Correspondence to: Robin T. Vollmer, M.D., Veterans Administration Medical Center, Laboratory Medicine 113, 508 Fulton St., Durham, NC 27705-3875.
Recently, Budman et al. (1) reported that "the beneficial effect of the higher dose adjuvant chemotherapy was limited to patients with four or more involved lymph nodes," and they illustrated this effectively with plots of the hazard function for disease-free interval (DFI). Nevertheless, they also warned that because the analysis was one of subgroups, it should be interpreted cautiously.
Their hazard plots for DFI and their overall survival curves (and derived hazards for survival) suggest that the hazards as well as the therapeutic effects on the hazards are time dependent, that is, both hazards and the differential effects of treatment change with time of follow-up. By 6 years, the hazards for both DFI and overall survival appear to stabilize, and there is no evidence of any difference due to the three treatments. The coincidence of this time dependency with the time dependency of lymph node status reported previously (2,3) and their results of Fig. 2 in (1) suggest that their conclusion about the selective effect of high dose on those with more positive nodes may be accurate. Yet, they are hesitant because of "subgroup analysis." I suggest that they consider using an interaction term "high dose x proportion of positive lymph nodes" (or high dose x square root [positive lymph nodes]) in their Cox model. (It might also be prudent to make these variables time dependent.) If the dosage of treatment as an interaction term were significant but the dosage of treatment alone were not, then this result would support their conclusion that the higher total dose was effective only in those with a greater number of positive lymph nodes and it would do so without a subgroup analysis. Reaching such a conclusion could be important to developing therapeutic strategies that maximize drug effect on tumor while minimizing toxicity.
REFERENCES
1
Budman DR, Berry DA, Cirrincione CT, Henderson IC, Wood
WC, Weiss RB, et al. Dose and dose intensity as determinants of outcome in the adjuvant
treatment of breast cancer. The Cancer and Leukemia Group B. J Natl Cancer Inst 1998;90:1205-11.
2 Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group. Lancet 1992;339:71-85.[Medline]
3 Vollmer RT. Multivariate statistical analysis for anatomic pathology. Part II: failure time analysis. Am J Clin Pathol 1996;102:522-34.
Affiliations of authors: D. A. Berry, Institute of Statistics and Decision Sciences, Duke University Medical Center, Durham, NC; D. R. Budman, Don Monti Division of Oncology, Department of Medicine, North Shore University HospitalNew York University School of Medicine, Manhasset.
Correspondence to: Donald A. Berry, Ph.D., Institute of Statistics and Decision Sciences, Duke University Medical Center, 223 Old Chemistry Bldg., ISDS, Box 90251, Durham, NC 27708-0251.
Dr. Vollmer raises two interesting and important issues. The first relates to subgroup analysis. Subgroup analyses are compelling, but they are dangerous (1). The only way to discover whether a treatment effect depends on patient characteristics is to examine the effect within the various types of patients. One must both pay heed to the underlying biology and also wear glasses that filter out chance differences. It behooves authors to acknowledge potential subgroup differences, for otherwise, they could not be adequately addressed by later investigators. Some subgroup differences are real, but most turn out to be spurious.
In the study by Budman et al. (2), the benefit of increasing dose is carried solely by the patients with the most positive lymph nodes. Whether this observation is real in the sense that it can be extrapolated beyond this study is open to question. Incorporating an interaction term in a multivariate model as suggested by Dr. Vollmer is problematic because it is essentially a subgroup analysis. In addition, multivariate modeling is not good at separating out associated effects, such as main effects and their interactions. To answer Dr. Vollmer, an interaction term is statistically significant only if the cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) dose main effect term is not also included in the model. If both the main effect for dose and the interaction between dose and number of involved lymph nodes are included, then neither is significant. The main effect for number of positive lymph nodes is highly significant in every model.
Breast cancer is a heterogeneous disease. A particular treatment may be better for one type of patient characteristics while another treatment is better for another type. (Estrogen receptor status and tumor erbB-2 overexpression are the prime examples.) However, extent of lymph node involvement measures degree of disease progression and is unlikely to discriminate between different types of disease. There is no known biologic reason to think that number of positive lymph nodes will identify patients who respond better to a particular chemotherapy.
Cancers that have spread to a greater number of lymph nodes are more likely to progress. One might argue that a subgroup of such patients will experience more events and that therefore they will carry more power for detecting any treatment effect. While this is true, in the study by Budman et al., more patients had one to three involved lymph nodes and the numbers of events in the one to three and four or more nodal groups were approximately the same.
Cancer and Leukemia Group B (CALGB) studies of patients with lymph node-positive breast cancer that preceded CALGB 8541 (2) also contain evidence favoring a differential treatment effect based on number of involved lymph nodes. Both CALGB 7581 (3) and CALGB 8082 (4) showed a moderate treatment effect (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone [CMFVP] over cyclophosphamide, methotrexate, and 5-fluorouracil [CMF] in CALGB 7581 and vinblastine, doxorubicin, thiotepa, and halotestin [VATH] over CMFVP in CALGB 8082). Just as in CALGB 8541, in both studies, the treatment benefit was carried solely by those patients with at least four involved lymph nodes. Therefore, Dr. Vollmer's assessment may be correct.
However, despite the evidence favoring an interaction between treatment and number of involved lymph nodes, we do not believe this interaction is real, especially in the study of Budman et al. A principal reason is the rather more compelling interaction between dose of CAF and erbB-2 overexpression (5). Our unpublished data show therapeutic interactions with erbB-2 overexpression both in patients having poor prognosespredominantly four or more involved lymph nodesand in patients having good prognosespredominantly one to three involved lymph nodes. For example, among erbB-2 overexpressors, 8-year disease-free survival estimates for patients with poor prognoses are 15% (low-dose CAF: four cycles at 300, 30, and 300 mg/m2) and 55% (intensive-dose CAF: four cycles at 600, 60, and 600 mg/m2), while in patients with good prognoses, these estimates are 54% (low dose) and 80% (intensive dose). Both dose comparisons are highly statistically significant.
The second point addressed by Dr. Vollmer is that among survivors the chances of disease recurrence tend to equalize over time. After about 5 years following treatment, all survivors have a similar risk of recurrence. In particular, any benefit of higher dose of CAF has apparently dissipated by then. Moreover, the number of lymph nodes involved at surgery is no longer relevant for someone who has survived disease free for 5 or more years. Intuitively, aggressive cancers recur early and less aggressive cancers reveal themselves as being less aggressive by not recurring. Therefore, survivors make up a relatively homogeneous good-prognosis group. A related interesting question is whether dose of CAF affects long-term survival. Because the sample sizes dwindle with longer follow-up, there is insufficient information in this study to answer this question.
REFERENCES
1 Berry DA. Subgroup analyses [letter]. Biometrics 1990;46:1227-30.[Medline]
2
Budman DR, Berry DA, Cirrincione CT, Henderson IC, Wood
WC, Weiss RB, et al. Dose and dose intensity as determinants of outcome in the adjuvant
treatment of breast cancer. J Natl Cancer Inst 1998;90:1205-11.
3 Tormey DC, Weinberg VE, Holland JF, Weiss RB, Glidewell OJ, Perloff M, et al. A randomized trial of five and three drug chemotherapy and chemoimmunotherapy in women with operable node positive breast cancer. J Clin Oncol 1983;1:138-45.[Abstract]
4 Perloff M, Norton L, Korzun AH, Wood WC, Carey RW, Gottlieb A, et al. Postsurgical adjuvant chemotherapy of stage II breast carcinoma with or without crossover to a non-cross-resistant regimen: a Cancer and Leukemia Group B study. J Clin Oncol 1996;14:1589-98.[Abstract]
5
Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson
IC, et al. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 1998;90:1346-60.
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