Chemotherapy in Metastatic Breast Cancer: What has been accomplished?
Update March 15, 2003: In the March 15, 2003 issue of the Journal of Clinical Oncology, there is an editorial by Valero and Hortobagyi which reviews all of the large, prospective, randomized trials published comparing the newer, taxane-based chemotherapy regimens. These authors conclude that none of these regimens have increased either complete response rates or overall survival, with median survivals remaining at 2 years or less, or precisely the same results which were being obtained 30 years ago. (Valero,V. and Hortobagyi,G.N. Are anthracycline-taxane regimens the new standard of care in the treatment of metastatic breast cancer? J Clin Oncol 21(6): 959-962, 2003).
In the September, 2002, issue of a new review journal (The American Journal of Oncology Review), there is a remarkable commentary by Lawrence N. Shulman, M.D., Vice Chair for Clinical Services/Adult Oncology, Dana-Farber Cancer Institute (Harvard Medical School), Boston.
The commentaryA is remarkable because it pulls no punches in describing the complete lack of progress in the chemotherapeutic treatment of metastatic breast cancer since 1970.
The following are verbatim quotations from the commentary. References cited by Dr. Shulman appear below. Clicking on each reference (listed at the end) will display the abstract.
"The article by Berry and colleagues represents the results of nearly 30 years of clinical investigation in the treatment of patients with metastatic breast cancer. The results are not encouraging1...the seminal message is that neither [standard or high dose chemotherapy] has done a great deal to improve the outcome of patients with this disease."
"[over the past 20 years]... We relentlessly combined chemotherapy agents in various regimens, with ever-increasing dose intensity...as seen in this compilation of data, the survival for patients participating in these studies is exactly the same, less than 2 years. These four studies are a snapshot of hundreds of studies done throughout the world, spanning 30 years, utilizing innumerable combinations of standard dose chemotherapy without a hint of significantly improved survival."
Shulman noted that a retrospective comparison1 of the above, well-characterized "standard dose" database with a less well characterized "high dose" database suggested that there was increased early mortality for high dose therapy (not surprising), while "the difficult aspect of this manuscript to accept is the somewhat uncertain conclusion of the long term benefit from high-dose therapy...there appears to be a small number of patients who have long-term survival after high dose therapy...the concept that highly selected patients whose tumors are responsive to chemotherapy can have long-term remissions from standard dose chemotherapy as well is supported by a [different] retrospective study2."
"The one large [prospective] randomized trial....showed no difference in survival for patients treated with standard-dose versus high-dose chemotherapy. The median survival for both groups was 2 years, and no subset of patients seemed to benefit from high dose therapy.3"
"Even if one were an optimist and concluded that the [high dose] data suggested that a small but significant subgroup of patients benefited from this approach, one must remember that the patients participating in these studies are already highly selected for age, performance status, response to induction therapy, and other factors, and that...at best we must be helping only an incredibly small percentage of the patients with this disease."
"Clearly, more effective therapies are desperately needed for women with metastatic breast cancer, and after 30 years of investigation aimed at intensified multiagent chemotherapy we should look for other avenues of study."
"[noted breast cancer oncologist] Powles...concluded4 that chemotherapy had not changed overall survival, which was approximately 2 years prior to the use of chemotherapy and afterward. This is the same survival seen in the studies outlined in [the present] manuscript....[Powles concluded] the fact that regressions of breast cancer had no influence on overall survival must reflect the inadequacy of present-day chemotherapy. Powles published his manuscript in 1980. One could say the same applies in 2002."
"Powles wonders how the use of chemotherapy , which clearly induces responses in some patients, cannot have affected the overall survival. Does chemotherapy shorten survival of some patients, while prolonging the survival of others?"
In other words, "standard" (one size fits all) chemotherapy of metastatic breast cancer is a zero sum game.
References:
A. Shulman, LN. Chemotherapy in the treatment of patients with metastatic breast cancer: high-dose, low-dose -- what have we accomplished? Am J Oncology Rev 1(3):169-70, 2002
1: J Clin Oncol 2002 Feb 1;20(3):743-50 High-dose versus standard chemotherapy in metastatic breast cancer: comparison of Cancer and Leukemia Group B trials with data from the Autologous Blood and Marrow Transplant Registry. Berry DA, Broadwater G, Klein JP, Antman K, Aisner J, Bitran J, Costanza M, Freytes CO, Stadtmauer E, Gale RP, Henderson IC, Lazarus HM, McCarthy PL Jr, Norton L, Parnes H, Pecora A, Perry MC, Rowlings P, Spitzer G, Horowitz MM. University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA. dberry@odin.mdacc.tmc.edu
2: J Clin Oncol 1997 Oct;15(10):3171-7 Comment in: J Clin Oncol. 1997 Oct;15(10):3169-70. J Clin Oncol. 1998 Mar;16(3):1238-9. Impact of selection process on response rate and long-term survival of potential high-dose chemotherapy candidates treated with standard-dose doxorubicin-containing chemotherapy in patients with metastatic breast cancer. Rahman ZU, Frye DK, Buzdar AU, Smith TL, Asmar L, Champlin RE, Hortobagyi GN. Department of Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. zrahman@notes.mdacc.tmc.edu
3: N Engl J Med 2000 Apr 13;342(15):1069-76 Comment in: N Engl J Med. 2000 Apr 13;342(15):1119-20. N Engl J Med. 2000 Aug 10;343(6):439-40; discussion 440-1. N Engl J Med. 2000 Aug 10;343(6):439; discussion 440-1. N Engl J Med. 2000 Aug 10;343(6):440; discussion 440-1. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. Stadtmauer EA, O'Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, Brodsky I, Martino S, Lazarus HM, Erban JK, Sickles C, Glick JH. Bone Marrow and Stem Cell Transplant Program, University of Pennsylvania Cancer Center, Philadelphia 19104, USA. stadtmau@mail.med.upenn.edu
4: Lancet 1980 Mar 15;1(8168 Pt 1):580-2 Failure of chemotherapy to prolong survival in a group of patients with metastatic breast cancer. Powles TJ, Coombes RC, Smith IE, Jones JM, Ford HT, Gazet JC.