Correspondence

Clodronate in Metastatic Breast Cancer

N Engl J Med 1998; 339:1940-1941December 24, 1998

Article

To the Editor:

In their interesting study, Diel et al. (Aug. 6 issue)1 demonstrate the efficacy of clodronate therapy when it is used in addition to standard systemic therapy in high-risk patients with early-stage breast cancer. However, it is unclear whether all patients will benefit from this therapy. Although the authors state that in their study, “all the women . . . had a high risk of distant metastases, as indicated by the presence of tumor cells in the bone marrow” and the presence of tumor cells in the bone marrow was associated with “unfavorable prognostic factors,” only a minority of the women in the two treatment groups had aggressive tumors. Even if prognostic factors in the two groups were well balanced, only about one quarter of all patients had estrogen-receptor–negative tumors (69 of 302) or poorly differentiated (grade III) tumors (78 of 302), as shown in Table 1 of the article. This raises the question whether the benefit found by the statistical analysis of the whole group is due entirely to a protective effect in the subgroup of patients with hormone-dependent, well-differentiated tumors. In other words, clodronate may have no beneficial effect on aggressive types of breast cancer. The results of subgroup analysis, even if methodologically questionable, may be interesting in this context.

The authors do not clearly define the term “visceral metastases.” Is the protective effect of clodronate to be expected to extend to soft tissue as well as to true visceral metastases such as liver or lung lesions? The possibility that the therapeutic benefit of clodronate is limited to a metastatic site in soft tissues and bone disease, associated with slowly growing tumors, again suggests that such treatment should be reserved for patients with advanced, but otherwise prognostically favorable, early breast cancers.

Maria Meli, M.D.
Luciano Rausa, M.D.
University of Palermo, 90127 Palermo, Italy

1 References

1. 1

   Diel IJ, Solomayer E-F, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357-363
   Full Text | Web of Science | Medline

To the Editor:

Diel et al. report that “clodronate can reduce the incidence and number of new bony and visceral metastases in women with breast cancer who are at high risk for distant metastases.” This interesting study could have major implications for the treatment of breast cancer. However, the study appears to have many methodologic problems. First of all, the classification of disease in patients was essentially according to nodal involvement — either present or absent. The prognosis of patients with breast cancer depends on the number of nodes involved: 1 to 3 nodes, 4 to 10, or more than 10. This information was not given, and thus it is difficult to know whether the groups were balanced with respect to this prognostic factor. The use of immunocytochemical detection of at least one tumor cell in a bone marrow aspirate as a criterion for inclusion is certainly not routine, and thus it is difficult to extrapolate these results to the usual population of women who receive adjuvant therapy for breast cancer.

In addition, the patients received various adjuvant treatments, including tamoxifen alone for two years; cyclophosphamide, methotrexate, and fluorouracil for six cycles; six cycles of epirubicin and cyclophosphamide with or without fluorouracil; goserelin alone for two years; and a combination of tamoxifen and cyclophosphamide, methotrexate, and fluorouracil. Although it appears from the data in Table 2 of the article that these factors were well balanced, it is difficult to judge from the small number of patients in the groups whether these various treatments would affect the final results. Furthermore, there is no information concerning the intensity of the dose of chemotherapy. The fact that there were more visceral metastases in the control group than in the clodronate group may simply mean that the groups were not balanced with respect to the various factors discussed above.

Lawrence C. Panasci, M.D.
Victor Sandor, M.D.
David Melnychuk, M.D.
Sir Mortimer B. Davis Jewish General Hospital, Montreal, QC H3T 1E2, Canada

To the Editor:

Diel et al. present provocative results of a randomized trial of clodronate as adjuvant therapy for the prevention of new metastases in patients with primary breast cancer. However, their analysis is marred by their failure to conform to the principles of intention-to-treat analysis. Although the numbers of patients with inadequate follow-up were similar in the treatment and control groups (3 and 2, respectively), there were 13 exclusions in the clodronate group and none in the control group. None of the exclusions were appropriate, since they all involved the adequacy of treatment. The exclusion of these 13 patients, who made up almost 10 percent of the treatment group, could easily have introduced bias into the analysis.1 To eliminate any question of confounding, the authors should reanalyze their results after including all patients with follow-up data.

Carl D. Atkins, M.D.
242 Merrick Rd., Rockville Centre, NY 11570

1 References

1. 1

   Weiss NS. Clinical trials. Selection of subjects. In: Rothman KJ, Greenland S, eds. Modern epidemiology. 2nd ed. Philadelphia: Lippincott–Raven, 1998:525.
   

Author/Editor Response

The authors reply:

To the Editor: Meli and Rausa refer to the fact that most of the tumors in our patients had steroid hormone receptors and were given a histologic grade of I or II, factors usually associated with a good prognosis. However, most of the patients (52.6 percent) had metastases in axillary lymph nodes and tumor cells in the bone marrow. In most multivariate analyses these factors have been associated with a very poor prognosis independently of other variables such as estrogen-receptor status and histologic grade.1 For these reasons we believe that our patients were at high risk for relapse and metastases. Despite the shortness of follow-up in our study, the finding that 63 patients (21 percent) had distant metastases is confirmation of the poor prognosis of these women. A positive interaction between bisphosphonates and tamoxifen can only be surmised, since studies of combinations of bisphosphonates with tamoxifen for metastatic breast cancer have revealed that they have minor effects on bone complications, in contrast to the combination of cytotoxic therapy and bisphosphonates.2,3

Visceral metastases included tumors that spread to the lung, liver, central nervous system, adrenal glands, and ovaries but not soft tissues. The number of axillary lymph nodes with metastases did not differ in the two groups that we studied, and the intensity of the dose of chemotherapy was similar in the two groups (data not shown). The differences among chemotherapy regimens given as adjuvant systemic treatment have been shown to be marginal at best, if standard doses of chemotherapy are administered. Our patients received standard doses of cyclophosphamide, methotrexate, and fluorouracil; epirubicin and cyclophosphamide; and fluorouracil, epirubicin, and cyclophosphamide according to the recommendations of the German Adjuvant Breast Cancer Study Group, which rely on the guidelines of the St. Gallen consensus conferences (1989–1995). The possibility of a reduced dose intensity as a major factor influencing outcome can be excluded. We agree with Panasci and colleagues that larger controlled studies are needed to identify the subgroups of patients for whom adjuvant clodronate therapy would offer the greatest benefit.

With regard to Atkins's comments: as we mentioned in our article, “all 302 patients were included in the intention-to-treat analysis.” Follow-up data were available for all but five patients (three in the clodronate group and two in the control group).

Ingo J. Diel, M.D.
University of Heidelberg, 69115 Heidelberg, Germany

Serban D. Costa, M.D.
Manfred Kaufmann, M.D.
University of Frankfurt, 60596 Frankfurt, Germany

3 References

1. 1

   Diel IJ, Kaufmann M, Costa SD, et al. Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. J Natl Cancer Inst 1996;88:1652-1658
   CrossRef | Web of Science | Medline

2. 2

   Theriault R, Lipton A, Leff R, et al. Reduction of skeletal related complications in breast cancer patients with osteolytic bone metastases receiving hormone therapy, by monthly pamidronate sodium infusion. Prog Proc Am Soc Clin Oncol 1996;15:9-9 abstract.
   

3. 3

   Hortobagyi GN, Theriault RL, Lipton A, et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 1998;16:2038-2044
   Web of Science | Medline