© 2001 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 30, 114-116,
2001
© 2001 Oxford University Press
Overview of the Six Available Randomized Trials of High-Dose Chemotherapy With Blood or Marrow Transplant in Breast Cancer
Affiliation of author: Department of Medicine and Pharmacology, Columbia University, and Herbert Irving Comprehensive Cancer Center, New York, NY.
Correspondence to: Karen H. Antman, M.D., Columbia University, MHB 6N-435, 177 Fort Washington Ave., New York, NY 10032 (e-mail: kha4{at}columbia.edu).
In animal models of breast cancer and other malignancies, dose of chemotherapy correlates with curative therapy, while cumulative dose is associated with survival (1). Thus, using high doses when cure is the objective, but using smaller doses over a prolonged period when palliation and survival are the goal may be appropriate strategies.
Of the 11 randomized trials of high-dose therapy in breast cancer reported to date (Table 1
), five included women with metastatic cancer. Of the six remaining adjuvant studies, one, the South African study, has been discredited (2). Two of the remaining studies randomly assigned fewer than 100 patients. Thus, neither one could exclude a survival difference of 30% or less. The Scandinavian study does not compare high-dose therapy with conventional-dose therapy. The two remaining moderately large trials include the Dutch and American intergroup studies with 885 and 785 patients, respectively.
|
Mortality was consistently low, in the 0%–2.5% range, for the high-dose regimens except for the carmustine (BCNU)-containing Cancer and Leukemia Group B (CALGB)/Intergroup study, which had a 7.4% toxic mortality rate. Mortality for the more conventional dose arms was in the range of 0%–1%.
The Dutch trial is the largest of all published studies (885 randomly assigned patients) and, therefore, has the greatest statistical power to detect modest differences (3). It compares four courses of FEC (i.e., a combination of 5-fluorouracil, epirubicin, and cyclophosphamide) with either an additional cycle of FEC or with CTCb (i.e., a combination of cyclophosphamide, thiotepa, and carboplatin) with stem cell support followed by surgery, radiation therapy, and tamoxifen for 2 years. In the study as a whole, the mortality was one of 443 patients on standard-dose FEC and four of 442 on high-dose CTCb. At a median of 3 years follow-up, a trend (P = .057) has emerged in disease-free survival (DFS) favoring high-dose therapy. In a planned analysis of the first 284 patients, at a median follow-up of 6 years, disease-free survival and overall survival were significantly better for the high-dose therapy.
The CALGB/Intergroup study compares high with intermediate-dose cyclophosphamide, BCNU, and cisplatin (CBP) after four cycles of a CAF (i.e., a combination of cyclophosphamide, doxorubicin, and 5 fluorouracil) induction (4). Although a critique of the study is that intermediate-dose CBP is not a standard regimen, scientifically, this design is a pure comparison between high- and intermediate-dose CBP.
This first-generation BCNU-containing regimen had a 7.4% mortality, which varied with the experience of the transplant center and increased with patient age. Pulmonary and hepatic toxicity was also substantial. With a median of 5.1 years of follow-up at the time of presentation at the consensus meeting, differences are not statistically significant in either progression-free survival or overall survival between the two groups. Fewer events have occurred than would have been predicted from historical series, suggesting either patient selection or an effect of the "intermediate"-dose CBP. Importantly, fewer relapses have occurred in the high-dose arm, but survival in the two arms is similar, presumably because of the early toxic mortality of 7.4%.
The Scandinavian trial compared three cycles of induction FEC followed by one high-dose cycle of CTCb with nine cycles of moderately high dose "tailored" FEC. (That is, the doses in mg/m2 of FEC were tailored to individual tolerance up to 600 of 5-fluorouracil, 120 of epirubicin, and 1800 of cyclophosphamide per cycle.) The cumulative doses for tailored therapy that were actually delivered substantially exceeded those for the CTCb arm. Therefore, this study assesses the role of one high-dose cycle compared with nine cycles of chemotherapy intensified to individual tolerance with a higher cumulative chemotherapy dose. The study probably includes some patients with metastatic disease, since patients with involved marrow and abnormal bone scans were included (5).
At a median follow-up of just 3 years, disease-free survival is significantly improved for the six cycles of tailored-dose therapy compared with one high-dose cycle. Of the 251 patients on the tailored-dose arm, six developed leukemia and three developed myelodysplasia, compared with none on the marrow transplant arm. Because the median follow-up is only 3 years, additional cases are possible or even likely. Topoisomerase-associated leukemias tend to occur early, but alkylating agent-associated leukemias would emerge later than the current median follow-up. Stem cells collected after three cycles of chemotherapy for use in stem cell support may be less damaged than those exposed in situ to nine chemotherapy cycles escalated to patient tolerance.
The South African study was reported to be a direct comparison of conventional CAF versus two cycles of high-dose chemotherapy (without a preceding induction phase) (2). An independent audit team documented many inconsistencies in eligibility criteria, as well as in reported data. Documentation of treatment and outcome for the control group was totally unavailable. The title of the protocol provided to the audit team, however, suggests that the control group was treated with cyclophosphamide, mitoxantrone, and vincristine and not CAF. On the basis of these findings, the abstract has been withdrawn and the data are best considered unreliable (6).
The Netherlands Cancer Institute randomly assigned 81 women with an involved apical axillary lymph node after four initial courses of FEC either to an additional cycle of FEC or to CTCb with stem cell support followed by surgery, radiation therapy, and tamoxifen for 2 years. At a median follow-up of 49 months, DSF and overall survival were similar. Although this randomized phase II study is mature, in that most of the expected events have already occurred, this small study cannot exclude differences of less than 30% in survival (7). Thus, the Dutch undertook their larger study, described above, which currently shows about a 15% advantage in DFS for high-dose therapy in the group with the longest follow-up.
A second small study at The University of Texas M. D. Anderson Cancer Center, Houston, randomly assigned 78 patients to eight cycles of FAC with or without two cycles of high-dose chemotherapy with cyclophosphamide, etoposide, and cisplatin. Three patients randomly assigned to conventional-dose therapy received transplants elsewhere; six patients randomly assigned to receive a transplant did not receive it. With a median follow-up exceeding 78 months, no advantage for high-dose chemotherapy has emerged. This study was closed because of slow accrual, but it has the statistical power to rule out differences in outcome of more than 30% (8).
Ongoing or unpublished randomized high-dose therapy studies in breast cancer are shown in Table 2.
|
SUMMARY OF RANDOMIZED ADJUVANT TRIALS
On the basis of the data so far, mortality is 0%–2% in all studies but one—about the same as for conventional dose therapy. The South African adjuvant study has been discredited. The Scandinavian study, which compares one high-dose cycle with six cycles of escalated dose tailored to individual tolerance, does not compare conventional- with high-dose chemotherapy. Two small studies, comparing standard FAC or FEC with or without high-dose chemotherapy, report no differences but can not exclude a 30% difference. In fact, one was the pilot study for the larger Netherlands trial, which currently has a trend in favor of high-dose therapy, with statistically significant differences in DFS and overall survival in the first 285 patients accrued with 6 years of follow-up. These two Dutch studies provide an object lesson in biostatistics: specifically, the issue of drawing conclusions from underpowered studies. The U.S. study, comparing high-dose therapy with an intermediate-dose therapy, has a statistically significant decreased relapse rate for the high-dose arm—a biological effect similar to that in the Dutch study. However, the higher mortality obviates any advantage of the high-dose therapy.
Survival curves for conventional adjuvant therapy of breast cancer show no plateau indicating cure for 15–20 years after diagnosis (9). Additional follow-up of the two larger randomized trials that compare high-dose with relatively conventional-dose chemotherapy and the completion of other ongoing randomized trials will provide more reliable information to determine what role high-dose chemotherapy regimens should have, if any, in the management of high-risk primary breast cancer.
REFERENCES
1 Skipper HE. Dose intensity versus total dose of chemotherapy: an experimental basis. In: DeVita VT, Hellman S, Rosenberg SA, editors. Important advances in oncology. Philadelphia (PA): Lippencott; 1990. p. 43–64.
2 Bezwoda WR. Randomised, controlled trial of high dose chemotherapy versus standard dose chemotherapy for high risk, surgically treated, primary breast cancer [abstract]. Proc ASCO 1999;18:2a.
3 Rodenhuis S, Bontenbal M, Beex L, van der Wall E, Richel D, Nooij M, et al. Randomized phase III study of high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin in operable breast cancer with 4 or more axillary lymph nodes [abstract]. Proc ASCO 2000;19:74.
4 Peters WP, Rosner G, Vredenburgh J, Shpall E, Crump M, Marks L, et al. A prospective, randomized comparison of two doses of combination alkyating agents as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes: preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13 [abstract]. Proc ASCO 1999; 18:1a.
5 Bergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, Malmstrom P, et al. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study. Lancet 2000;356:1384–91.[CrossRef][ISI][Medline]
6 Weiss RB, Rifkin RM, Stewart FM, Theriault RL, Williams LA, Herman AA, et al. High-dose chemotherapy for high-risk primary breast cancer: an on-site review of the Bezwoda study. Lancet 2000;355:999–1003.[CrossRef][ISI][Medline]
7 Rodenhuis S, Richel DJ, van der Wall E, Schornagel JH, Baars JW, Koning CC, et al. Randomized trial of high-dose chemotherapy and hematopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement. Lancet 1998;352:515–21.[CrossRef][ISI][Medline]
8
Hortobagyi GN, Buzdar AU, Theriault RL, Valero V, Frye D, Booser DJ, et al. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 2000;92:225–33.
9
Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 1995;332:901–6.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||