Correspondence

Pamidronate and Metastatic Breast Cancer

N Engl J Med 1997; 336:1609-1610May 29, 1997

Article

To the Editor:

I am disturbed by the design of the trial reported by Hortobagyi et al. (Dec. 12 issue).1 The standard of care for painful lytic metastases is radiation therapy or surgery, especially for lesions involving a risk of pathologic fracture.2 These treatments are extremely effective if implemented in a timely manner. In large series, a rate of pain relief approaching 90 percent has been reported for radiation therapy,3 and surgery usually results in prompt relief as well.4 With such effective treatments readily available, it is arguably unethical to have a placebo arm in the trial; the two arms should have consisted of standard treatment and pamidronate therapy. Alternatively, the authors could have examined the role of pamidronate after radiation or surgical treatment. Instead, it appears that a large group of women were forced to endure substantial pain for up to one year — the duration of the trial — before definitive treatment was rendered; even more tragically, over a third of the women enrolled in this trial had probably permanently disabling pathologic fractures that could have easily been prevented or delayed by prompt radiation or surgical treatment. It is of dubious validity to classify “radiation to bone” or “surgery on bone” as “skeletal complications”; the point of these treatments is to prevent skeletal complications such as pathologic fractures.

Was the goal of the trial to test a new, more effective, less costly, or less morbid treatment? The acquisition cost of a single 90-mg dose of pamidronate at our pharmacy is approximately $700; a one-year course thus costs at least $8,400, not an inconsiderable amount in an era of cost containment. Contrary to the conclusions of the authors, pamidronate treatment as rendered in the trial was costly yet less effective than standard therapy (judging by the unimpressive pain relief, not significantly different from that with placebo at three and six months and of borderline significance at nine months). This study does not support pamidronate as the new standard in the prophylactic treatment of painful lytic metastases.

Gary Kao, M.D.
Hospital of the University of Pennsylvania, Philadelphia, PA 19104

4 References

1
Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 1996;335:1785-1791
Full Text | Web of Science | Medline

2
Galasko CSB. The role of the orthopaedic surgeon in the treatment of bone pain. Cancer Surv 1988;7:103-125
Medline

3
Tong D, Gillick L, Hendrickson FR. The palliation of symptomatic osseous metastases: final results of the study by the Radiation Therapy Oncology Group. Cancer 1982;50:893-899
CrossRef | Web of Science | Medline

4
Haentjens P, Casteleyn PP, Opdecam P. Evaluation of impending fractures and indications for prophylactic fixation of metastases in long bones: review of the literature. Acta Orthop Belg 1993;59:Suppl 1:6-11
Medline

To the Editor:

Hortobagyi et al. compared pamidronate and placebo in patients with breast cancer who had lytic bone metastases and were receiving simultaneous chemotherapy. The design of the study allows a bias, because chemotherapy and hormone therapy were not necessarily uniform, although the authors claim that they were similar at study entry and throughout the trial and that there were no differences between groups in the proportion of patients treated with doxorubicin-containing regimens or tamoxifen. However, they do not report the number treated with each regimen nor the criteria for changing or discontinuing these treatments. The higher radiologic bone response with pamidronate could reflect selection of patients with better likelihood of response. An imbalance in the probability of response, duration of treatment,1 or reasons to change cytotoxic therapy may partially explain the clinical gain observed in the patients treated with pamidronate and merits further clarification.

Álvaro S. Rubiales, M.D.
Carlos Centeno, M.D.
Hospital Universitario de Valladolid, 47011 Valladolid, Spain

1 References

1
Coates A, Gebski V, Bishop JF, et al. Improving the quality of life during chemotherapy for advanced breast cancer: a comparison of intermittent and continuous treatment strategies. N Engl J Med 1987;317:1490-1495
Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree with Dr. Kao that radiotherapy and surgery have important roles in the management of bone metastases, along with systemic therapy. Unfortunately, none of these treatments produce lasting benefits, and most patients require two or more of them for optimal palliation. The design of our study did allow radiotherapy, surgery, or both whenever the attending physician considered them appropriate, except for the two weeks preceding randomization. Close to 30 percent of the patients in the clinical trial (similar proportions in both treatment groups) had received radiotherapy to bone metastases even before this study. Since this was a double-blind trial, the fact that fewer patients treated with pamidronate (19 percent) than with placebo (33 percent) required radiotherapy during the first 12 months indicates the benefit derived from pamidronate. Despite this lower frequency of use of radiotherapy, patients treated with pamidronate had less pain, required fewer analgesic agents, and had slower deterioration of performance status and quality-of-life measurements than those treated with placebo. We found in previous studies that physicians' judgment in recommending radiotherapy to bone metastases was a reproducible end point that reflected the progression of bone metastases. For this reason we chose to include these events as skeletal complications. The reduction in the frequency of skeletal complications and the pain relief observed in this study were obtained with pamidronate in addition to all standard methods of treatment.

Drs. Rubiales and Centeno ask about the distribution of cytotoxic therapy in the two groups. Table 1Table 1Use of Cytotoxic Therapy, According to Study Group. shows the percentage of patients who used each cytotoxic agent during the trial. Table 1 of our article shows that the distributions of patients according to disease-free interval and according to duration of bone metastases before enrollment were similar in the two groups. This suggests that a response to therapy administered before treatment, or differences in concomitant chemotherapy, cannot account for the therapeutic benefit observed.