Canadian Cancer Trials Group Bulletins

General


Accomplishments of MA.5

The MA.5 trial is a stellar example of a high quality Canadian Cancer Trials Group trial. This trial was activated on December 1, 1989. The trial compared standard adjuvant therapy with CMF as compared with intensive CEF in premenopausal patients with newly diagnosed breast cancer and histologically involved axillary nodes. The experimental arm, CEF, was developed in Canada through pilot work conducted by the Ontario Clinical Oncology Group. Between December 1989 and July 1993, 716 women from across Canada entered this trial. The primary results were reported in the Journal of Clinical Oncology in 1998 and showed a 10% increase in 5-year relapse-free survival and a 7% increase in 5-year overall survival associated with the experimental treatment. These results led to regulatory approval of epirubicin for the treatment of breast cancer and adoption of CEF as a standard therapy. This CEF regimen has gone on to be tested further in the Canadian Cancer Trials Group MA.21 trial, in which preliminary reporting demonstrated superior disease free survival as compared with standard treatment with Adriamycin, cyclophosphamide, and paclitaxel.

Furthermore, the MA.5 trial has been an outstanding example of attaching correlative-translational research work to our clinical trials. Groundbreaking work with respect to Her 2 expression and use of anthracycline therapy and most recently, topoisomerase II alpha and outcome according to anthracycline treatment are outstanding examples of such work. The MA.5 trial was the first Canadian Cancer Trials Group trial to be associated with a Quality of Life publication; in this instance, patient compliance was assessed. Finally, the results of MA.5 have been included in large individual-patient data meta-analyses assessing treatments of breast cancer.

The publication list associated with MA.5 is extensive. Omitting abstract and review publications, 13 primary research papers have resulted from the MA.5 trial and have been published in high-impact journals that include the New England Journal of Medicine, the Lancet, the Journal of Clinical Oncology, and Journal of the National Cancer Institute.

In closing MA.5 it is important for the outstanding accomplishments that have resulted from this trial to be recognized. Special recognition goes to the Study Chair, Dr. Mark Levine, the Disease Site Chair during the conduct of MA.5, Dr. Kathy Pritchard, the Canadian Cancer Trials Group Physician Coordinator Dr. Lois Shepherd and Senior Biostatistician Dr. Dongsheng and to Kathy Bennett, Jon Ottaway and Nancy Paul who, as study coordinators, oversaw the conduct of the trial for many years. Our thanks and congratulations go to each of these trial leaders and the many investigators, clinical research associates, and Central Office staff who have contributed to this outstanding project.

With future closure of Canadian Cancer Trials Group trials, we will strive to make note of those that have been associated with particularly outstanding research accomplishments. In addition, we will develop a user-friendly linkage on our website so that those interested can find the publications associated with a specific closed trial. In the meantime, we will post this Bulletin item as a memo, with the listed citations on the "Permanent Trial Closure" website at http://www.ctg.queensu.ca/trials/closure.html.

Reference List for MA5 as of June 8, 2009

1. O'Malley FP, Chia S, Tu D, Shepherd LE, Levine MN, Bramwell VH, Andrulis IL, Pritchard KI. Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 101: 644-50, 2009.

2. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Clarke M, Coates AS, Darby SC, Davies C, Gelber RD, Godwin J, Goldhirsch A, Gray R, Peto R, Pritchard KI, Wood WC. Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patient-level meta-analysis of randomised trials. Lancet 371: 29-40, 2008.

3. Pritchard KI, Shepherd LE, O'Malley FP, Andrulis I, Andrulis IL, Tu D, Bramwell VH, ancer to adjuvant chemotherapy. N Engl J Med 354: 2103-11, 2006.

4. Levine MN, Pritchard KI, Bramwell VHC, Shepherd LE, Tu D, Paul N. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol 23: 5166-70, 2005.

5. Ouyang Y, Li D, Pater JL, Levine M. The importance of temporal effects in evaluating the prognostic impact of joint ERPR expression in premenopausal women with node-positive breast cancer. Breast Cancer Res Treat 92: 115-23, 2005.

6. Parulekar WR, Day A, Ottaway J, Shepherd LE, Trudeau ME, Bramwell V, Levine M, Pritchard KI. Incidence and Prognostic Impact of Amenorrhea During Adjuvant Therapy in High-Risk Premenopausal Breast Cancer: Analysis of a National Cancer Institute of Canada Clinical Trials Group Study┐Canadian Cancer Trials Group MA.5. J Clin Oncol 23: 6002-8, 2005.

7. Praga C, Bergh J, Bliss J, Bonneterre J, Cesana B, Coombes C, Fargeot P, Folin A, Fumoleau P, Giuliani R, Kerbrat P, Hery M, Nilsson J, Onida F, Piccart M, Shepherd L, Therasse P, Wils J, Rogers D. Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol 23: 4179-91, 2005.

8. Crump M, Tu D, Shepherd L, Levine M, Bramwell V, Pritchard K. Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: A report from the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21: 3066-71, 2003.

9. Levine M, Bramwell V, Pritchard K, Norris B, Shepherd L, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CKO, Tu D. Randomized trial of cyclophosphamide, epirubicin, fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, fluorouracil in premenopausal women with node positive breast cancer. Classic Papers & Current Comments 5: 694-702, 2001.

10. Levine M, Bramwell V, Pritchard K, Norris B, Shepherd L, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CKO, Tu D. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node positive breast cancer. J Clin Oncol 16: 2651-8, 1998.

11. Levine M, Pritchard K, Bramwell V, Shepherd L. Adjuvant chemotherapy with CEF versus CMF for node-positive breast cancer (in reply letter to the editor). J Clin Oncol 16: 3917, 1998.

12. Shepherd L, Ottaway J, Myles J, Levine M. Therapy-related leukemia associated with high-dose 4-epi-doxorubicin and cyclophosphamide used as adjuvant chemotherapy for breast cancer (letter to the editor). J Clin Oncol 12: 2514-5, 1994.

13. Sadura A, Pater J, Osoba D, Levine M, Palmer M, Bennett K. Quality of life assessment: patient compliance with questionnaire completion. J Natl Cancer Inst 84: 1023-6, 1992.