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edge

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Just in the space of 24 hours I have received over a couple  of dozen inquiries (from two continents) about the just reported TACT trial[1] which purports to demonstrate that there is no overall gain from the addition of a taxane, docetaxel (Taxotere), to standard anthracycline chemotherapy, which if valid would undermine such mainstay regimens such as AC/T via the suggestion that we could dispense with the following sequential taxane in clinical practice, and these conclusions have been reported with alarm on a number of online BC forums.  So  to set the record straight, I will advise below that there  are a number of critical problems and issues making for serious methodological compromise of the TACT trial's design and more importantly, conclusions:

 

Contra-TACT: Flaws in the Woodwork

 

  1. The TACT trial findings run against  the weight of the evidence base to  date on taxane benefit in breast cancer: a review by Laura Estévez team2 of 6 major methodologically strong randomized clinical trials (RCTs) evaluating the role of adjuvant taxanes for node-positive breast cancer, concluded that there is sufficiently robust evidence supporting the benefit of routine use of taxanes to the adjuvant treatment of node-positive BC, and furthermore all six RCTs demonstrated significant improvements in terms of efficacy in favor of the taxane treatment arm. This is  further confirmed and independently supported by  the FNCLCC PACS 01 Trial, the BIG 02-98 trial, the Taxit216 trial, the infamous FinHER trial, Joseph  Sparano's recent seminal weekly paclitaxel study, as well as the JCO 2008 DeLaurentis meta-analysis and the latest  Cochrane systematic review2-10.  And note that in the Cochrane systematic review, the hazard ratios for the taxane/anthracycline regimens as compared with the non-taxane combinations were 0.88 for overall survival and 0.81 for time-to-progression (TTP), and with 5 trials reporting on response, the odds ratio for response for the taxane/anthracycline regimens as compared with the non-taxane/anthracycline combinations was 1.7.  Finally, the TACT findings are non-congruent with those of major BC guidelines,  NCCN16, the UK NICE15, CCO (Cancer Care Ontario)14, SIGN17, BCCA (BC Cancer Agency)18, CECOG19, among many others.
  2. In this connection, it should be noted that the important  recent meta-analyses by the Piccart–Gebhart group13 also, like the TACT trial, directly addressed the issue of taxane/anthracycline regimens as compared with non-taxane/anthracycline combination therapy, with individual patient data from eight randomized trials included (4 trials with docetaxel and 4 with paclitaxel), finding the hazard ratios for the taxane/anthracycline regimen as compared with the non-taxane/anthracycline combination to be 0.95 for overall survival and 0.92 progression-free survival (PFS), hence with response rates significantly favoring the taxane/anthracycline regimens (57% vs. 46%). 
  3. In the TACT trial the dose of the anthracycline, epirubicin (Ellence) selected for the FEC regimen was 60 mg/m², a suboptimal schedule: FEC-100 (epirubicin at 100 mg/m2) is the standard, and even FEC-75 is debatable but FEC-60 would, and is, considered to be a significantly compromised anthracycline-based regimen; epirubicin doses of 50 mg/m² and 60 mg/m² have been decisively demonstrated inferior to those containing 100 mg/m² by the 15-year efficacy results of the Belgian Multicentre Study (BMS) from Evandro de Azambuja's team11 (JCO 2009), with significantly improved 15-year EFS (event-free survival) compared with lower doses, re-confirming the findings of Jacques Bonneterre's landmark FASG 05 (French Adjuvant Study Group) trial12.
  4. Since the TACT trial design, somewhat imprudently, dictated the assurance of the same number of cycles (8) in each comparator group, this artificially protracted regimen forced the selection of a low, and suboptimal, dose of epirubicin in the controls and therefore also in the experimental group in order to avoid excess toxicity of epirubicin cumulative dosing, and in the experimental group this could have jeopardized the efficacy of docetaxel by inducing multidrug resistance (MDR), a common phenomenon inducible by a preceding suboptimal therapy in any sequential chemotherapy regimen.   This induction of MDR was not controlled for by the investigators who apparently,  again against evidence and clinical experience, somehow failed to anticipate or appreciate the efficacy compromise to the following taxane (docetaxel (Taxotere)) agent of a preceding suboptimal anthracycline dosing schedule, something I and most researchers  are on guard for (and one of the reasons I advocate whenever possible pegylated liposomal Doxil over the traditional anthracyclines,  as this allows for higher cumulative dosing that evades the induction of MDR without compromising efficacy, with an additional benefit of lower near-null risk of cardiotoxicity). 
  5. In addition, the TACT trial included - predominantly in fact on the authors own admission - a population of patients with whose tumors are likely to have a low sensitivity to taxanes: this includes endocrine-positive and HER2-negative subpopulations, and such a skewing towards low taxane-sensitive cohorts can distort and depress the observed docetaxel (Taxotere) efficacy results.

 


Lessons Learned 

In conclusion, the multiple methodological compromises I have appraised coupled with trial findings being overwhelming against the cumulative taxane outcome data base to date, suggests that the TACT trial is insufficiently robust and methodologically powered to support its conclusions, which  must  therefore remain elliptical to the balance of the evidence, requiring further large-scale well-designed prospective confirmation before the TACT trial proposed conclusions can inform or change current or projected clinical practice.

 


References

 

  1. Ellis P, Barrett-Lee P, Johnson L, et al, for the TACT Trial Management Group and the TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet 2009; 373: 1681–92.
  2. Estévez LG, Muñoz M, Alvarez I, et al. Evidence-based use of taxanes in the adjuvant setting of breast cancer. A review of randomized phase III trials.  Cancer Treat Rev 2007 Jun 8.
  3. Roche H, Fumoleau P, Spielmann M, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol 2006; 24: 5664–71.
  4. Francis P, Crown J, Di Leo A, et al, on behalf of the BIG 02-98 Collaborative Group. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. J Natl Cancer Inst 2008; 100: 121–33.
  5. Bianco AR, De Matteis A, Manzione L, et al. Sequential epirubicin-docetaxel-CMF as adjuvant therapy of early breast cancer: results of the Taxit216 multicenter phase III trial. J Clin Oncol 2006; 24 (suppl 18): LBA520 (abstr).
  6. De Laurentiis M, Cancello G, D’Agostino D, et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 2008; 26: 44–53.
  7. Fergason T, Wilcken N, Vagg R, Ghersi D, Nowak AK. Taxanes for adjuvant treatment of early breast cancer. Cochrane Database Syst Rev 2007: 4: CD004421.
  8. Bria E, Nistico C, Cuppone F, et al. Benefit of taxanes as adjuvant chemotherapy for early breast cancer: pooled analysis of 15 500 patients. Cancer 2006; 106: 2337–44.
  9. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al, for the FinHer Study

Investigators. Adjuvant docetaxel or vinorelbine with or without

trastuzumab for breast cancer. N Engl J Med 2006; 354: 809–20.

  1. Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant

treatment of breast cancer. N Engl J Med 2008; 358: 1663–71.

  1. de Azambuja E, Paesmans M, Beauduin M, et al. Long-Term Benefit of High-Dose Epirubicin in Adjuvant Chemotherapy for Node-Positive Breast Cancer: 15-Year Efficacy Results of the Belgian Multicentre Study. J Clin Oncol 2008 Dec 22.
  2. Bonneterre J, Roché H, Kerbrat P, et al. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 2005 Apr 20; 23(12):2686-93.
  3. Piccart–Gebhart MJ, Burzykowski T, Buyse M, et al. Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer. J Clin Oncol 2008;26:1980–6.
  4. Verma S, Trudeau M, Pritchard K, Oliver T and the members of the Breast Cancer Disease Site Group. The Role of the Taxanes in the Management of Metastatic Breast Cancer. Practice Guideline Report 1-3. Ver. 2.2003. Hamilton, ON: Cancer Care Ontario.
  5. United Kingdom, National Institute for Health and Clinical Excellence (nice). Guidance on the Use of Taxanes for the Treatment of Breast Cancer. Technology appraisal guidance no. 30. London, U.K.: nice; 2001.
  6. National Comprehensive Cancer Network (NCCN). Invasive Breast Cancer. NCCN Clinical Practice Guidelines in Oncology. V.1.2009. Fort Washington, PA: NCCN; 2009.
  7. Scottish Intercollegiate Guidelines Network (sign). Management of Breast Cancer in Women. A National Clinical Guideline. SIGN #84. Edinburgh, U.K.: sign; 2005. [Available online at: http://www.sign.ac.uk/pdf/sign84.pdf; cited June 15, 2009]
  8. BC Cancer Agency. Cancer Management Guidelines: A Guide for Women with Advanced Breast Cancer. Vancouver, BC: BC Cancer Agency; 2007.
  9. Beslija S, Bonneterre J, Burstein H, et al. Second consensus on medical treatment of metastatic breast cancer. Ann Oncol 2007;18:215–25.

 


Constantine Kaniklidis

Breast Cancer Watch

edge@evidencewatch.com

nosurrender

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Reply with quote  #2 
Thank God we have you to spell things out for us!!!!!

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