Regular Article

British Journal of Cancer (2001) 85, 1–8. doi:10.1054/bjoc.2001.1829 www.bjcancer.com
Published online 3 July 2001

Adjuvant high-dose medroxyprogesterone acetate for early breast cancer: 13 years update in a multicentre randomized trial

C Focan1, M Beauduin2, E Salamon3, J de Greve4, G de Wasch4, J P Lobelle5, F Majois2, A Tagnon6, J Tytgat7, S van Belle8, R Vandervellen9 and A Vindevoghel3 for the Adjuvant Breast Cancer Project Belgium

  1. 1Saint-Joseph Clinics, Liège, Belgium
  2. 2Jolimont Hospital , Haine Saint-Paul, Belgium
  3. 3Sainte-Elisabeth Clinic, Namur, Belgium
  4. 4Oncology Centre, AZ-VUB, Jette, Belgium
  5. 5Pharmacia & Upjohn, Benelux, Brussels, Belgium
  6. 6Institut Medico-Chirurgical, Tournai, Belgium
  7. 7Heilige Hart Clinic, Roeselaere, Belgium
  8. 8Oncology Centre University, Gent, Belgium
  9. 9Saint-Michel Clinic , Brussels, Belgium

Received 23 February 2000; Revised 2 October 2000; Accepted 9 February 2001.

Top

Abstract

The authors updated their report on a randomized trial initiated in 1982 comparing, in early breast cancer, high-dose IM Medroxyprogesterone acetate (HD-MPA) adjuvant hormonotherapy during 6 months with no hormonotherapy; node-positive patients also received 6 courses of IV CMF (day 1, day 8; q.4 weeks). 246 node-negative (NN) and 270 node-positive (NP) patients had been followed for a median duration of 13 years. Previous results were confirmed in this analysis on mature data. In NN patients, relapse-free survival (RFS) was improved in the adjuvant hormonotherapy arm, regardless of age while overall survival (OAS) was also increased in younger (less then 50 years) patients. In the whole group of NP patients, no difference was seen regarding RFS or OAS. However, an age-dependant opposite effect was observed: younger patients (< 50) experienced a worse and significant outcome of relapse-free and overall survivals when receiving adjuvant HD-MPA while older patients (> = 50) enjoyed a significant improvement of their relapse-free survival. For both NN and NP patients, differences in overall survivals observed in older women with a shorter follow-up, were no longer detected. © 2001 Cancer Research Campaign http://www.bjcancer.com

Top

References

  1. Alberts SR, Ingle JN, Roche PR, Cha S, Wold LE, Favr GH Jr, Knook JE and Wieand HS (1996) Comparison of estrogen receptor determination by a biochemical ligand binding assay and immunohistochemical staining with monoclonal antibody ER1D5 in females with lymph node positive breast carcinoma entered on prospective clinical trials. Cancer 78: 764–772 | Article | PubMed | ISI | ChemPort |
  2. Andersen J (1992) Determination of estrogen receptors in paraffin-embedded tissue. Technic and the value in breast cancer treatment. Acta Oncol 31: 611–627 | PubMed |
  3. Andersson M, Kamby C, Jensen MB, Mouridsen H, Ejlerstsen B, Dombernowsky P, Rose C, Cold S, Overgaard M, Andersen J and Kjaer M (1999) Tamoxifen in high-risk premenopausal women with primary breast cancer receiving adjuvant chemotherapy. Report from the Danish Breast Cancer Co-operative Group DBCG 82B Trial. Eur J Cancer 35: 1659–1666 | PubMed |
  4. Beex L, Burghouts J, van Turnhout J, Breed W, Hillen H, Holdrinet A, Boetius G, Hoogendoorn G, Doesburg W and Verhulst M (1987) Oral versus i.m. administration of high-dose medroxyprogesterone acetate in pretreated patients with advanced breast cancer. Cancer Treat Rep 71: 1151–1156 | PubMed |
  5. Blossey HC, Wander HE, Koebberling J and Nagel GA (1984) Pharmacokinetic and pharmacodynamic basis for the treatment of metastatic breast cancer with high-dose medroxyprogesterone acetate. Cancer 54: 1208–1215 | PubMed |
  6. Bramwell VHC and Pritchard KI (1999) Tamoxifen added to adjuvant chemotherapy in premenopausal women with early breast cancer: is it standard practice or still a subject for study?. Eur J Cancer 35: 1625–1627 | PubMed |
  7. Canney PA, Dowsett M and Priestman TJ (1988) The pharmacokinetics of medroxyprogesterone acetate following two different loading dose schedules in advanced carcinoma of the breast. Br J Cancer 58: 73–76 | PubMed |
  8. Castiglione-Gertsch M, Pampallona S, Varini M, Cavalli F, Brunner K, Senn HJ, Goldhirsch A and Metzger U (1993) Primary endocrine therapy for advanced breast cancer: to start with tamoxifen or with medroxyprogesterone acetate?. Ann Oncol 4: 735–740 | PubMed |
  9. Cavalli F, Goldhirsch A, Jungi F, Martz G, Mermillod B and Alberto P(for the Swiss Group for Clinical Cancer Research) (1984) Randomized trial of low-versus high-dose medroxyprogesterone-acetate in the induction treatment of postmenopausal patients with advanced breast cancer. J Clin Oncol 2: 414–419 | PubMed |
  10. Cox DR (1972) Regression models and life-tables (with discussion). J. R. Stat S [B] 34: 187–220
  11. Early Breast Cancer Trialists' Collaborative Group (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. The Lancet 351: 1451–1467
  12. Early Breast Cancer Trialists' Collaborative Group (1996) Ovarian ablation in early breast cancer: overview of the randomised trials. The Lancet 348: 1189–1199
  13. Ejlertsen B, Dombernowsky P, Mouridsen HT, Kamby C, Kjaer M, Rose C, Andersen KW, Jensen MB, Bengtsson NO and Bergh J (1999) Comparable effect of ovarian ablation (OA) and CMF chemotherapy in premenopausal hormone receptor positive breast cancer patients (PRP). Proc of ASCO 18: 660 (abstr. 248)
  14. Etienne MC, Milano G, Frenay M, Renee N, François E, Thyss A, Schneider M and Namer M (1992) Pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate in advanced breast cancer patients. J Clin Oncol 1992 10: 1176–1182
  15. Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, Bryant J, Dimitrov NV, Abramson N, Atkins JN, Shibata H, Deschenes L and Margolese RG (1997) Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89: 1673–1682 | Article | PubMed | ChemPort |
  16. Focan C, Baudoux A, Beauduin M, Bunescu U, Dehasque N, Dewasch G, Lobelle JP, Longeval E, Majois F, Salamon E, Spapen H, Tagnon A, Tytgat J, Van Belle S, Vanderlinden B, Vandervellen R and Vindevoghel A (1986) Improvement of hematological and general tolerance to CMF by high-dose medroxyprogesterone-acetate (HD-MPA) adjuvant treatment for primary node positive breast cancer (analysis of 100 patients). Anticancer Res 6: 1095–1100 | PubMed |
  17. Focan C, Baudoux A, Beauduin M, Bunescu U, Dehasque N, Dewasch G, Lobelle JP, Longeval E, Majois F, Mazy V, Nickers P, Salamon E, Tagnon A, Tytgat J, van Belle S, Vanderlinden B, Vandervellen R and Vindevoghel A (1989) Adjuvant treatment with high dose medroxyprogesterone-acetate in node-negative early breast cancer. A 3-year interim report on a randomized trial. Acta Oncologica 28: 237–250 | PubMed |
  18. Focan C, Beauduin M, Salamon E, De Wasch G, Driesschaert P, Lobelle JP, Longeval E, Majois F, Tagnon A, Tytgat J, Van Belle S, Vanderlinden B, Vanderhoven P, Vandervellen R, Vindevoghel A and Warnier A (1990). Influence of age, node involvement and CMF chemotherapy on the outcome of early breast cancer treated with high dose medroxyprogesterone acetate (HD-MPA) as adjuvant hormonotherapy: 5 years Results of a randomized trial, in SE Salmon (ed): Adjuvant Therapy of Cancer VI. pp 319–329
  19. Focan C, Beauduin M, Salamon E, De Grève J, De Wasch G, Lobelle JP, Majois F, Tagnon A, Tytgat J, van Belle S, Vandervellen R and Vindevoghel A (1995) High-dose medroxyprogesterone acetate as adjuvant hormonotherapy in early breast cancer: 9 years results of a multicenter randomized trial. In Jonat W, Kaufmann M, Munk K (eds): Hormone-Dependent Tumors. Basic Research and Clinical Studies, vol 50, pp 145–158. Contrib Oncol. Basel, Karger
  20. Focan C, Beauduin M, Salamon E, De Gréve J, De Wasch G, Lobelle JP, Majois F, Tagnon A, Tytgat J, van Belle S, Vandervellen R and Vindevoghel A (1996) High dose medroxyprogesterone acetate (HD-MPA) as adjuvant hormonotherapy for early breast cancer. Ten years results of a multicenter randomized trial. Acta Clin Belgica, 51 3: 194
  21. Gill PG, Gebski V, Snyder R, Burns I, Levi J, Byrne M and Coates A (1993) Randomized comparison of the effects of tamoxifen, megestrol acetate, or tamoxifen plus megestrol acetate on treatment of response and survival in patients with metastatic breast cancer. Ann Oncol 4: 741–744 | PubMed |
  22. Hryniuk WM and Levine MN (1986) Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4: 1162–1170 | PubMed | ISI | ChemPort |
  23. Hupperets PSGJ, Wils J, Volovics L, Schouten L, Fickers M, Bron H, Schouten H, Jager J, de Jong J and Beex L (1993) Adjuvant chemo-hormonal therapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) with or without medroxyprogesterone acetate for node-positive breast cancer patients. Update at 7 year follow-up. Ann Oncol 4: 295–301 | PubMed |
  24. Hutchins L, Green S, Ravdin P, Lew D, Martino S, Abeloff M, Lyss A, Henderson C, Alfred C, Dakhil S, Pierce J, Goodwin W, Caton J, Rivkin S, Chapman R and Osborne K (1999) CMF versus CAF +/– Tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node negative patients: update of tamoxifen results. Breast Cancer Research and Treatment 57: 25
  25. Hyder SM, Murthy L and Stacel GM (1998) Progestin regulation of vascular endothelial growth factor in human breast cancer cells. Cancer Res 58: 392–395 | PubMed | ISI | ChemPort |
  26. Jakesz R, Hausmaninger H, Samonigg H, Kubista E, Depisch D, Fridrik M, Stierer M, Gnant M, Steger G, Kolb R, Jatzko G, Hofbauer F, Reiner G and Luschin-Ebengreuth G (1999) Comparison of adjuvant therapy with tamoxifen and goserelin vs CMF in premenopausal stage I and II hormone-responsive breast cancer patients: Four-year results of Austrian breast cancer study group (ABCSG) trial 5. Proc of ASCO 18: abstr. 250
  27. Kaplan EL and Meier P (1958) Non parametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481 | Article | ISI |
  28. Löber J, Rose C, Salimtschik M and Mouridsen HT (1981) Treatment of advanced breast cancer with progestins. Acta Obstet Gynecol Scand (suppl 101) 39–46
  29. Martoni A, Longhi A, Canova N and Pannuti F (1991) High-dose medroxyprogesterone acetate versus oophorectomy as first-line therapy of advanced breast cancer in premenopausal patients. Oncology 48: 1–6 | PubMed |
  30. Mattsson W (1980). A phase III trial of treatment with tamoxifen versus treatment with high-dose medroxyprogesterone-acetate in advanced post-menopausal breast cancer, in lacobelli S and di Marco A (ed): Role of medroxyprogesterone in endocrine-related tumors – Progress in cancer research and therapy,
  31. Muss HB, Case LD, Capizzi RL, Cooper MR, Cruz J, Jackson D, Richards F, Powell BL, Spurr CL and White D (1990) High-versus standard-dose megestrol acetate in women with advanced breast cancer. A phase III trial of the Piedmont Oncology Association. J Clin Oncol 8: 1797–1805 | PubMed |
  32. Muss HB, Wells B, Paschold EH, Black WR, Coopper MR, Capizzi RL, Christian R, Cruz JM, Jackson DV and Powell BL (1988) Megestrol acetate versus tamoxifen in advanced breast cancer: 5 year analysis – a phase III trial of the Piedmont Oncology Association. J Clin Oncol 6: 1098–1106 | PubMed |
  33. Ng V, Ragaz J, Spinelli HJ and Jackson S (1989) Introduction of cumulative dose intensity product (DIP) for measuring the delivered dose intensity (DI) of chemotherapy – Analysis of the British Columbia Breast Cancer Randomized Study. Proceedings of Am Soc Clin Oncol 8: 47 (Abstr 181)
  34. Pannuti F, Martoni A, Cilenti G, Camaggi CM and Fruet F (1988) Adjuvant therapy for operable breast cancer with medroxyprogesterone acetate alone in postmenopausal patients or in combination with CMF in premenopausal patients. Eur J Cancer Clin Oncol 24: 423–429 | PubMed |
  35. Paridaens R, Becquart D, Michel J, Vanderlinden B, Longueville J, Majois F, Beauduin M, Focan C, Wildiers J, Bernheim J, Lobelle JP, Arrigo C, Sylvester RJ and Heuson JC (1986) Oral versus intramuscular high-dose medroxyprogesterone (HD-MPA) in advanced breast cancer. Anticancer Res 6: 1089–1094 | PubMed |
  36. Pertschuk LP, Kim YD, Axiotis CA, Braverman AS, Carter AC, Eisenberg KB and Braithwaite LV (1994) Estrogen receptor immunocytochemistry: the promise and the perils. J Cell Biochem Suppl 19: 134–137 | PubMed |
  37. Robustelli Della Cuna G, Calciati A, Bernardo Strada MR, Bumma C and Campio L (1980). High-dose medroxyprogesterone-acetate (HD-MPA) combined with chemotherapy for metastatic breast carcinoma, in lacobelli S, Di Marco A (ed): Role of medroxyprogesterone acetate in endocrine-related tumors, pp 53–64,
  38. Rubens RD (1993) Towards improved endocrine therapy for advanced breast cancer. Ann Oncol 4: 712–713 | PubMed |
  39. Rutqvist LE (1999). Zoladex and tamoxifen as adjuvant therapy in premenopausal breast cancer: a randomised trial by the cancer research campaign (C.R.C.) Breast Cancer Trials Group, the Stockholm Breast Cancer Study Group, The South-East Sweden Breast Cancer Group & the Gruppo Interdisciplinare Valutazione Interventi in Oncologica (G.I.V.I.O.), Proc of ASCO ASCO, vol. 18, 67a (abstr. 251).
  40. Stewart HJ and Everington D (1995) Ovarian ablation versus CMF chemotherapy as adjuvant therapy for breast cancer. In Jonat W, Kaufmann M, Munk K (eds): Hormone-Dependent Tumors. Basic Research and Clinical Studies. Vol 50, pp 176–183 Contrib Oncol. Basel, Karger
  41. Tamassia V, Battaglia A, Gangina F, Isetta AM, Sacchetti G, Cavalli F, Goldhirsch A, Brunner K, Bernardo G and Robustelli della Cuna G (1982) Pharmacokinetic approach to the selection of dose schedules for medroxyprogesterone-acetate in clinical oncology. Cancer Chemother Pharmacol 8: 151–156 | PubMed |
  42. Tchekmedyian NS, Tait N and Aisner J (1986) High-dose megestrol acetate in the treatment of postmenopausal women with advanced breast cancer. Semin Oncol 13: 20–25 | PubMed |
  43. Van Veelen H, Willemse PH, Sleijfer DT, Sluiter WJ and Doorenbos H (1985) Endocrine effects of medroxyprogesterone acetate: relation between plasma level and suppression of adrenal steroids in patients with breast cancer. Cancer Treat Rep 69: 979–983
  44. Van Veelen H, Willemse PHB, Tabies T, Sleijfer DT, Sluiter WJ and Doorenbos J (1986) Oral high-dose medroxyprogesterone acetate versus tamoxifene. A randomized cross-over trial in postmenopausal patients with advanced breast cancer. Cancer 58: 7–13 | PubMed |
  45. Wils JA (1988) Myeloprotective effect of high dose medroxyprogesterone acetate (MPA). Chemioterapia 7: 60–62 | PubMed |