preoperative therapy reduced the size of most breast tumors and decreased the incidence of positive nodes. The greatest increase in lumpectomy after preoperative therapy occurred in women with tumors > or = 5 cm, since women with tumors less than 5 cm were already lumpectomy candidates. Preoperative therapy should be considered for the initial management of breast tumors judged too large for lumpectomy.
  77. 77. NSABP Protocol B-27. Preoperative doxorubicin plus cyclophosphamide followed by preoperative or postoperative docetaxel.
  78. 78. Preoperative Chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. • Abstract Purpose: National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was designed to determine whether four cycles of doxorubicin and cyclophosphamide (AC) administered preoperatively improved breast cancer disease-free survival (DFS) and overall survival (OS) compared with AC administered postoperatively. Protocol B-27 was designed to determine the effect of adding docetaxel (T) to preoperative AC on tumor response rates, DFS, and OS. Patients and Methods: Analyses were limited to eligible patients. In B-18, 751 patients were assigned to receive preoperative AC, and 742 patients were assigned to receive postoperative AC. In B-27, 784 patients were assigned to receive preoperative AC followed by surgery, 783 patients were assigned to AC followed by T and surgery, and 777 patients were assigned to AC followed by surgery and then T. Results: Results from B-18 show no statistically significant differences in DFS and OS between the two groups. However, there were trends in favor of preoperative chemotherapy for DFS and OS in women less than 50 years old (hazard ratio [HR] = 0.85, P = .09 for DFS; HR = 0.81, P = .06 for OS). DFS conditional on being event free for 5 years also demonstrated a strong trend in favor of the preoperative group (HR = 0.81, P = .053). Protocol B-27 results demonstrated that the addition of T to AC did not significantly impact DFS or OS. Preoperative T added to AC significantly increased the proportion of patients having pathologic complete responses (pCRs) compared with preoperative AC alone (26% v 13%, respectively; P < .0001). In both studies, patients who achieved a pCR continue to have significantly superior DFS and OS outcomes compared with patients who did not. Conclusion: B-18 and B-27 demonstrate that preoperative therapy is equivalent to adjuvant therapy. B-27 also showed that the addition of preoperative taxanes to AC improves response. • J Clin Oncol. 2008 Feb 10;26(5):778-85.
  79. 79. Clin Breast Cancer. 2002 Oct;3 Suppl 2:S69-74. Neoadjuvant docetaxel in breast cancer: 3-year survival results from the Aberdeen trial. • Abstract • Over the past 30 years there has been an increased use of neoadjuvant (or primary) chemotherapy for treating patients with breast cancer. However, while it is clear that chemotherapy given in the adjuvant setting after surgery does prolong patients' overall and disease-free survival, the evidence that chemotherapy in the neoadjuvant setting also increases survival remains unproven. In the Aberdeen study, 162 patients with large and locally advanced breast cancer underwent 4 cycles of CVAP (cyclophosphamide/vincristine/doxorubicin/prednisone) primary chemotherapy. Patients with a complete or partial response were then randomized to either 4 further cycles of CVAP or 4 cycles of docetaxel (100 mg/m2). It was shown that the addition of sequential docetaxel (100 mg/m2) to CVAP neoadjuvant chemotherapy resulted in a significantly enhanced clinical response rate (94% vs. 64%) and a substantially increased complete histopathological response rate (34% vs. 16%) when compared to patients receiving CVAP alone. Furthermore, patients receiving docetaxel had an increased breast conservation rate (67% vs. 48%) and an increased survival at a median follow-up of 3 years. It is important to note that this was a small study, and the survival results should be interpreted with caution. The results are encouraging, however, and further studies are urgently required.
  80. 80. GEPAR duo TRIAL Neoadjuvant docetaxel followed by adjuvant doxorubicin and cyclophosphamide in patients with stage III breast cancer • Background: To evaluate clinical and pathologic response to neoadjuvant docetaxel therapy in patients with stage III breast cancer. • Patients and methods: Forty-five patients were planned to receive four cycles of docetaxel 100 mg/m2 every 3 weeks, followed by surgery, four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 (AC) every 3 weeks, radiation therapy (RT), and tamoxifen when indicated. • Results: After four cycles of neoadjuvant docetaxel, the clinical response rate within the breast was 59% (95% CI 42% to 73%) and overall (breast and axilla) was 49% (95% CI 38% to 72%) in the intention-to-treat (ITT) population. At the time of surgery, 10% (n=4) of patients had a pathologic complete response (pCR) in the breast, 27% (n=11) had a pCR within the axillary lymph nodes, and 7% (n=3) had a pCR in the breast and axilla (95% CI 2% to 21%). An additional 5% (n=2) had minimal residual invasive tumor (<5 mm). The 5-year overall survival rate was 80%. The percentage of patients with grade 3/4 neutropenia was similar during docetaxel (93%) and AC (86%), while a greater percentage of patients had febrile neutropenia during docetaxel treatment (27%) compared with AC treatment (7%). • Conclusions: Neoadjuvant docetaxel followed by surgery, adjuvant AC, hormonal therapy where indicated, and RT is an active regimen for patients with stage III breast cancer.
  81. 81. Breast Cancer Res Treat. 2003;79 Suppl 1:S19-24. Neoadjuvant docetaxel in locally advanced breast cancer. • Neoadjuvant chemotherapy produces substantial increases in clinical response rates and rates of breast conserving therapy. Pathologic response rate, though generally low, is an important outcome as it is presumably associated with eradication of micrometastatic disease and may likely result in improved outcomes. Anthracyclines have long been considered the most efficacious chemotherapy agents for neoadjuvant therapy of early breast cancer. Unfortunately, not all patients respond to neoadjuvant anthracycline-based chemotherapy. In an effort to improve primary tumor response, docetaxel, an active agent in breast cancer, has been evaluated in the neoadjuvant setting. Several randomized trials, including the NSABP B-27, GEPAR-duo, and the Aberdeen trial, evaluating docetaxel in sequence with a doxorubicin-based neoadjuvant regimen have been reported, with encouraging findings. We designed the Aberdeen trial with two primary aims: (1) to evaluate primary docetaxel in patients that initially fail a neoadjuvant anthracycline-based polychemotherapy regimen, and (2) to compare a docetaxel-based neoadjuvant regimen with a standard anthracycline-based regimen in patients who do respond to the first four cycles of the anthracycline-based regimen. Eligible patients (n = 162) had previously untreated large (> or = 3 cm) or locally advanced (T3, T4, T x N2) breast cancer. All received four cycles of CVAP, after which clinical response was assessed. Responding patients were then randomized to four additional cycles of CVAP or to docetaxel 100 mg/m2 every 3 weeks for four cycles. Patients failing to respond to CVAP received the docetaxel regimen. After the first four cycles of CVAP, the overall response rate (ORR) was 67%. Ultimately, responses were higher in the group randomized to docetaxel compared with those continuing CVAP (cCR: 94% vs. 66%; p = 0.001; pCR 34% vs. 16%; p = 0.04). The addition of docetaxel improved overall survival and disease-free survival for patients responding to four cycles of CVAP as compared with those receiving eight cycles of CVAP. Relative dose intensity was higher and the incidence of severe leukopenia was lower in the group randomized to docetaxel. These data and data from the NSABP B-27 and GEPAR-duo trials strongly support a combined anthracycline/docetaxel regimen in the neoadjuvant setting. • PMID: 12868802 [PubMed - indexed for MEDLINE]
  83. 83. Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study • Abstract • Background: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992. Methods: Women (N = 13 388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35–59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n = 6707) or 20 mg/day tamoxifen (n = 6681) for 5 years. Gail's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time. Results: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50–59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = 2.53; 95% confidence interval = 1.35–4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older. • Conclusions: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease. [J Natl Cancer Inst 1998;90:1371–88] • © 1998 Oxford University Press
  84. 84. PROTOCOL B-14 A Clinical Trial to Assess Tamoxifen in Patients With Primary Breast Cancer and Negative Axillary Nodes Whose Tumors are Positive for Estrogen Receptors
  85. 85. NSABP 14 • Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. • Fisher B, Dignam J, Bryant J, Wolmark N. • Author information • Abstract • BACKGROUND: • Previously reported information from B-14, a National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized, placebo-controlled clinical trial, demonstrated that patients with estrogen receptor (ER)-positive breast cancer and negative axillary lymph nodes experienced a prolonged benefit from 5 years of tamoxifen therapy. When these women were rerandomized to receive either placebo or more prolonged tamoxifen therapy, they obtained no additional advantage from tamoxifen through 4 years of follow-up. Because the optimal duration of tamoxifen administration continues to be controversial and because there have been 3 more years of follow-up and a substantial increase in the number of events since our last report, an update of the B-14 study is appropriate. • METHODS: • Patients (n = 1172) who had completed 5 years of tamoxifen therapy and who were disease free were rerandomized to receive placebo (n = 579) or tamoxifen (n = 593). Survival, disease-free survival (DFS), and relapse-free survival (RFS) were estimated by the Kaplan-Meier method; the differences between the treatment groups were assessed by the log-rank test. Relative risks of failure (with 95% confidence intervals) were determined by the Cox proportional hazards model. P values were two-sided. • RESULTS: • Through 7 years after reassignment of tamoxifen-treated patients to either placebo or continued tamoxifen therapy, a slight advantage was observed in patients who discontinuedtamoxifen relative to those who continued to receive it: DFS = 82% versus 78% (P =.03), RFS = 94% versus 92% (P =.13), and survival = 94% versus 91% (P =.07), respectively. The lack of benefit from additional tamoxifen therapy was independent of age or other characteristics. • CONCLUSION: • Through 7 years of follow-up after rerandomization, there continues to be no additional benefit from tamoxifen administered beyond 5 years in women with ER-positive breast cancer and negative axillary lymph nodes.
  86. 86. Lancet Oncol. 2010 Dec;11(12):1135-41. doi: 10.1016/S1470- 2045(10)70257-6. Epub 2010 Nov 17. Effect of anastrozole and tamoxifen as adjuvant treatment for early- stage breast cancer: 10-year analysis of the ATAC trial.
  87. 87. ATAC • Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. • Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists' Group. • Author information • Abstract • The standard adjuvant endocrine treatment for postmenopausal women with hormone-receptor- positive localised breast cancer is 5 years of tamoxifen, but recurrences and side-effects restrict its usefulness. The aromatase inhibitor anastrozole was compared with tamoxifen for 5 years in 9366 postmenopausal women with localised breast cancer. After a median follow-up of 68 months, anastrozole significantly prolonged disease-free survival (575 events with anastrozole vs 651 with tamoxifen, hazard ratio 0.87, 95% CI 0.78-0.97, p=0.01) and time-to-recurrence (402 vs 498, 0.79, 0.70-0.90, p=0.0005), and significantly reduced distant metastases (324 vs 375, 0.86, 0.74-0.99, p=0.04) and contralateral breast cancers (35 vs 59, 42% reduction, 12-62, p=0.01). Almost all patients have completed their scheduled treatment, and fewer withdrawals occurred with anastrozole than with tamoxifen. Anastrozole was also associated with fewer side-effects than tamoxifen, especially gynaecological problems and vascular events, but arthralgia and fractures were increased. Anastrozole should be the preferred initial treatment for postmenopausal women with localised hormone-receptor-positive breast cancer.
  88. 88. ATAC • Abstract • BACKGROUND: • The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer. In this analysis, we assess the long-term outcomes after a median follow-up of 120 months. • METHODS: • We used a proportional hazards model to assess the primary endpoint of disease-free survival, and the secondary endpoints of time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death with or without recurrence in all randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone-receptor- positive patients (anastrozole n=2618, tamoxifen n=2598). After treatment completion, we continued to collect data on fractures and serious adverse events in a masked fashion (safety population: anastrozole n=3092, tamoxifen n=3094). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. • FINDINGS: • Patients were followed up for a median of 120 months (range 0-145); there were 24,522 woman-years of follow-up in the anastrozole group and 23,950 woman-years in the tamoxifen group. In the full study population, there were significant improvements in the anastrozole group compared with the tamoxifen group for disease-free survival (hazard ratio [HR] 0·91, 95% CI 0·83-0·99; p=0·04), time to recurrence (0·84, 0·75-0·93; p=0·001), and time to distant recurrence (0·87, 0·77-0·99; p=0·03). For hormone-receptor-positive patients, the results were also significantly in favour of the anastrozole group for disease-free survival (HR 0·86, 95% CI 0·78-0·95; p=0·003), time to recurrence (0·79, 0·70-0·89; p=0·0002), and time to distant recurrence (0·85, 0·73-0·98; p=0·02). In hormone-receptor-positive patients, absolute differences in time to recurrence between anastrozole and tamoxifen increased over time (2·7% at 5 years and 4·3% at 10 years) and recurrence rates remained significantly lower on anastrozole than tamoxifen after treatment completion (HR 0·81, 95% CI 0·67-0·98; p=0·03), although the carryover benefit was smaller after 8 years. There was weak evidence of fewer deaths after recurrence with anastrozole compared with tamoxifen treatment in the hormone-receptor-positive subgroup (HR 0·87, 95% CI 0·74- 1·02; p=0·09), but there was little difference in overall mortality (0·95, 95% CI 0·84-1·06; p=0·4). Fractures were more frequent during active treatment in patients receiving anastrozole than those receiving tamoxifen (451 vs 351; OR 1·33, 95% CI 1·15-1·55; p<0·0001), but were similar in the post-treatment follow-up period (110 vs 112; OR 0·98, 95% CI 0·74-1·30; p=0·9). Treatment-related serious adverse events were less common in the anastrozole group than the tamoxifen group (223 anastrozole vs 369 tamoxifen; OR 0·57, 95% CI 0·48-0·69; p<0·0001), but were similar after treatment completion (66 vs 78; OR 0·84, 95% CI 0·60-1·19; p=0·3). No differences in non-breast cancer causes of death were apparent and the incidence of other cancers was similar between groups (425 vs 431) and continue to be higher with anastrozole for colorectal (66 vs 44) and lung cancer (51 vs 34), and lower for endometrial cancer (six vs 24), melanoma (eight vs 19), and ovarian cancer (17 vs 28). No new safety concerns were reported.
  89. 89. Neoadjuvant chemotherapy with trastuzumab followed by Neo adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally Neoadjuvant chemotherapy with advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort • Background • The monoclonal antibody trastuzumab has survival benefit when given with chemotherapy to patients with early, operable, and metastatic breast cancer that has HER2 (also known as ERBB2) overexpression or amplification. We aimed to assess event-free survival in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without 1 year of trastuzumab. • Methods • We compared 1 year of treatment with trastuzumab (given as neoadjuvant and adjuvant treatment; n=117) with no trastuzumab (118), in women with HER2-positive locally advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Randomisation was done with a computer program and minimisation technique, taking account of geographical area, disease stage, and hormone receptor status. Investigators were informed of treatment allocation. A parallel cohort of 99 patients with HER2- negative disease was included and treated with the same chemotherapy regimen. Primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered, number ISRCTN86043495. • Findings • Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer (3- year event-free survival, 71% [95% CI 61—78; n=36 events] with trastuzumab, vs 56% [46—65; n=51 events] without; hazard ratio 0·59 [95% CI 0·38—0·90]; p=0·013). Trastuzumab was well tolerated and, despite concurrent administration with doxorubicin, only two patients (2%) developed symptomatic cardiac failure. Both responded to cardiac drugs. • Interpretation • The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve event-free survival, survival, and clinical and pathological tumour responses.
  90. 90. • Program for the Assessment of Clinical Cancer Tests (PACCT-1): Trial Assigning Individualized Options for Treatment: The TAILORx Trial • Women with estrogen receptor and/or progesterone receptor positive, lymph node negative (cancer that has not spread to the lymph nodes), HER2/neu negative breast cancer are eligible to enroll in TAILORx. The tumor size must be 1.1 to 5.0 cm (or 0.5 mm to 1.0 cm, with unfavorable histologic features). Participants must meet standard clinical criteria and be medically suitable candidates for adjuvant chemotherapy.
  91. 91. Hormone Therapy With or Without Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Negative Breast Cancer (The TAILORx Trial) • GROUP 1 (SECONDARY STUDY GROUP 1; ONCOTYPE DX RECURRENCE SCORE [ODRS] < 11): Patients receive standard hormonal therapy (e.g., tamoxifen alone orally (PO), aromatase inhibitor [e.g., anastrozole, letrozole, or exemestane] alone PO, or tamoxifen PO followed by aromatase inhibitor PO) at the discretion of the treating physician for 5 or 10 years. • GROUP 2 (PRIMARY STUDY GROUP; ODRS 11-25): Patients are stratified according to tumor size (=< 2.0 cm vs >= 2.1 cm), menopausal status (postmenopausal vs premenopausal vs perimenopausal), planned chemotherapy (taxane-containing [i.e., paclitaxel, docetaxel] vs non taxane-containing), planned radiotherapy (whole breast with no boost planned vs whole breast with boost planned vs partial breast irradiation planned vs no planned radiation therapy [for patients who have had a mastectomy]) and Oncotype DX Recurrence Score (11-15 vs 16-20 vs 21- 25). Patients are then randomized to receive either hormonal therapy alone or combination chemotherapy and hormonal therapy.
  92. 92. • To determine whether adjuvant hormonal therapy with chemotherapy is better than adjuvant hormonal therapy alone in women whose tumors fall in a range where the benefit from chemotherapy is uncertain as indicated by a molecular test. The primary studyendpoint is disease-free survival. Another primary endpoint is overall survival.
  94. 94. Lancet. 2011 Nov 12;378(9804):1707-16. doi: 10.1016/S0140- 6736(11)61629-2. Epub 2011 Oct 19. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. • Abstract • BACKGROUND: • After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk. • METHODS: • We undertook a meta-analysis of individual patient data for 10,801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node- positive (pN+) disease. • FINDINGS: • Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35·0% to 19·3% (absolute reduction 15·7%, 95% CI 13·7-17·7, 2p<0·00001) and reduced the 15-year risk of breast cancer death from 25·2% to 21·4% (absolute reduction 3·8%, 1·6-6·0, 2p=0·00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31·0% to 15·6% (absolute recurrence reduction 15·4%, 13·2-17·6, 2p<0·00001) and from 20·5% to 17·2% (absolute mortality reduction 3·3%, 0·8-5·8, 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (≥20%), intermediate (10-19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7·8% (95% CI 3·1-12·5), 1·1% (-2·0 to 4·2), and 0·1% (-7·5 to 7·7) respectively (trend in absolute mortality reduction 2p=0·03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63·7% to 42·5% (absolute reduction 21·2%, 95% CI 14·5-27·9, 2p<0·00001) and the 15-year risk of breast cancer death from 51·3% to 42·8% (absolute reduction 8·5%, 1·8-15·2, 2p=0·01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease. • INTERPRETATION: • After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made.
  95. 95. Studies Median Follow-up Op LR w/o RT LR with RT NSABP B-06 125 months Lump- ectomy 35% 9% Scottish Cancer Trial 68 months Lump- ectomy 24% 6% Uppsala-Örebro Study Group 106 months Segment- ectomy 22% 7% Ontario Cancer Inst. 91 months Lump- ectomy 35% 11% Milano III 109 months Quadrant- ectomy 22% 5% Local relapse: BC surgery +/- RT BREAST CONSERVATION
  96. 96. • J Natl Cancer Inst. 2012 Jul 18;104(14):1080-93. doi: 10.1093/jnci/djs272. Epub 2012 Jul 17. • Mammography screening and breast cancer mortality in Sweden. • Autier P, Koechlin A, Smans M, Vatten L, Boniol M. • Author information • Abstract • BACKGROUND: • Swedish women aged 40-69 years were gradually offered regular mammography screening since 1974, and nationwide coverage was achieved in 1997. We hypothesized that this gradual implementation of breast cancer screening would be reflected in county-specific mortality patterns during the last 20 years. • METHODS: • Using data from the Swedish Board of Health and Welfare from 1960 to 2009, we used joinpoint regression to analyze breast cancer mortality trends in women aged 40 years and older (1,286,000 women in 1995-1996). Poisson regression models were used to compare observed mortality trends with expected trends if screening had resulted in breast cancer mortality reductions of 10%, 20%, or 30% among women screened during 18 years of follow-up after the introduction of screening. All statistical tests were two- sided. • RESULTS: • From 1972 to 2009, breast cancer mortality rates in Swedish women aged 40 years and older declined by 0.98% annually, from 68.4 to 42.8 per 100,000, and it continuously declined in 14 of the 21 Swedish counties. In three counties, breast cancer mortality declined sharply during or soon after the implementation of screening; in two counties, a steep decline started at least 5 years after screening was introduced; and in two counties, breast cancer mortality increased after screening started. In counties in which screening started in 1974-1978, mortality trends during the next 18 years were similar to those before screening started, and in counties in which screening started in 1986-1987, mortality increased by approximately 12% (P = .007) after the introduction of screening compared with previous trends. In counties in which screening started in 1987-1988 and in 1989-1990, mortality declined by approximately 5% (P = .001) and 8% (P < .001), respectively, after the introduction of screening. Conclusion County- specific mortality statistics in Sweden are consistent with studies that have reported limited or no impact of screening on mortality from breast cancer.
  97. 97. • As have other gadgets in medical tool box- steth,Echo,MRI – the clinical trial has been adapted and refined to new users ,has acquired its own place in medical culture. As with other tools,however the real function of RCT ha been and remains to assist and not to replace CLINICAL JUDGEMENT - Clinics of North America(2000) THANK U ………