Correspondence
High-Dose Chemotherapy for Breast Cancer
N Engl J Med 2003; 349:1476-1479October 9, 2003
- Article
To the Editor:
The conclusion drawn by Rodenhuis et al. (July 3 issue)1 — that high-dose therapy improves relapse-free survival among patients with 10 or more positive nodes — is untenable. The authors failed to apply the method specified in their Statistical Analysis section — namely, the use of tests for interaction to evaluate differences in the treatment effect within subgroups. Such analysis does not provide good evidence that there is greater benefit for patients with 10 or more positive nodes than for those with fewer than 10. The P values in individual subgroups are unimportant; the P value for the interaction indicates whether treatment effects differ.2 The absence of an interaction (P=0.2) means that a benefit for patients with 10 or more positive nodes cannot be claimed when no significant benefit exists overall (P=0.09).
Furthermore, unplanned subgroup analyses were performed with respect to 10 other variables. With such multiple testing, spurious, “false positive” results can easily arise. Hence, the apparent interaction with HER2/neu status may well be a chance finding.
Invalid conclusions are frequently drawn from analyses of subgroups,3 resulting in misleading, usually overly positive, impressions of treatment efficacy. To define the true role of high-dose therapy reliably, meta-analysis of patient data from all relevant randomized trials (such as that performed for trials of tamoxifen4) is needed.
4 ReferencesKeith Wheatley, D.Phil.
Richard G. Gray, M.A., M.Sc.
Natalie J. Ives, M.Sc.
University of Birmingham Clinical Trials Unit, Birmingham B15 2RR, United Kingdom
k.wheatley@bham. ac. uk 1
Rodenhuis S ,Bontenbal M ,Beex LVAM , et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 2003;349:7-16
Full Text | Web of Science | Medline2
Matthews JNS ,Altman DG . Interaction 3: how to examine heterogeneity. BMJ 1996;313:862-862
CrossRef | Web of Science | Medline3
Assmann SF ,Pocock SJ ,Enos LE ,Kasten LE . Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet 2000;355:1064-1069
CrossRef | Web of Science | Medline4
Early Breast Cancer Trialists' Collaborative Group
CrossRef | Web of Science | Medline
To the Editor:
In the study by Tallman et al. (July 3 issue),1 511 patients were randomly assigned to treatment with six cycles of adjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil or the same treatment followed by high-dose chemotherapy; there was no significant difference in disease-free survival or overall survival between the two groups. Nevertheless, among the 417 patients who fulfilled strict eligibility criteria, the time to recurrence was significantly longer for those assigned to high-dose chemotherapy than for those assigned to conventional adjuvant chemotherapy alone. We think that the delay in the time to relapse represents a clinically important outcome because it is associated with longer survival off therapy and, consequently, a better quality of life. The study by Tallman et al. supports the use of high-dose chemotherapy in patients with high-risk breast cancer.
1 ReferencesAlfredo Tartarone, M.D.
Giovanni Iodice, M.D.
Nicola Di Renzo, M.D.
Centro di Riferimento Oncologico di Basilicata, 85028 Rionero in Vulture, Italy
tarta1@virgilio.it 1
Tallman MS ,Gray R ,Robert NJ , et al. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 2003;349:17-26
Full Text | Web of Science | Medline
To the Editor:
The articles by Rodenhuis et al. and Tallman et al. raise a general but important issue regarding the use of the number of positive lymph nodes for prognostic and therapeutic purposes. In neither article is the method of lymph-node evaluation reported. The detection of metastatic carcinoma varies according to the degree of diligence applied in searching for lymph nodes, the use of complete or incomplete sampling, the thickness of the tissue sections, and the number and depth of the sections examined. When uniform detection methods, such as those recommended by the College of American Pathologists1 and the Association of Directors of Anatomic and Surgical Pathology,2 are not followed, conclusions based on the number of positive lymph nodes may not lead to appropriate decisions about patient care and may not be applicable at all institutions or suitable for meta-analysis. These two studies may have used appropriate methods, and the large number of positive lymph nodes used as a cutoff may reduce the importance of the exact method of nodal evaluation. However, unless the method of evaluation is described, future researchers may not be able truly to compare or analyze these studies.
2 ReferencesMark M. Mangano, M.D.
Milford–Whitinsville Regional Hospital, Milford, MA 017571
Fitzgibbons PL ,Page DL ,Weaver D , et al. Prognostic factors in breast cancer: College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 2000;124:966-978
Web of Science | Medline2
ADASP recommendations for processing and reporting of lymph node specimens submitted for evaluation of metastatic disease. Mod Pathol 2001;14:629-632
CrossRef | Web of Science | Medline
To the Editor:
In his editorial (July 3 issue), Elfenbein1 points out that “relapse-free survival is the best end point for evaluating a treatment.” We think that in the adjuvant setting, relapse-free survival represents a measure of activity and not a measure of efficacy. Torri et al.2 have demonstrated that large improvements in response rates correspond to very small improvements in median survival. Hence, the use of disease-free survival as an end point may result in the administration of aggressive and toxic treatments without any benefit.
2 ReferencesClaudio Dazzi, M.D.
Anna Cariello, M.D.
City Hospital, 48100 Ravenna, Italy
dazzicla@libero.it 1
Elfenbein GJ . Stem-cell transplantation for high-risk breast cancer. N Engl J Med 2003;349:80-82
Full Text | Web of Science | Medline2
Torri V ,Simon R ,Russek-Cohen E ,Midthune D ,Friedman M . Statistical model to determine the relationship of response and survival in patients with advanced ovarian cancer treated with chemotherapy. J Natl Cancer Inst 1992;84:407-414
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Author/Editor Response
As we report in our article, the result of the only planned subgroup analysis suggests that high-dose therapy improves the relapse-free survival of patients with 10 or more axillary-lymph-node metastases. It is correct that there was no evidence of a difference in benefit between the nodal subgroups when tests for interaction were used, whereas such interactions with therapy were statistically significant with respect to HER2/neu receptor expression, age, and grade of cancer. Thus, both biologic and statistical considerations suggest that the number of tumor-positive axillary lymph nodes is probably not useful in selecting patients for high-dose therapy, but HER2/neu expression and, possibly, age could very well be important. Since these subgroup analyses were not planned, however, confirmation from other randomized studies is required. We attempted to make these points in our figures and in the Discussion section of our article.
We agree with Wheatley et al. that the meta-analysis of all randomized trials of high-dose chemotherapy (planned for 2005 by the Early Breast Cancer Trialists' Collaborative Group) will probably define the role of high-dose therapy in the adjuvant setting. By that time, the follow-up may approach the duration required for a first estimate of overall survival effects. All 14 available randomized studies (including ours) are underpowered to demonstrate a clinically important decrease in the hazard ratios for relapse-free survival and overall survival, but in all the trials combined, a total of at least 5574 patients have been studied. Six trials, involving a total of 2702 patients, had a symmetrical study design in which the treatment in both groups was identical apart from the use of a single course of high-dose therapy in the experimental group. In all of them, there were fewer relapses in the high-dose group than in the control group.1-5 Of these, our study is the only one in which a pathology review was performed. We hope that similar reviews will be conducted for some of the other studies as well, since such reviews could help to determine whether our explanation is correct and whether the relapse-free survival of patients with HER2/neu-negative disease is truly improved by high-dose alkylating chemotherapy.
5 ReferencesSjoerd Rodenhuis, M.D.
Harm van Tinteren, M.Sc.
Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
sroden@nki.nl Elisabeth G.E. de Vries, M.D.
University Hospital Groningen, 9700 RB Groningen, the Netherlands1
Peters W ,Rosner G ,Vredenburgh J , et al. A prospective, randomized comparison of two doses of combination alkylating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13. Prog Proc Am Soc Clin Oncol 1999;18:1a-1a abstract.2
Tallman MS ,Gray R ,Robert NJ , et al. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 2003;349:17-26
Full Text | Web of Science | Medline3
Roche HH ,Pouillart P ,Meyer N , et al. Adjuvant high dose chemotherapy (HDC) improves early outcome for high risk (N>7) breast cancer patients: the Pegase 01 trial. Prog Proc Am Soc Clin Oncol 2001;20:26a-26a abstract.4
Tokuda Y ,Tajima T ,Narabayashi M , et al. Randomized phase III study of high-dose chemotherapy (HDC) with autologous stem cell support as consolidation in high-risk postoperative breast cancer. Prog Proc Am Soc Clin Oncol 2001;20:38a-38a abstract.5
Schrama JG ,Faneyte IF ,Schornagel JH , et al. Randomized trial of high-dose chemotherapy and hematopoietic progenitor-cell support in operable breast cancer with extensive lymph node involvement: final analysis with 7 years of follow-up. Ann Oncol 2002;13:689-698
CrossRef | Web of Science | Medline
Author/Editor Response
We appreciate the point made by Dr. Tartarone and colleagues, who suggest that the delay in the time to relapse in our study, among the 417 patients fulfilling strict eligibility criteria, represents a potentially clinically important outcome. However, these data need to be interpreted cautiously. The difference in outcome in this subgroup analysis is only marginally significant. In addition, the results in this subgroup analysis do not take into account the development of myelodysplastic syndrome or acute myelogenous leukemia. It may or may not be true that a delay in the time to relapse is associated with a longer period of survival without therapy and, consequently, a better quality of life, since intuitively it takes more time for complete recovery after high-dose chemotherapy than after conventional adjuvant chemotherapy. We do not believe that the data generated in our trial support the use of high-dose chemotherapy in patients with high-risk breast cancer outside the context of a well-designed, phase 3 clinical trial in which contemporary standard chemotherapy is used as a control and transplantation is performed by contemporary techniques.
We believe that the issues raised by Dr. Mangano with regard to lymph-node sampling are important. The staging method used in this study represented standard practice in the United States. A uniform approach to complete lymph-node sampling should be part of any clinical trial of adjuvant therapy.
Martin S. Tallman, M.D.
Northwestern University Feinberg School of Medicine, Chicago, IL 60611
m-tallman@northwestern.edu Nicholas J. Robert, M.D.
Inova Fairfax Hospital, Falls Church, VA 22031Hillard M. Lazarus, M.D.
Case Western Reserve University School of Medicine, Cleveland, OH 44106Author/Editor Response
Dazzi and Cariello ask whether even a small improvement in disease-free survival justifies giving all patients “aggressive and toxic treatments.” Oncologists have debated this question since the advent of “curative” chemotherapy. However, most oncologists treat diseases, such as acute myelogenous leukemia, with appropriately aggressive therapy so that no patient in whom cure may be possible is not cured because of undertreatment. What is not debatable is that women with stage II breast cancer and 10 or more positive axillary nodes have only a 46 percent rate of disease-free survival and only a 52 percent rate of overall survival at five years after conventional treatment.1 One could say that conventional therapy is undertreatment for women who have a relapse.
The goal of high-dose chemotherapy is to identify subgroups of patients with high-risk primary breast cancer so that those who will benefit are not undertreated and those who will not benefit are not overtreated.2,3 Benefit for the former group of women can be demonstrated only when randomized trials with clearly formulated hypotheses, appropriate end points, and sufficient power to detect at least a 5 percent absolute difference between treatments are well executed. Such a degree of benefit ultimately justifies therapy that may be more toxic than conventional chemotherapy alone.
3 ReferencesGerald J. Elfenbein, M.D.
Roger Williams Medical Center, Providence, RI 02908
gelfenbein@rwmc.org 1
Cancer Information Reference File, version 6.07. Hackensack, N.J.: Impath Information Services, February 28, 2002.
2
Rodenhuis S ,Bontenbal M ,Beex LVAM , et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 2003;349:7-16
Full Text | Web of Science | Medline3
Davol PA, Bagdasaryan R, Elfenbein GJ, Maizel AL, Frackelton AR Jr. Shc proteins are strong, independent prognostic markers for both node negative and node positive breast cancer. Cancer Res (in press).
