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LANDMARK TRIALS IN BREAST CANCER -Dr.A.Joseph Stalin Mch Postgraduate PROF.DR.R.RAJARAMANS UNITCENTRE FOR ONCOLOGYGOVT. ROYAPETTAH HOSPITALThe farther backward you can look, the farther forward you are likely to see.Winston ChurchillStudy the past if you would define the future.ConfuciusSURGICAL ASPECTSCHEMOTHERAPHYHORMONE THERAPHYRADIOTHERAPHY

A JOURNEY ON CARCINOMA BREASTSURGICAL ASPECTS * RADICAL MASTECTOMY VS MODIFIED RADICAL MASTECTOMY * MODIFIED RADICAL MASTECTOMY VS BREAST CONSRVATION SURGERY* AXILLARY DISSECTION VS SENTINEL NODE BIOPSY PRE INDUSTRIAL ERAHIPPOCRATES- 2400 years back described many forms of cancer and coined the term CANCER.1600 BC,theEdwin Smith Papyrusdescribes 8 cases of tumors or ulcers of the breast that were treated bycauterization. GALEN-200 AD classified tumours and considered cancer as a systemic disease related to excess of black bile.PRE INDUSTRIAL ERA

CONSIDERED AS INCURABLE TILL 17TH CENTURYTHEORY OF HUMORALISM, DIVINE CURSE PREVAILEDHALSTEDIAN ERAVALSALVA(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.

Your Text HereHALSTEDIAN PRINCIPLETumor spreads in an orderdly patternLymphnodes acts as barrier to spread, blood stream is of little significanceMore radical the surgery , more the chance of cureRecurrance & death are due to inadequacy of surgeryFISHER CONCEPTDuring 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 diseaseBlood stream is of considerable importance for tumour disseminationNo orderly spreadRegional lymph nodes are of biological importance

The Contribution of Recent NSABP Clinical Trials of PrimaryBreast Cancer Therapy to an Understanding of TumorBiology -An Overview of FindingsBERNARD FISHER, MD, CAROL REDMOND, SCD, EDWIN R. FISHER, MDAND PARTICIPATING NSABP INVESTIGATORS*

Disagreement about local-regional management of primary breast cancer is related to differences inperception of the biology of the disease. Other factors are secondary and obscure the reality that alltreatment must be related to biological considerations; otherwise, the basis for therapy is relegated tospeculation and to personal experience. As a result of extensive laboratory and clinical studies duringthe past two decades, there has arisen an altered concept of cancer biology. The National SurgicalAdjuvant Project for Breast and Bowel Cancers (NSABP) has made a major contribution to the changethrough findings from a series of prospective randomized clinical trials. That group of American andCanadian investigators has implemented a series of trials aimed at answering biological as well as clinicalquestions. Those studies have not only been concerned with defining proper local-regional treatment buthave also pointed out the need for, and value of, systemic therapy when used in conjunction withoperation.This report will provide an overview of past and present NSABP contributions and will consider thosefindings in relation to observations from other clinical trials of pertinence. It will emphasize that controversiesconcerning breast cancer management are related to biological issues that cannot be resolved bypopulism or appeals to emotion.Cancer 46:1009-1025, 1980Prospective randomised clinical trial has been recognised as a clinical problem solving tool by the middle of 19th centuryNSABP B-04Between 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.SCHEMA

RESULTS

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 1.28In node positive patients overall survival 14% in each arm.P=0.72,Confidece Interval :0.87-1.23CONCLUSION : MRM = RM (OS,DFS)

MODIFIED RADICAL MASTECTOMY VS BREAST CONSERVATIVE SURGERYNSABP 6OBJECTIVE : 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)

NSABP 62163 patients entered the study from 1976-1984.(354 patients from St.Lukes hospital excluded)

NSABP 6No significant difference in overall survival , disease free survival between three arm .

NSABP 6After 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 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:MF 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.

30 years' follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort studyBMJ2005;330(Published 27 Jan 2005)

ResultsAfter 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.ConclusionsWhen delivered optimally, CMF benefits patients at risk of relapse of distant disease without evidence of detrimental effects in any of the examined subgroups.

ANTHRACYCLINESBr 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.AbstractAdriamycin, 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.

NSABP B 15To 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.

NSABP 15J 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 informationAbstractThe 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.

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 informationAbstractBACKGROUND: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.

CMF VS CAF REGIMEN 2005 by American Society of Clinical OncologyRandomized, 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

SWOG INT0102AbstractPurposeWe 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 MethodsNode-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-sidedPvalues for planned comparisons were calculated.ResultsTen-year estimates indicated that CAF was not significantly better than CMF (P= .13) for the primary outcome of DFS (77%v75%; HR = 1.09; 95% CI, 0.94 to 1.27). CAF had slightly better OS than CMF (85%v82%, HR = 1.19 for CMFvCAF; 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 TAMvTAM; 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 TAMvTAM; 95% CI, 0.64 to 1.03; OS, HR = 0.79; 95% CI, 0.60 to 1.05).ConclusionCAF 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.

EBCTCG 2010 OVERVIEWPOLYCHEMOTHERAPHY VS NONE10 YR RESULTS IN23500 PATIENTSCMF VS NO ADJUVANT

ANTHRACYCLINES VS NO ADJUVANT

ANTHRACYCLINES(AC) VS CMF

ADJUVANT CHEMOTHERAPHY HAS DEFNITIVE BENEFIT IN ALL SUBGROUPSOverall, 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: http://www.cancernetwork.com/review-article/anthracycline-vs-nonanthracycline-adjuvant-therapy-breast-cancer#sthash.J7msq62m.dpufTAXANESCALGB 93443128 patients with positive LNs were randomized to 3 groupsA(60mg/m2)C x 4 course +/- Taxol (175mg/m2) x 4 coursesA(75mg/m2)C x 4 course +/- Taxol (175mg/m2) x 4 coursesA(90mg/m2)C x 4 course +/- Taxol (175mg/m2) x 4 coursesAt 5 years, disease free survival was 69%, 66% and 67 % for patients with different adrimycin dosageThe hazard reduction from adding paclitaxel to AC were 17% for recurrence (p=0.0011) and 18% for death (p=0.0098)JCO 2003;21:976-98370Tamoxifen for the HR positive diseaseCALGB 9344 Adjuvant Study A = Doxorubicin (doses shown)C = Cyclophosphamide (600 mg/m2)P = Paclitaxel (175 mg/m2 3 hour infusion)No PA75 C 4N=3,170

Node+

Statification:Premenopausal &Postmenopausal

P 4RANDOMIZE

A90 C 4A60 C 4ER+ or PR+ patients received Tamoxifen 5 y71Paclitaxel dose = 175mg/m2 IV q 3 weeks 2005 by American Society of Clinical OncologyPaclitaxel After Doxorubicin Plus Cyclophosphamide As Adjuvant Chemotherapy for Node-Positive Breast Cancer: Results From NSABP B-28

AbstractPurposeThe 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 MethodsBetween 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.ResultsThe 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 andP= .44, respectively). Toxicity with the AC PTX regimen was acceptable for the adjuvant setting.ConclusionThe 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.

BCIRG 001Lancet 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,Rodrguez-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,Hou V,Vogel C;TRIO/BCIRG 001 investigators.Collaborators (72)Author informationAbstractBACKGROUND: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 ClinicalTrials.gov, 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] 080, 95% CI 068-093; log-rank p=00043). 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 074, 061-090; log-rank p=00020). 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.

2006 by American Society of Clinical OncologySequential Adjuvant Epirubicin-Based and Docetaxel Chemotherapy for Node-Positive Breast Cancer Patients: The FNCLCC PACS 01 Trial

AbstractPurposeThe 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 MethodsBetween 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-receptorpositive patients received tamoxifen for 5 years after chemotherapy. The primary end point was 5-year disease-free survival (DFS).ResultsMedian follow-up was 60 months. Five-year DFS rates were 73.2% with FEC and 78.4% with FEC-D (unadjustedP= .011; adjustedP= .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 (unadjustedP= .014; adjustedP= .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.ConclusionSequential 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.

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.

AbstractPURPOSE: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.

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

AbstractPurposeDocetaxel 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 MethodsOne thousand ten women with axillary nodepositive 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 withHER2-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.ResultsWomen assigned to docetaxel had better distant diseasefree survival (DDFS) than those assigned to vinorelbine (hazard ratio [HR] = 0.66; 95% CI, 0.49 to 0.91;P= .010). In the subgroup ofHER2-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.ConclusionAdjuvant 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.

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.AbstractBACKGROUND: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 ClinicalTrials.gov, 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] 099, 95% CI 085-114, p=086). 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 [204%] vs 275 [163%] grade 3-4 adverse events, and 120 [72%] vs 69 [41%] decreases in left ventricular ejection fraction, respectively). HRs for a comparison of 1 year of trastuzumab treatment versus observation were 076 (95% CI 067-086, p 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.

NSABP Protocol B-27. Preoperative doxorubicin plus cyclophosphamide followed by preoperative or postoperative docetaxel.

Preoperative Chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27.AbstractPurpose: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.Clin Breast Cancer.2002 Oct;3 Suppl 2:S69-74.Neoadjuvant docetaxel in breast cancer: 3-year survival results from the Aberdeen trial.

AbstractOver 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.

GEPAR duo TRIALNeoadjuvant 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 100mg/m2every 3 weeks, followed by surgery, four cycles of doxorubicin 60mg/m2and cyclophosphamide 600mg/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 ( 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]

HORMONE THERAPHYTamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study

AbstractBackground: 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 3559 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